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9a3afb35238c68161b98fd0182132e2fe6e92771 | wikidoc | RAB11A | RAB11A
Ras-related protein Rab-11A is a protein that in humans is encoded by the RAB11A gene.
# Function
The protein encoded by this gene belongs to the small GTPase superfamily, Rab family. It is associated with both constitutive and regulated secretory pathways, and may be involved in protein transport.
Rab-11a controls intracellular trafficking of the innate immune receptor TLR4, and thereby also receptor signalling
# Interactions
RAB11A has been shown to interact with:
- RAB11FIP1,
- RAB11FIP2,
- RAB11FIP3,
- RAB11FIP4, and
- RAB11FIP5 | RAB11A
Ras-related protein Rab-11A is a protein that in humans is encoded by the RAB11A gene.[1][2]
# Function
The protein encoded by this gene belongs to the small GTPase superfamily, Rab family. It is associated with both constitutive and regulated secretory pathways, and may be involved in protein transport.[3]
Rab-11a controls intracellular trafficking of the innate immune receptor TLR4, and thereby also receptor signalling[4]
# Interactions
RAB11A has been shown to interact with:
- RAB11FIP1,[5][6][7]
- RAB11FIP2,[8][5][9]
- RAB11FIP3,[5]
- RAB11FIP4,[10] and
- RAB11FIP5[5][9][11] | https://www.wikidoc.org/index.php/RAB11A | |
066002ceef5910fe2d52464be04cff887452ce9c | wikidoc | RAB11B | RAB11B
Ras-related protein Rab-11B is a protein that in humans is encoded by the RAB11B gene. Rab11b is reported as most abundantly expressed in brain, heart and testes.
Rab (Ras-related in brain) proteins form the largest section of the Ras superfamily of small GTPases. The Rab family proteins regulate intracellular membrane trafficking processes including vesicle budding, tethering, and fusion. The isoforms Rab11a, Rab11b, and Rab11c/Rab25 constitute the Rab11 subfamily based on specific sequence motifs. While RAB11A is located on chromosome 15 and RAB11C on chromosome 1, RAB11B is placed on chromosome 19. Rab11 proteins are implicated in endocytosis and exocytosis. Rab11b is reported as most abundantly expressed in brain, heart and testes. Early studies with deletions of RAB11 homologs in Saccharomyces cerevisiae proved their importance in cell survival.
Despite sharing high sequence homology, Rab11a and Rab11b appear to reside within distinct vesicle compartments. Majority of Rab11b neither colocalize with transferrin receptor nor with the polymeric IgA receptor. This protein also exhibits a dependence on the microtubule cytoskeleton that is different from Rab11a. High sequence diversity in the C-terminal hypervariable region is responsible for variable membrane targeting between these proteins.
# Function
Members of the Rab11 subfamily act in recycling of proteins from the endosomes to the plasma membrane, in transport of molecules from the trans-Golgi network to the plasma membrane and in phagocytosis. This subfamily also acts in polarized transport in epithelial cells. Whereas most studies refer to the Rab11a isoform, little is known about Rab11b so far. Rab11b localizes predominantly in the pericentriolar recycling compartment and serves as an important component of the vesicular machinery. It is required for the transfer of internalized transferrin from the recycling compartment to the plasma membrane for which active Rab11b as well as GTP hydrolysis is necessary.
# Structure
All Ras GTPases consist of a similar core structure and highly conserved P-loop, switch 1 and switch 2 regions. The Rab11b monomer exhibits a typical Ras-like, small GTPase fold with a six stranded β-sheet core (β1-β6) surrounded by five major α-helices (α1-α5) and one minor α-helix (α6). According to the sequence similarity to other Rab GTPases can be assumed that they show closely resembling characteristics in nucleotide binding and hydrolysis. However, Rab11 isoforms could differ in hydrolysis kinetics owing to the differences in conformation, since Rab11a and Rab11b do not show an α-helical switch 2 region like other Rab GTPases. Rab11b shares 90% amino acid identity to Rab11a. Kinetic experiments with Rab11a/b and Rab11-interacting proteins (FIPs) indicate that FIPs cannot differentiate between GTP-bound Rab11a and Rab11b in vitro. The major divergence reveals in the inactive state. While Pasqualato et al. crystallized inactive Rab11a as a dimer in the asymmetric unit, Scapin et al. observed single crystallographically independent monomers of both the GDP- and the GppNHp-bound Rab11b structures.
# Clinical significance
Due to their crucial importance in vesicle transport and recycling, Rab11 proteins are linked to various non-pathogen or pathogen induced diseases. Most of the published data do not specify whether it is the a- or the b-isoform. Rab11 proteins have been implicated in Alzheimer’s disease, Arthrogryposis-renal dysfunction-cholestasis (ARC), Batten disease, and Charcot-Marie-Tooth Neuropathy Type 4C (CMT4C).
Intracellular bacteria Chlamydia pneumoniae and Chlamydia trachomatis that replicate in membrane bound compartments hijack the trafficking machinery recruiting Rab GTPases to promote their replication within the host cell. Knock down of Rab11 decreased the formation of infectious particles.
Recent studies report a similar use of intracellular trafficking by Hantavirus and Influenza A virus. Replicated viruses benefit from Rab11 mediated recycling endosome pathway to exit the cell and infect surrounding tissue. | RAB11B
Ras-related protein Rab-11B is a protein that in humans is encoded by the RAB11B gene.[1][2] Rab11b is reported as most abundantly expressed in brain, heart and testes.
Rab (Ras-related in brain) proteins form the largest section of the Ras superfamily of small GTPases. The Rab family proteins regulate intracellular membrane trafficking processes including vesicle budding, tethering, and fusion. The isoforms Rab11a, Rab11b, and Rab11c/Rab25 constitute the Rab11 subfamily based on specific sequence motifs.[3] While RAB11A is located on chromosome 15[4] and RAB11C on chromosome 1, RAB11B is placed on chromosome 19. Rab11 proteins are implicated in endocytosis and exocytosis.[5] Rab11b is reported as most abundantly expressed in brain, heart and testes.[6] Early studies with deletions of RAB11 homologs in Saccharomyces cerevisiae proved their importance in cell survival.[7][8]
Despite sharing high sequence homology, Rab11a and Rab11b appear to reside within distinct vesicle compartments.[9] Majority of Rab11b neither colocalize with transferrin receptor nor with the polymeric IgA receptor. This protein also exhibits a dependence on the microtubule cytoskeleton that is different from Rab11a.[9] High sequence diversity in the C-terminal hypervariable region is responsible for variable membrane targeting between these proteins.
# Function
Members of the Rab11 subfamily act in recycling of proteins from the endosomes to the plasma membrane, in transport of molecules from the trans-Golgi network to the plasma membrane and in phagocytosis. This subfamily also acts in polarized transport in epithelial cells.[10][11][12][13][14] Whereas most studies refer to the Rab11a isoform, little is known about Rab11b so far. Rab11b localizes predominantly in the pericentriolar recycling compartment and serves as an important component of the vesicular machinery.[15] It is required for the transfer of internalized transferrin from the recycling compartment to the plasma membrane for which active Rab11b as well as GTP hydrolysis is necessary.[15]
# Structure
All Ras GTPases consist of a similar core structure and highly conserved P-loop, switch 1 and switch 2 regions. The Rab11b monomer exhibits a typical Ras-like, small GTPase fold with a six stranded β-sheet core (β1-β6) surrounded by five major α-helices (α1-α5)[12] and one minor α-helix (α6). According to the sequence similarity to other Rab GTPases can be assumed that they show closely resembling characteristics in nucleotide binding and hydrolysis. However, Rab11 isoforms could differ in hydrolysis kinetics owing to the differences in conformation, since Rab11a and Rab11b do not show an α-helical switch 2 region like other Rab GTPases. Rab11b shares 90% amino acid identity to Rab11a.[12] Kinetic experiments with Rab11a/b and Rab11-interacting proteins (FIPs) indicate that FIPs cannot differentiate between GTP-bound Rab11a and Rab11b in vitro.[16] The major divergence reveals in the inactive state. While Pasqualato et al. crystallized inactive Rab11a as a dimer in the asymmetric unit, Scapin et al. observed single crystallographically independent monomers of both the GDP- and the GppNHp-bound Rab11b structures.[12][17]
# Clinical significance
Due to their crucial importance in vesicle transport and recycling, Rab11 proteins are linked to various non-pathogen or pathogen induced diseases. Most of the published data do not specify whether it is the a- or the b-isoform. Rab11 proteins have been implicated in Alzheimer’s disease,[18][19] Arthrogryposis-renal dysfunction-cholestasis (ARC),[20] Batten disease,[21] and Charcot-Marie-Tooth Neuropathy Type 4C (CMT4C).[22]
Intracellular bacteria Chlamydia pneumoniae and Chlamydia trachomatis that replicate in membrane bound compartments hijack the trafficking machinery recruiting Rab GTPases to promote their replication within the host cell. Knock down of Rab11 decreased the formation of infectious particles.[23][24][25]
Recent studies report a similar use of intracellular trafficking by Hantavirus and Influenza A virus. Replicated viruses benefit from Rab11 mediated recycling endosome pathway to exit the cell and infect surrounding tissue.[26][27][28][29] | https://www.wikidoc.org/index.php/RAB11B | |
b13296770b67acf264a9f4d69ca4b8d7c09672a8 | wikidoc | RABEPK | RABEPK
Rab9 effector protein with Kelch motifs also known as p40 is a protein that in humans is encoded by the RABEPK gene.
Membrane-associated p40, in together with RAB9A, facilitates the transport of the mannose 6-phosphate receptor (MPR) from endosomes to the trans-Golgi network.
# Interactions
RABEPK has been shown to interact with RAB9A and FYVE finger-containing phosphoinositide kinase. | RABEPK
Rab9 effector protein with Kelch motifs also known as p40 is a protein that in humans is encoded by the RABEPK gene.[1][2]
Membrane-associated p40, in together with RAB9A, facilitates the transport of the mannose 6-phosphate receptor (MPR) from endosomes to the trans-Golgi network.[1]
# Interactions
RABEPK has been shown to interact with RAB9A[1] and FYVE finger-containing phosphoinositide kinase.[3] | https://www.wikidoc.org/index.php/RABEPK | |
ce0ad06731e03b72ff7a988572d98713bacfe810 | wikidoc | RAD23B | RAD23B
UV excision repair protein RAD23 homolog B is a protein that in humans is encoded by the RAD23B gene.
# Function
The protein encoded by this gene is one of two human homologs of Saccharomyces cerevisiae Rad23, a protein involved in nucleotide excision repair (NER). This protein was found to be a component of the protein complex that specifically complements the NER defect of xeroderma pigmentosum group C (XP-c) cell extracts in vitro. This protein was also shown to interact with, and elevate the nucleotide excision activity of 3-methyladenine-DNA glycosylase (MPG), which suggested a role in DNA damage recognition in base excision repair. This protein contains an N-terminal ubiquitin-like domain, which was reported to interact with 26S proteasome, and thus this protein may be involved in the ubiquitin mediated proteolytic pathway in cells.
# Role in DNA repair
The complex of XPC-RAD23B is the initial damage recognition factor in global genomic nucleotide excision repair (GG-NER). XPC-RAD23B recognizes a wide variety of lesions that thermodynamically destabilize DNA duplexes, including UV-induced photoproducts (cyclopyrimidine dimers and 6-4 photoproducts ), adducts formed by environmental mutagens such as benzopyrene or various aromatic amines, certain oxidative endogenous lesions such as cyclopurines and adducts formed by cancer chemotherapeutic drugs such as cisplatin. The presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo. Although most studies have been performed with XPC-RAD23B, it is part of a trimeric complex with centrin-2, a calcium-binding protein of the calmodulin family.
# Epigenetic repression
The protein expression level of RAD23B can be epigenetically repressed, either by promoter methylation of the RAD23B gene or by either of two microRNAs (miR-744-3p or miR-373).
# Deficiency of RAD23B in cancer
A deficiency in expression of a DNA repair gene increases the risk for cancer (see Deficient DNA repair in carcinogenesis). The expression of RAD23B is reduced in tumor tissue of women with breast cancer. A low percentage of RAD23B positive nuclei in high grade breast cancer was also observed.
RAD23B was substantially reduced by promoter methylation in a cell line derived from multiple myeloma. and reduced by promoter methylation in a small proportion of non-small cell lung cancer (NSCLC) tumours.
RAD23B appears to be one of 26 DNA repair genes that are epigenetically repressed in various cancers (see Cancer epigenetics).
# Interactions
RAD23B has been shown to interact with PSMD4 and Ataxin 3. | RAD23B
UV excision repair protein RAD23 homolog B is a protein that in humans is encoded by the RAD23B gene.[1][2]
# Function
The protein encoded by this gene is one of two human homologs of Saccharomyces cerevisiae Rad23, a protein involved in nucleotide excision repair (NER). This protein was found to be a component of the protein complex that specifically complements the NER defect of xeroderma pigmentosum group C (XP-c) cell extracts in vitro. This protein was also shown to interact with, and elevate the nucleotide excision activity of 3-methyladenine-DNA glycosylase (MPG), which suggested a role in DNA damage recognition in base excision repair. This protein contains an N-terminal ubiquitin-like domain, which was reported to interact with 26S proteasome, and thus this protein may be involved in the ubiquitin mediated proteolytic pathway in cells.[3]
# Role in DNA repair
The complex of XPC-RAD23B is the initial damage recognition factor in global genomic nucleotide excision repair (GG-NER). XPC-RAD23B recognizes a wide variety of lesions that thermodynamically destabilize DNA duplexes, including UV-induced photoproducts (cyclopyrimidine dimers and 6-4 photoproducts ), adducts formed by environmental mutagens such as benzo[a]pyrene or various aromatic amines, certain oxidative endogenous lesions such as cyclopurines and adducts formed by cancer chemotherapeutic drugs such as cisplatin. The presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo.[4] Although most studies have been performed with XPC-RAD23B, it is part of a trimeric complex with centrin-2, a calcium-binding protein of the calmodulin family.[4]
# Epigenetic repression
The protein expression level of RAD23B can be epigenetically repressed, either by promoter methylation of the RAD23B gene[5][6] or by either of two microRNAs (miR-744-3p[7] or miR-373[8]).
# Deficiency of RAD23B in cancer
A deficiency in expression of a DNA repair gene increases the risk for cancer (see Deficient DNA repair in carcinogenesis). The expression of RAD23B is reduced in tumor tissue of women with breast cancer.[9] A low percentage of RAD23B positive nuclei in high grade breast cancer was also observed.[10]
RAD23B was substantially reduced by promoter methylation in a cell line derived from multiple myeloma.[5] and reduced by promoter methylation in a small proportion of non-small cell lung cancer (NSCLC) tumours.[6]
RAD23B appears to be one of 26 DNA repair genes that are epigenetically repressed in various cancers (see Cancer epigenetics).
# Interactions
RAD23B has been shown to interact with PSMD4[11] and Ataxin 3.[12] | https://www.wikidoc.org/index.php/RAD23B | |
d9f2332722a338d3c958cc3c254ba769a698f21d | wikidoc | RAD51C | RAD51C
RAD51 homolog C (S. cerevisiae), also known as RAD51C, is a protein which in humans is encoded by the RAD51C gene.
# Function
The RAD51C protein is one of five paralogs of RAD51, including RAD51B (RAD51L1), RAD51C (RAD51L2), RAD51D (RAD51L3), XRCC2 and XRCC3. They each share about 25% amino acid sequence identity with RAD51 and each other.
The RAD51 paralogs are all required for efficient DNA double-strand break repair by homologous recombination and depletion of any paralog results in significant decreases in homologous recombination frequency.
RAD51C forms two distinct complexes with other related paralogs: BCDX2 (RAD51B-RAD51C-RAD51D-XRCC2) and CX3 (RAD51C-XRCC3). These two complexes act at two different stages of homologous recombinational DNA repair. The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites. The BCDX2 complex appears to act by facilitating the assembly or stability of the RAD51 nucleoprotein filament.
The CX3 complex acts downstream of RAD51 recruitment to damage sites. The CX3 complex was shown to associate with Holliday junction resolvase activity, probably in a role of stabilizing gene conversion tracts.
The RAD51C gene is one of genes four localized to a region of chromosome 17q23 where amplification occurs frequently in breast tumors. Overexpression of the four genes during amplification has been observed and suggests a possible role in tumor progression. Alternative splicing has been observed for this gene and two variants encoding different isoforms have been identified.
# Clinical significance
A characteristic of many cancer cells is that parts of some genes contained within these cells have been recombined with other genes. One such gene fusion that has been identified in a MCF-7 breast cancer cell line is a chimera between the RAD51C and ATXN7 genes. Since the RAD51C protein is involved in repairing double strand chromosome breaks, this chromosomal rearrangement could be responsible for the other rearrangements.
# Mutation, splicing, and epigenetic deficiency in cancer
RAD51C mutation increases the risk for breast and ovarian cancer, and was first established as a human cancer susceptibility gene in 2010. Carriers of an RAD51C mutation had a 5.2-fold increased risk of ovarian cancer, indicating that RAD51C is a moderate ovarian cancer susceptibility gene. A pathogenic mutation of RAD51C was present in approximately 1% to 3% of unselected ovarian cancers, and among mutation carriers, the lifetime risk of ovarian cancer was approximately 10-15%.
In addition, there are three other causes of RAD51C deficiency that also appear to increase cancer risk. These are alternative splicing, promoter methylation and repression by over-expression of EZH2.
Three alternatively spliced RAD51C transcripts were identified in colorectal cancers. Variant 1 is joined from the 3' end of exon-6 to the 5' end of exon-8, variant 2 is joined at the 3' end of exon-5 to the 5' end of exon-8, and variant 3 is joined from the 3' end of exon-6 to the 5' end of exon-9. Presence and mRNA expression of variant 1 RAD51C was found in 47% of colorectal cancers. Variant 1 mRNA was expressed about 5-fold more frequently in colorectal tumors than in non-tumor tissues, and when present, was expressed 8-fold more frequently than wild-type RAD51C mRNA. The authors concluded that variant 1 mRNA was associated with the malignant phenotype of colorectal cancers
In the case of gastric cancer, reduced expression of RAD51C was found in about 40% to 50% of tumors, and almost all tumors with reduced RAD51C expression had methylation of the RAD51C promoter. On the other hand, methylation of the RAD51C promoter was only found in about 1.5% of ovarian cancer cases.
EZH2 protein is up-regulated in numerous cancers. EZH2 mRNA is up-regulated, on average, 7.5-fold in breast cancer, and between 40% to 75% of breast cancers have over-expressed EZH2 protein. EZH2 is the catalytic subunit of Polycomb Repressor Complex 2 (PRC2) which catalyzes methylation of histone H3 at lysine 27 (H3K27me) and mediates epigenetic gene silencing of target genes via local chromatin reorganization. EZH2 targets RAD51C, reducing RAD51C mRNA and protein expression (and also represses other RAD51 paralogs RAD51B, RAD51D, XRCC2 and XRCC3). Increased expression of EZH2, leading to repression of RAD51 paralogs and consequent reduced homologous recombinational repair, was proposed as a cause of breast cancer.
# Interactions
RAD51C has been shown to interact with:
- RAD51L1,
- RAD51L3, and
- XRCC2, and
- XRCC3. | RAD51C
RAD51 homolog C (S. cerevisiae), also known as RAD51C, is a protein which in humans is encoded by the RAD51C gene.[1][2]
# Function
The RAD51C protein is one of five paralogs of RAD51, including RAD51B (RAD51L1), RAD51C (RAD51L2), RAD51D (RAD51L3), XRCC2 and XRCC3. They each share about 25% amino acid sequence identity with RAD51 and each other.[3]
The RAD51 paralogs are all required for efficient DNA double-strand break repair by homologous recombination and depletion of any paralog results in significant decreases in homologous recombination frequency.[4]
RAD51C forms two distinct complexes with other related paralogs: BCDX2 (RAD51B-RAD51C-RAD51D-XRCC2) and CX3 (RAD51C-XRCC3). These two complexes act at two different stages of homologous recombinational DNA repair. The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites.[4] The BCDX2 complex appears to act by facilitating the assembly or stability of the RAD51 nucleoprotein filament.
The CX3 complex acts downstream of RAD51 recruitment to damage sites.[4] The CX3 complex was shown to associate with Holliday junction resolvase activity, probably in a role of stabilizing gene conversion tracts.[4]
The RAD51C gene is one of genes four localized to a region of chromosome 17q23 where amplification occurs frequently in breast tumors.[5] Overexpression of the four genes during amplification has been observed and suggests a possible role in tumor progression. Alternative splicing has been observed for this gene and two variants encoding different isoforms have been identified.[1]
# Clinical significance
A characteristic of many cancer cells is that parts of some genes contained within these cells have been recombined with other genes. One such gene fusion that has been identified in a MCF-7 breast cancer cell line is a chimera between the RAD51C and ATXN7 genes.[6][7] Since the RAD51C protein is involved in repairing double strand chromosome breaks, this chromosomal rearrangement could be responsible for the other rearrangements.[7]
# Mutation, splicing, and epigenetic deficiency in cancer
RAD51C mutation increases the risk for breast and ovarian cancer, and was first established as a human cancer susceptibility gene in 2010.[8][9][10] Carriers of an RAD51C mutation had a 5.2-fold increased risk of ovarian cancer, indicating that RAD51C is a moderate ovarian cancer susceptibility gene.[11] A pathogenic mutation of RAD51C was present in approximately 1% to 3% of unselected ovarian cancers, and among mutation carriers, the lifetime risk of ovarian cancer was approximately 10-15%.[12][13][14][15]
In addition, there are three other causes of RAD51C deficiency that also appear to increase cancer risk. These are alternative splicing, promoter methylation and repression by over-expression of EZH2.
Three alternatively spliced RAD51C transcripts were identified in colorectal cancers. Variant 1 is joined from the 3' end of exon-6 to the 5' end of exon-8, variant 2 is joined at the 3' end of exon-5 to the 5' end of exon-8, and variant 3 is joined from the 3' end of exon-6 to the 5' end of exon-9.[16] Presence and mRNA expression of variant 1 RAD51C was found in 47% of colorectal cancers. Variant 1 mRNA was expressed about 5-fold more frequently in colorectal tumors than in non-tumor tissues, and when present, was expressed 8-fold more frequently than wild-type RAD51C mRNA. The authors concluded that variant 1 mRNA was associated with the malignant phenotype of colorectal cancers[16]
In the case of gastric cancer, reduced expression of RAD51C was found in about 40% to 50% of tumors, and almost all tumors with reduced RAD51C expression had methylation of the RAD51C promoter.[17] On the other hand, methylation of the RAD51C promoter was only found in about 1.5% of ovarian cancer cases.[13]
EZH2 protein is up-regulated in numerous cancers.[18][19] EZH2 mRNA is up-regulated, on average, 7.5-fold in breast cancer, and between 40% to 75% of breast cancers have over-expressed EZH2 protein.[20] EZH2 is the catalytic subunit of Polycomb Repressor Complex 2 (PRC2) which catalyzes methylation of histone H3 at lysine 27 (H3K27me) and mediates epigenetic gene silencing of target genes via local chromatin reorganization.[19] EZH2 targets RAD51C, reducing RAD51C mRNA and protein expression (and also represses other RAD51 paralogs RAD51B, RAD51D, XRCC2 and XRCC3).[21] Increased expression of EZH2, leading to repression of RAD51 paralogs and consequent reduced homologous recombinational repair, was proposed as a cause of breast cancer.[22]
# Interactions
RAD51C has been shown to interact with:
- RAD51L1,[23][24][25]
- RAD51L3,[24][26] and
- XRCC2,[24][26] and
- XRCC3.[23][24][26][27] | https://www.wikidoc.org/index.php/RAD51C | |
51fa0eb5c2de8476b608f626bbcc9ca71a4b3288 | wikidoc | RAD54B | RAD54B
DNA repair and recombination protein RAD54B is a protein that in humans is encoded by the RAD54B gene.
The protein encoded by this gene belongs to the DEAD-like helicase superfamily. It shares similarity with Saccharomyces cerevisiae RAD54 and RDH54, both of which are involved in homologous recombination and repair of DNA. This protein binds to double-stranded DNA, and displays ATPase activity in the presence of DNA. This gene is highly expressed in testis and spleen, which suggests active roles in meiotic and mitotic recombination. Homozygous mutations of this gene were observed in primary lymphoma and colon cancer.
# Interactions
RAD54B has been shown to interact with RAD51.
# Cancer
The RAD54B gene is somatically mutated or deleted in numerous types of cancer including colorectal cancer (~3.3%), breast cancer (~3.4%), and lung cancer (~2.6%). In North America, these three cancers alone account for about 20,500 individuals diagnosed annually with RAD54B defective cancer. In a pre-clinical study, colon cancer cells defective in RAD54B were determined to be selectively killed by inhibitors of the DNA repair protein PARP1. Inhibitors of PARP1 likely impede alternative DNA repair responses that might otherwise compensate for loss of the RAD54B pathway in cancer cells. Thus RAD54B-deficient cancer cells treated with a PARP1 inhibitor are apparently more vulnerable to killing by naturally occurring DNA damages than non-cancerous cells without a RAD54 defect (see article Synthetic lethality). | RAD54B
DNA repair and recombination protein RAD54B is a protein that in humans is encoded by the RAD54B gene.[1][2][3]
The protein encoded by this gene belongs to the DEAD-like helicase superfamily. It shares similarity with Saccharomyces cerevisiae RAD54 and RDH54, both of which are involved in homologous recombination and repair of DNA. This protein binds to double-stranded DNA, and displays ATPase activity in the presence of DNA. This gene is highly expressed in testis and spleen, which suggests active roles in meiotic and mitotic recombination. Homozygous mutations of this gene were observed in primary lymphoma and colon cancer.[3]
# Interactions
RAD54B has been shown to interact with RAD51.[2]
# Cancer
The RAD54B gene is somatically mutated or deleted in numerous types of cancer including colorectal cancer (~3.3%), breast cancer (~3.4%), and lung cancer (~2.6%).[4] In North America, these three cancers alone account for about 20,500 individuals diagnosed annually with RAD54B defective cancer. In a pre-clinical study, colon cancer cells defective in RAD54B were determined to be selectively killed by inhibitors of the DNA repair protein PARP1.[4] Inhibitors of PARP1 likely impede alternative DNA repair responses that might otherwise compensate for loss of the RAD54B pathway in cancer cells. Thus RAD54B-deficient cancer cells treated with a PARP1 inhibitor are apparently more vulnerable to killing by naturally occurring DNA damages than non-cancerous cells without a RAD54 defect (see article Synthetic lethality). | https://www.wikidoc.org/index.php/RAD54B | |
ff9808e58f93bcaca7e8165bbbeb28f94914332c | wikidoc | RANBP1 | RANBP1
Ran-specific binding protein 1 is an enzyme that in humans is encoded by the RANBP1 gene.
Ran/TC4-binding protein, RanBP1, interacts specifically with GTP-charged RAN. RANBP1 encodes a 23-kD protein that binds to RAN complexed with GTP but not GDP. RANBP1 does not activate GTPase activity of RAN but does markedly increase GTP hydrolysis by the RanGTPase-activating protein (RanGAP1). The RANBP1 cDNA encodes a 201-amino acid protein that is 92% similar to its mouse homolog. In both mammalian cells and in yeast, RANBP1 acts as a negative regulator of RCC1 by inhibiting RCC1-stimulated guanine nucleotide release from RAN.
# Interactions
RANBP1 has been shown to interact with XPO1, KPNB1 and Ran. | RANBP1
Ran-specific binding protein 1 is an enzyme that in humans is encoded by the RANBP1 gene.[1][2][3]
Ran/TC4-binding protein, RanBP1, interacts specifically with GTP-charged RAN. RANBP1 encodes a 23-kD protein that binds to RAN complexed with GTP but not GDP. RANBP1 does not activate GTPase activity of RAN but does markedly increase GTP hydrolysis by the RanGTPase-activating protein (RanGAP1). The RANBP1 cDNA encodes a 201-amino acid protein that is 92% similar to its mouse homolog. In both mammalian cells and in yeast, RANBP1 acts as a negative regulator of RCC1 by inhibiting RCC1-stimulated guanine nucleotide release from RAN.[3]
# Interactions
RANBP1 has been shown to interact with XPO1,[4][5] KPNB1[5][6] and Ran.[5][7][8] | https://www.wikidoc.org/index.php/RANBP1 | |
eca4d550d6147594b1855d0daa3fb9c59eb17f2b | wikidoc | RANBP2 | RANBP2
RAN binding protein 2 (RANBP2) is protein which in humans is encoded by the RANBP2 gene. It is also known as nucleoporin 358 (Nup358) since it is a member nucleoporin family that makes up the nuclear pore complex. RanBP2 has a mass of 358 kDa.
# Function
RAN is a small GTP-binding protein of the RAS superfamily. Ran GTPase is a master regulatory switch, which among other functions, controls the shuttling of proteins between the nuclear and cytoplasm compartments of the cell. Ran GTPase controls a variety of cellular functions through its interactions with other proteins. The RanBP2 gene encodes a very large RAN-binding protein that localizes to cytoplasmic filaments emanating from the nuclear pore complex. RanBP2/Nup358 is a giant scaffold and mosaic cyclophilin-related nucleoporin implicated in controlling selective processes of the Ran-GTPase cycle. RanBP2 is composed of multiple domains. Each domain of RanBP2 selectively and directly interacts with distinct proteins such as Ran GTPase, importin-beta, exportin-1/CRM1, red opsin, subunits of the proteasome, cox11 and the kinesin-1 isoforms, KIF5B and KIF5C. Another partner of RanBP2 is the E2 enzyme UBC9. RanBP2 strongly enhances SUMO1 transfer from UBC9 to the SUMO1 target SP100. Another target for SUMOylation is RanGAP which is the GTPase activating protein for Ran. SUMO-RanGAP interacts with a domain near the carboxyl terminus of RanBP2. These findings place sumoylation at the cytoplasmic filaments of the nuclear pore complex and suggest that, for some substrates, modification and nuclear import are linked events. The pleiotropic (multifunctional) role of RanBP2 reflects its interaction with multiple partners, each presenting distinct cellular or molecular functions. This gene is partially duplicated in a gene cluster that lies in a hot spot for recombination on human chromosome 2q.
# Clinical significance
Insufficiency of RanBP2 is directly linked to carcinogenesis, aneuploidy, and neuroprotection of photoreceptor neurons to light-elicited stress and aging. Human missense mutations in RanBP2 were identified in its leucine-rich domain and they cause autosomal dominant necrotizing encephalopathy (ADNE).
# Interactions
RANBP2 has been shown to interact with KPNB1 and UBE2I. | RANBP2
RAN binding protein 2 (RANBP2) is protein which in humans is encoded by the RANBP2 gene.[1] It is also known as nucleoporin 358 (Nup358) since it is a member nucleoporin family that makes up the nuclear pore complex. RanBP2 has a mass of 358 kDa.
# Function
RAN is a small GTP-binding protein of the RAS superfamily. Ran GTPase is a master regulatory switch, which among other functions, controls the shuttling of proteins between the nuclear and cytoplasm compartments of the cell. Ran GTPase controls a variety of cellular functions through its interactions with other proteins. The RanBP2 gene encodes a very large RAN-binding protein that localizes to cytoplasmic filaments emanating from the nuclear pore complex. RanBP2/Nup358 is a giant scaffold and mosaic cyclophilin-related nucleoporin implicated in controlling selective processes of the Ran-GTPase cycle. RanBP2 is composed of multiple domains. Each domain of RanBP2 selectively and directly interacts with distinct proteins such as Ran GTPase, importin-beta, exportin-1/CRM1, red opsin, subunits of the proteasome, cox11 and the kinesin-1 isoforms, KIF5B and KIF5C. Another partner of RanBP2 is the E2 enzyme UBC9. RanBP2 strongly enhances SUMO1 transfer from UBC9 to the SUMO1 target SP100. Another target for SUMOylation is RanGAP which is the GTPase activating protein for Ran. SUMO-RanGAP interacts with a domain near the carboxyl terminus of RanBP2. These findings place sumoylation at the cytoplasmic filaments of the nuclear pore complex and suggest that, for some substrates, modification and nuclear import are linked events. The pleiotropic (multifunctional) role of RanBP2 reflects its interaction with multiple partners, each presenting distinct cellular or molecular functions. This gene is partially duplicated in a gene cluster that lies in a hot spot for recombination on human chromosome 2q.
# Clinical significance
Insufficiency of RanBP2 is directly linked to carcinogenesis, aneuploidy, and neuroprotection of photoreceptor neurons to light-elicited stress and aging. Human missense mutations in RanBP2 were identified in its leucine-rich domain and they cause autosomal dominant necrotizing encephalopathy (ADNE).[2]
# Interactions
RANBP2 has been shown to interact with KPNB1[3][4][5] and UBE2I.[6][7] | https://www.wikidoc.org/index.php/RANBP2 | |
add87442857bef7770a7a1ac56e804832e2e8673 | wikidoc | RASSF1 | RASSF1
Ras association domain-containing protein 1 is a protein that in humans is encoded by the RASSF1 gene.
# Function
This gene encodes a protein similar to the RAS effector proteins. Loss or altered expression of this gene has been associated with the pathogenesis of a variety of cancers, which suggests the tumor suppressor function of this gene. The inactivation of this gene was found to be correlated with the hypermethylation of its CpG-island promoter region. The encoded protein was found to interact with DNA repair protein XPA. The protein was also shown to inhibit the accumulation of cyclin D1, and thus induce cell cycle arrest. Seven alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported.
# Interactions
RASSF1 has been shown to interact with:
- CNKSR1,
- Death associated protein 6
- HRAS,
- MAP1B,
- MAP1S, and
- RASSF5.
# Pathology
Cervical cancer is known to be one of the most severe forms of cancer and is frequently associated with human papilloma virus (HPV). A few studies have been done to investigate the relationship between cervical cancers and RASSF1A, an isoform of RASSF1 that has been shown to suppress the proliferation in tumor cells. Through these studies, it was found that RASSF1A is commonly inactivated in adenocarcinomas (ACs) due to hypermethylation of the promotor region. However, this is not observed in squamous cell carcinomas (SCC) of the cervix, though they can be associated with HPV as well. It was found that RASSF1A was silenced in cancer cells when the promotor region was hypermethylated. It is speculated that cancer subtypes may develop due to the inverse relationship of RASSF1A and HPV. RASSF1A promoter hypermethylation and oncogenic HPV were detected in ACs, but SCCs displayed a high level of HPV DNA and no RASSF1A promoter methylation. Another study used Hela cells to study the potential therapeutic effects of RASSF1A. Hela cells are a line of cells that are derived from cervical cancer cells and are used in scientific research. When Hela cells were generated with RASSF1A expression, the growth of these cells decreased when compared to cells without RASSF1A expression. The rate of apoptosis in those cells had also increased with RASSF1A expression. Through these studies, it was indicated that RASSF1A expression could induce apoptosis and regulate proliferation to suppress tumors, making it a potential therapeutic mechanism for cervical cancers. | RASSF1
Ras association domain-containing protein 1 is a protein that in humans is encoded by the RASSF1 gene.
# Function
This gene encodes a protein similar to the RAS effector proteins. Loss or altered expression of this gene has been associated with the pathogenesis of a variety of cancers, which suggests the tumor suppressor function of this gene. The inactivation of this gene was found to be correlated with the hypermethylation of its CpG-island promoter region. The encoded protein was found to interact with DNA repair protein XPA. The protein was also shown to inhibit the accumulation of cyclin D1, and thus induce cell cycle arrest. Seven alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported.[1]
# Interactions
RASSF1 has been shown to interact with:
- CNKSR1,[2]
- Death associated protein 6[3]
- HRAS,[4]
- MAP1B,[5]
- MAP1S,[5][6] and
- RASSF5.[7]
# Pathology
Cervical cancer is known to be one of the most severe forms of cancer and is frequently associated with human papilloma virus (HPV).[8] A few studies have been done to investigate the relationship between cervical cancers and RASSF1A, an isoform of RASSF1 that has been shown to suppress the proliferation in tumor cells.[9] Through these studies, it was found that RASSF1A is commonly inactivated in adenocarcinomas (ACs) due to hypermethylation of the promotor region.[8] However, this is not observed in squamous cell carcinomas (SCC) of the cervix, though they can be associated with HPV as well. It was found that RASSF1A was silenced in cancer cells when the promotor region was hypermethylated.[10] It is speculated that cancer subtypes may develop due to the inverse relationship of RASSF1A and HPV. RASSF1A promoter hypermethylation and oncogenic HPV were detected in ACs, but SCCs displayed a high level of HPV DNA and no RASSF1A promoter methylation. Another study used Hela cells to study the potential therapeutic effects of RASSF1A.[9] Hela cells are a line of cells that are derived from cervical cancer cells and are used in scientific research. When Hela cells were generated with RASSF1A expression, the growth of these cells decreased when compared to cells without RASSF1A expression. The rate of apoptosis in those cells had also increased with RASSF1A expression. Through these studies, it was indicated that RASSF1A expression could induce apoptosis and regulate proliferation to suppress tumors, making it a potential therapeutic mechanism for cervical cancers.[9] | https://www.wikidoc.org/index.php/RASSF1 | |
86e59bef54e14e5bfd76fa5b420b7a28c5cb8ea0 | wikidoc | RASSF5 | RASSF5
Ras association domain-containing protein 5 is a protein that in humans is encoded by the RASSF5 or F5 gene.
# Function
This gene is a member of the Ras association domain family. It functions as a tumor suppressor, and is inactivated in a variety of cancers. The encoded protein localizes to centrosomes and microtubules, and associates with the GTP-activated forms of Ras, Rap1, and several other Ras-like small GTPases. The protein regulates lymphocyte adhesion and suppresses cell growth in response to activated Rap1 or Ras. Multiple transcript variants encoding different isoforms have been found for this gene.
# Interactions
RASSF5 has been shown to interact with RRAS, RAP2A, MRAS and RASSF1. | RASSF5
Ras association domain-containing protein 5 is a protein that in humans is encoded by the RASSF5 or F5 gene.[1][2][3]
# Function
This gene is a member of the Ras association domain family. It functions as a tumor suppressor, and is inactivated in a variety of cancers. The encoded protein localizes to centrosomes and microtubules, and associates with the GTP-activated forms of Ras, Rap1, and several other Ras-like small GTPases. The protein regulates lymphocyte adhesion and suppresses cell growth in response to activated Rap1 or Ras. Multiple transcript variants encoding different isoforms have been found for this gene.[3]
# Interactions
RASSF5 has been shown to interact with RRAS,[4] RAP2A,[4] MRAS[4] and RASSF1.[4] | https://www.wikidoc.org/index.php/RASSF5 | |
526389cc34657eeef1a2d379748cc75426ba1405 | wikidoc | RASSF9 | RASSF9
Ras association domain-containing protein 9 (RASSF9), also known as PAM COOH-terminal interactor protein 1 (PCIP1) or peptidylglycine alpha-amidating monooxygenase COOH-terminal interactor (PAMCI) is a protein that in humans is encoded by the RASSF9 gene.
# Function
RASSF9 the N-terminal RASSF family member Ras association (RalGDS/AF-6) domain family (N-terminal) member 9 12q21.31, is one of two new wild type RASSF9 and RASSF10 proteins. Three proteins that interact with a fragment of the PAM cytosolic domain containing signaling switch I and II the RA1 and RA2ras complex. RASSF7, the first member of the N-terminal RASSF family is required for mitosis. RASSF9 is recently found to be involved in regulation of epidermal homeostasis.
# Regulation
The mutant proregion encoding PAM COOH-terminal interactor protein-1 (P-CIP1) is comparable to that of human band 4.1-like TF (blood plasma protein) as a recycling endosomal pathway in microtubule locations, does NOT bind RasGTP. Specificity of interaction may all be related to microtubule locations of the endosomal-lysosomal system localized within the centrosome with Transferrin and different Ras proteins or with that one (N-Ras), but on the other hand, it interacts with three (Ha-Ras, Ki-Ras, and Rap) residues function, blocked by a mutation that affects Ras effector function is the critical product of the t (6:11) abnormality associated with some human leukemias. Phosphatidylinositol-3-kinase make contacts with both (6:11) switch I and II regions of ras and yeast adenylyl cyclase molecules carrying these mutations are rendered unactivatable by Ras in vitro. Ras-interacting residues, are appreciably different from that of RalGDS-RBD through their C-terminal Ras-binding domains (RBD). Such outliers as afadin/AF-6 and Rin1 were found to inhibit the binding of Raf to Ras. Adenylyl cyclase molecules carrying these mutations are rendered unactivatable by Ras in vitro with the Ras-associating domain-RA, not all RA domains bind RasGTP it is a primary Ras-binding site.
# Interactions
- PAM Peptidyl-glycine alpha-amidating monooxygenase precursor (PAM)
- RASSF7 Ras association domain-containing protein 7 (HRAS1-related cluster protein 1)
- BLOC1S2 Biogenesis of lysosome-related organelles complex-1 subunit 2 (BLOC subunit 2)
- TF Serotransferrin precursor (Transferrin) (Beta-1-metal- binding globulin)
- RAB11A Ras-related protein Rab-11A | RASSF9
Ras association domain-containing protein 9 (RASSF9), also known as PAM COOH-terminal interactor protein 1 (PCIP1) or peptidylglycine alpha-amidating monooxygenase COOH-terminal interactor (PAMCI) is a protein that in humans is encoded by the RASSF9 gene.[1]
# Function
RASSF9 the N-terminal RASSF family member Ras association (RalGDS/AF-6) domain family (N-terminal) member 9 12q21.31,[2][3] is one of two new wild type RASSF9 and RASSF10[3] proteins. Three proteins that interact with a fragment of the PAM cytosolic domain containing signaling switch I and II the RA1 and RA2ras complex.[4] RASSF7, the first member of the N-terminal RASSF family is required for mitosis.[3] RASSF9 is recently found to be involved in regulation of epidermal homeostasis.[5]
# Regulation
The mutant proregion encoding PAM COOH-terminal interactor protein-1 (P-CIP1) is comparable to that of human band 4.1-like TF (blood plasma protein) as a recycling endosomal pathway[2] in microtubule locations, does NOT bind RasGTP.[6] Specificity of interaction may all be related to microtubule locations of the endosomal-lysosomal system localized within the centrosome with Transferrin and different Ras proteins or with that one (N-Ras), but on the other hand, it interacts with three[7] (Ha-Ras, Ki-Ras,[8] and Rap[9]) residues function,[10] blocked by a mutation that affects Ras effector function[11] is the critical product of the t (6:11) abnormality associated with some human leukemias.[8] Phosphatidylinositol-3-kinase make contacts with both (6:11) switch I and II[8] regions of ras[4] and yeast adenylyl cyclase molecules carrying these mutations are rendered unactivatable by Ras in vitro.[12] Ras-interacting residues, are appreciably different from that of RalGDS-RBD[13] through their C-terminal Ras-binding domains (RBD).[14] Such outliers as afadin/AF-6 and Rin1[12] were found to inhibit the binding of Raf to Ras.[10] Adenylyl cyclase molecules carrying these mutations are rendered unactivatable by Ras in vitro with the Ras-associating domain-RA,[12] not all RA domains bind RasGTP it is a primary Ras-binding site.
# Interactions
- PAM Peptidyl-glycine alpha-amidating monooxygenase precursor (PAM)
- RASSF7 Ras association domain-containing protein 7 (HRAS1-related cluster protein 1)
- BLOC1S2 Biogenesis of lysosome-related organelles complex-1 subunit 2 (BLOC subunit 2)
- TF Serotransferrin precursor (Transferrin) (Beta-1-metal- binding globulin)
- RAB11A Ras-related protein Rab-11A[15] | https://www.wikidoc.org/index.php/RASSF9 | |
80d6a8b93ac665f8129cf67025f5a2691a970fc7 | wikidoc | RBFOX1 | RBFOX1
Fox-1 homolog A, also known as ataxin 2-binding protein 1 (A2BP1) or hexaribonucleotide-binding protein 1 (HRNBP1) or RNA binding protein, fox-1 homolog (Rbfox1), is a protein that in humans is encoded by the RBFOX1 gene.
# Function
Rbfox1 has an RNA recognition motif that is highly conserved among RNA-binding proteins. Rbfox1, and the related protein Rbfox2, bind the consensus RNA sequence motif (U)GCAUG within introns to exert their functions as alternative splicing factors.
Additionally, the Rbfox1/A2BP1 protein binds to the C-terminus of ataxin-2, and may contribute to the restricted pathology of spinocerebellar ataxia type 2 (SCA2). Ataxin-2 is the gene product of the SCA2 gene which causes familial neurodegenerative diseases. Several alternatively spliced transcript variants have been found for this gene. Some of these variants localize to the nucleus and some other to the cytoplasm. Nuclear variants have a well-established role in tissue specific alternative splicing. Rbfox1 cytoplasmic variants modulate mRNA stability and translation. In stressed cells, Rbfox1 has been demonstrated to localize to cytoplasmic stress granules. | RBFOX1
Fox-1 homolog A, also known as ataxin 2-binding protein 1 (A2BP1) or hexaribonucleotide-binding protein 1 (HRNBP1) or RNA binding protein, fox-1 homolog (Rbfox1), is a protein that in humans is encoded by the RBFOX1 gene.[1]
# Function
Rbfox1 has an RNA recognition motif that is highly conserved among RNA-binding proteins. Rbfox1, and the related protein Rbfox2, bind the consensus RNA sequence motif (U)GCAUG within introns to exert their functions as alternative splicing factors.[2][3]
Additionally, the Rbfox1/A2BP1 protein binds to the C-terminus of ataxin-2, and may contribute to the restricted pathology of spinocerebellar ataxia type 2 (SCA2). Ataxin-2 is the gene product of the SCA2 gene which causes familial neurodegenerative diseases. Several alternatively spliced transcript variants have been found for this gene. Some of these variants localize to the nucleus and some other to the cytoplasm. Nuclear variants have a well-established role in tissue specific alternative splicing.[4] Rbfox1 cytoplasmic variants modulate mRNA stability and translation.[5][6] In stressed cells, Rbfox1 has been demonstrated to localize to cytoplasmic stress granules.[7][8] | https://www.wikidoc.org/index.php/RBFOX1 | |
34139cfb1fdb617cd2c2b79fdf7363bb69bc898d | wikidoc | RECQL4 | RECQL4
ATP-dependent DNA helicase Q4 is an enzyme that in humans is encoded by the RECQL4 gene.
Mutations in RECQL4 are associated with the autosomal recessive disease Rothmund-Thomson Syndrome, a disorder that has features of premature aging. In addition to the Rothmund-Thomson syndrome, RECQL4 mutations are also associated with RAPADILINO and Baller-Gerold syndromes. There are two types of Rothmund Thomson syndrome and it is Type 2 that occurs in patients carrying deleterious mutations in both copies of the RECQL4 gene. This condition is associated with a high risk of developing osteosarcoma (malignant tumor of the bone).
RECQL4 gets its name from being homologous (sharing sequence) with other members of the RecQ helicase family. Two other genetic diseases are due to mutations in other RECQ helicases. Bloom syndrome is associated with mutations in the BLM gene and Werner syndrome is associated with mutations in the WRN gene.
# DNA repair
Double-strand breaks in DNA are potentially lethal to a cell and need to be repaired. Repair of double-strand breaks by homologous recombination (HR) is an important cellular mechanism for avoiding this lethality. RECQL4 has a crucial role in the first step of HR, referred to as end resection. When RECQL4 is deficient, end resection, and thus HR, is reduced. Evidence suggests that other forms of DNA repair including non-homologous end joining, nucleotide excision repair and base excision repair also depend on RECQL4 function. In the Rothmund-Thomson syndrome, the association of deficient RECQL4-mediated DNA repair and premature aging is consistent with the DNA damage theory of aging. | RECQL4
ATP-dependent DNA helicase Q4 is an enzyme that in humans is encoded by the RECQL4 gene.[1][2][3]
Mutations in RECQL4 are associated with the autosomal recessive disease Rothmund-Thomson Syndrome, a disorder that has features of premature aging.[4][5] In addition to the Rothmund-Thomson syndrome, RECQL4 mutations are also associated with RAPADILINO and Baller-Gerold syndromes.[6] There are two types of Rothmund Thomson syndrome and it is Type 2 that occurs in patients carrying deleterious mutations in both copies of the RECQL4 gene. This condition is associated with a high risk of developing osteosarcoma (malignant tumor of the bone).[7]
RECQL4 gets its name from being homologous (sharing sequence) with other members of the RecQ helicase family. Two other genetic diseases are due to mutations in other RECQ helicases. Bloom syndrome is associated with mutations in the BLM gene and Werner syndrome is associated with mutations in the WRN gene.[8]
# DNA repair
Double-strand breaks in DNA are potentially lethal to a cell and need to be repaired. Repair of double-strand breaks by homologous recombination (HR) is an important cellular mechanism for avoiding this lethality. RECQL4 has a crucial role in the first step of HR, referred to as end resection.[9] When RECQL4 is deficient, end resection, and thus HR, is reduced. Evidence suggests that other forms of DNA repair including non-homologous end joining, nucleotide excision repair and base excision repair also depend on RECQL4 function.[5] In the Rothmund-Thomson syndrome, the association of deficient RECQL4-mediated DNA repair and premature aging is consistent with the DNA damage theory of aging. | https://www.wikidoc.org/index.php/RECQL4 | |
3363978988690225dbb0c1f726584591b98df47d | wikidoc | RHBDF2 | RHBDF2
Rhomboid family member 2 is a protein that in humans is encoded by the RHBDF2 gene. The alternative name iRhom2 has been proposed, in order to clarify that it is a catalytically inactive member of the rhomboid family of intramembrane serine proteases.
The RHBDF2 gene is located on the long arm of chromosome 17 (17q25.1) on the Crick (minus) strand. It is 30.534 kilobases in length and encodes a protein of 856 amino acids with a predicted molecular weight of 96.686 kiloDaltons.
The RHBDF2 protein plays an important role in the secretion of tumor necrosis factor alpha, and has also been implicated in familial esophageal cancer.
It is involved in the regulation of the secretion of several ligands of the epidermal growth factor receptor. | RHBDF2
Rhomboid family member 2 is a protein that in humans is encoded by the RHBDF2 gene.[1][2] The alternative name iRhom2 has been proposed, in order to clarify that it is a catalytically inactive member of the rhomboid family of intramembrane serine proteases.[3][4]
The RHBDF2 gene is located on the long arm of chromosome 17 (17q25.1) on the Crick (minus) strand. It is 30.534 kilobases in length and encodes a protein of 856 amino acids with a predicted molecular weight of 96.686 kiloDaltons.
The RHBDF2 protein plays an important role in the secretion of tumor necrosis factor alpha,[5][6][7] and has also been implicated in familial esophageal cancer.[8]
It is involved in the regulation of the secretion of several ligands of the epidermal growth factor receptor.[9] | https://www.wikidoc.org/index.php/RHBDF2 | |
2b4b2f66622d56ea54b7615074bd5a60564590ca | wikidoc | RICTOR | RICTOR
Rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR) is a protein that in humans is encoded by the RICTOR gene.
RICTOR and mTOR are components of a protein complex that integrates nutrient- and growth factor-derived signals to regulate cell growth.
# Structure
The gene RICTOR is located on chromosome 5 at 5p13.1 with a sequence length of 5440 bp, oriented on the minus strand. The translated RICTOR protein contains 1709 amino acids and is present in the cytosol. RICTOR contains few conserved regions and function domains of RICTOR have yet to be observed. However, using liquid chromatography-tandem mass spectrometry analysis, 21 phosphorylation sites were identified on RICTOR. Of these sites, T1135 has been shown to undergo growth factor-responsive phosphorylation via S6K1.
# Function
RICTOR is a subunit of the mammalian target of rapamycin complex 2 (mTORC2) which contains mTOR, GβL, RICTOR (this protein) and mSIN1.
The mammalian target of rapamycin (mTOR) is a highly conserved Ser/Thr kinase that regulates cell growth and proliferation.
mTOR may exist as mTOR complex 1 (mTORC1) or mTOR complex 2 (mTORC2). RICTOR is a key component of mTORC2, which, unlike mTORC1, is not directly inhibited by rapamycin. mTORC2, and RICTOR, specifically, has been shown to phosphorylate Akt/protein kinase B (PKB) on SER473. This phosphorylation activates Akt/PKB, where deregulation of Akt/PKB has been implicated in cancer and diabetes.
RICTOR and mTORC2 have been shown to play an essential role in embryonic growth and development, perhaps due to the control that mTORC2 exerts on actin cytoskeleton organization.
## Regulation
FoxO transcription factors can activate expression of RICTOR. FoxO has been shown to inhibit mTORC1, while activating Akt through RICTOR elevation.
## Degradation
Perifosine has been shown to interfere with mTOR activity by degrading its components, such as RICTOR.
# Interactions
RICTOR has been shown to interact with and play a role in:
# Clinical relevance
Diseases associated with mutation in the RICTOR gene include foramen magnum meningioma and syringomyelia. Akt/PMB activation is also involved in glucose metabolism and activation of Akt by RICTOR has been shown to mediate glucose and lipid metabolism. Therefore, the influence of RICTOR and mTORC2 on Akt signaling has been associated with insulin resistance and type 2 diabetes.
## Cancer
Akt/PMB activation leads to proliferation and survival, therefore over-activation of the Akt/PMB pathway by mTORC2 (including RICTOR) is implicated in cancerous growth.
In human colorectal carcinoma, RICTOR has been shown to association with FBXW7 (outside of mTORC2) to mediate the ubiquitination of growth-promoting factors cyclin E and c-Myc. Furthermore, elevated growth factor signaling may suppress the ubiquitinating action of RICTOR-FBXW7, resulting in accumulation of cyclin E and c-Myc and subsequent progression through the cell cycle.
In glioblastoma (GBM), RICTOR(along with EGFR) may serve as an effective therapeutic target for silencing RNA, leading to decreased cell proliferation. Co-silencing of RICTOR and EGFR lead to increased sensitivity to alkaloids and alkylating agents. For one particular PTEN-mutant cell line, co-silencing resulted in tumor eradication.
RICTOR has been shown to be significantly overexpressed in well-differentiated leiomyosarcomas. Due to the influence of RICTOR on actin polymerization, RICTOR could play a role in allowing transcription and subsequent differentiation in these muscle cells.
mTOR subunits RICTOR and RAPTOR both showed increased expression, which increased with pituitary adenoma tumor staging. Therefore, mTOR, RPTOR and RICTOR were significantly correlated with the growth and invasion of pituitary adenomas and may have an important predictive and prognostic value in such patients. | RICTOR
Rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR) is a protein that in humans is encoded by the RICTOR gene.[1][2]
RICTOR and mTOR are components of a protein complex that integrates nutrient- and growth factor-derived signals to regulate cell growth.[2]
# Structure
The gene RICTOR is located on chromosome 5 at 5p13.1 with a sequence length of 5440 bp, oriented on the minus strand.[3][4] The translated RICTOR protein contains 1709 amino acids and is present in the cytosol. RICTOR contains few conserved regions and function domains of RICTOR have yet to be observed.[5] However, using liquid chromatography-tandem mass spectrometry analysis, 21 phosphorylation sites were identified on RICTOR. Of these sites, T1135 has been shown to undergo growth factor-responsive phosphorylation via S6K1.[6]
# Function
RICTOR is a subunit of the mammalian target of rapamycin complex 2 (mTORC2) which contains mTOR, GβL, RICTOR (this protein) and mSIN1.[7]
The mammalian target of rapamycin (mTOR) is a highly conserved Ser/Thr kinase that regulates cell growth and proliferation.[8]
mTOR may exist as mTOR complex 1 (mTORC1) or mTOR complex 2 (mTORC2). RICTOR is a key component of mTORC2, which, unlike mTORC1, is not directly inhibited by rapamycin. mTORC2, and RICTOR, specifically, has been shown to phosphorylate Akt/protein kinase B (PKB) on SER473. This phosphorylation activates Akt/PKB, where deregulation of Akt/PKB has been implicated in cancer and diabetes.[9]
RICTOR and mTORC2 have been shown to play an essential role in embryonic growth and development, perhaps due to the control that mTORC2 exerts on actin cytoskeleton organization.[10]
## Regulation
FoxO transcription factors can activate expression of RICTOR. FoxO has been shown to inhibit mTORC1, while activating Akt through RICTOR elevation.[11]
## Degradation
Perifosine has been shown to interfere with mTOR activity by degrading its components, such as RICTOR.[12]
# Interactions
RICTOR has been shown to interact with and play a role in:
# Clinical relevance
Diseases associated with mutation in the RICTOR gene include foramen magnum meningioma and syringomyelia. Akt/PMB activation is also involved in glucose metabolism and activation of Akt by RICTOR has been shown to mediate glucose and lipid metabolism.[20] Therefore, the influence of RICTOR and mTORC2 on Akt signaling has been associated with insulin resistance and type 2 diabetes.
## Cancer
Akt/PMB activation leads to proliferation and survival, therefore over-activation of the Akt/PMB pathway by mTORC2 (including RICTOR) is implicated in cancerous growth.
In human colorectal carcinoma, RICTOR has been shown to association with FBXW7 (outside of mTORC2) to mediate the ubiquitination of growth-promoting factors cyclin E and c-Myc. Furthermore, elevated growth factor signaling may suppress the ubiquitinating action of RICTOR-FBXW7, resulting in accumulation of cyclin E and c-Myc and subsequent progression through the cell cycle.[21]
In glioblastoma (GBM), RICTOR(along with EGFR) may serve as an effective therapeutic target for silencing RNA, leading to decreased cell proliferation. Co-silencing of RICTOR and EGFR lead to increased sensitivity to alkaloids and alkylating agents. For one particular PTEN-mutant cell line, co-silencing resulted in tumor eradication.[22]
RICTOR has been shown to be significantly overexpressed in well-differentiated leiomyosarcomas. Due to the influence of RICTOR on actin polymerization, RICTOR could play a role in allowing transcription and subsequent differentiation in these muscle cells.[23]
mTOR subunits RICTOR and RAPTOR both showed increased expression, which increased with pituitary adenoma tumor staging. Therefore, mTOR, RPTOR and RICTOR were significantly correlated with the growth and invasion of pituitary adenomas and may have an important predictive and prognostic value in such patients.[24] | https://www.wikidoc.org/index.php/RICTOR | |
38bfd3e37782f22c5dd1f09df47b8d8e93637f46 | wikidoc | RIPOR2 | RIPOR2
RHO family interacting cell polarization regulator 2 is a protein that in humans is encoded by the RIPOR2 gene.
# Function
The protein encoded by this gene stimulates the formation of a non-mitotic multinucleate syncytium from proliferative cytotrophoblasts during trophoblast differentiation. Alternative splicing of this gene results in multiple transcript variants. .
# Clinical significance
Mutations in RIPOR2 are associated to hearing loss . | RIPOR2
RHO family interacting cell polarization regulator 2 is a protein that in humans is encoded by the RIPOR2 gene.[1]
# Function
The protein encoded by this gene stimulates the formation of a non-mitotic multinucleate syncytium from proliferative cytotrophoblasts during trophoblast differentiation. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Nov 2013].
# Clinical significance
Mutations in RIPOR2 are associated to hearing loss .[2] | https://www.wikidoc.org/index.php/RIPOR2 | |
f61f95958b819e26200ac8309de09b8bf5e5990f | wikidoc | RMND5B | RMND5B
Required for meiotic nuclear division 5 homolog B (S. cerevisiae), also known as RMND5B, is a protein which in humans is encoded by the RMND5B gene. It has a zinc finger domain and is highly conserved throughout many eukaryotic organisms.
# Protein sequence
This protein is rich in leucine (14.0%) and might belong to the protein family of leucine-rich repeats
# Homology
CAD28476 is highly conserved in many eukaryotic organism. Its high conservation suggests that it plays a primary role in meiosis.
# Orthologs
# Zinc finger domain
Two domains were predicted by the program BLIMPS to exist in the protein of which one of the domains contains a zinc finger domain.
Zinc finger domains assist the binding of the protein to nucleic acids. This points to a direct interaction of CAD28476 with DNA during meiosis. By comparing CAD28476 with a related zinc finger protein in a local sequence alignment using LALIGN, the amino acids His359, Cys381 and Cys384 could be attributed to the zinc finger domain. This zinc finger structure is uncommon in the way that it involves one histidine instead of two.
# Expression
Microarray data show that CAD28476 is highly expressed in tissue where meiosis occurs like in testis and ovaries. Moreover it is also highly expressed in the brain around the hypothalamus.
# Transcriptional regulation
The analysis of the promoter region (tools on the page rVista . were used) shows that there are several transcription factor binding sites localized in conserved regions .
It is very likely that the transcription factor Ets-1 which belongs to the ETS transcription factor family and its core binding factor CBF are involved in regulation of transcription since they both have independent binding sites.
# Interacting proteins
There were two proteins predicted which interact with CAD28476. | RMND5B
Required for meiotic nuclear division 5 homolog B (S. cerevisiae), also known as RMND5B, is a protein which in humans is encoded by the RMND5B gene.[1] It has a zinc finger domain and is highly conserved throughout many eukaryotic organisms.
# Protein sequence
This protein is rich in leucine (14.0%) and might belong to the protein family of leucine-rich repeats
# Homology
CAD28476 is highly conserved in many eukaryotic organism. Its high conservation suggests that it plays a primary role in meiosis.
# Orthologs
# Zinc finger domain
Two domains were predicted by the program BLIMPS[2] to exist in the protein of which one of the domains contains a zinc finger domain.
Zinc finger domains assist the binding of the protein to nucleic acids. This points to a direct interaction of CAD28476 with DNA during meiosis. By comparing CAD28476 with a related zinc finger protein[3] in a local sequence alignment using LALIGN,[4] the amino acids His359, Cys381 and Cys384 could be attributed to the zinc finger domain. This zinc finger structure is uncommon in the way that it involves one histidine instead of two.
# Expression
Microarray data show that CAD28476 is highly expressed in tissue where meiosis occurs like in testis and ovaries. Moreover it is also highly expressed in the brain around the hypothalamus.
# Transcriptional regulation
The analysis of the promoter region (tools on the page rVista .[5] were used) shows that there are several transcription factor binding sites localized in conserved regions .
It is very likely that the transcription factor Ets-1 which belongs to the ETS transcription factor family and its core binding factor CBF are involved in regulation of transcription since they both have independent binding sites.
# Interacting proteins
There were two proteins predicted[6] which interact with CAD28476. | https://www.wikidoc.org/index.php/RMND5B | |
4e49d1071114231c19bcdcc64e22c2c7a5b95731 | wikidoc | RNF111 | RNF111
E3 ubiquitin-protein ligase Arkadia is an enzyme that in humans is encoded by the RNF111 gene.
# Function
The protein encoded by this gene contains a RING finger domain, a motif known to be involved in protein-protein and protein-DNA interactions. The mouse counterpart of this gene (Rnf111/arkadia) has been shown to genetically interact with the transforming growth factor (TGF) beta-like factor Nodal, and act as a modulator of the nodal signaling cascade, which is essential for the induction of mesoderm during embryonic development.
# Interactions
RNF111 has been shown to interact with Mothers against decapentaplegic homolog 7 and Mothers against decapentaplegic homolog 3. | RNF111
E3 ubiquitin-protein ligase Arkadia is an enzyme that in humans is encoded by the RNF111 gene.[1][2]
# Function
The protein encoded by this gene contains a RING finger domain, a motif known to be involved in protein-protein and protein-DNA interactions. The mouse counterpart of this gene (Rnf111/arkadia) has been shown to genetically interact with the transforming growth factor (TGF) beta-like factor Nodal, and act as a modulator of the nodal signaling cascade, which is essential for the induction of mesoderm during embryonic development.[2]
# Interactions
RNF111 has been shown to interact with Mothers against decapentaplegic homolog 7[3] and Mothers against decapentaplegic homolog 3.[3][4] | https://www.wikidoc.org/index.php/RNF111 | |
df6a808804e6402470f4b480c01960dc4acdb910 | wikidoc | RSPH4A | RSPH4A
Radial spoke head protein 4 homolog A, also known as radial spoke head-like protein 3, is a protein that in humans is encoded by the RSPH4A gene.
# Function
TRadial spoke head protein 4 homolog A appears to be a component the radial spoke head, as determined by homology to similar proteins in the biflagellate alga Chlamydomonas reinhardtii and other ciliates. Radial spokes, which are regularly spaced along cilia, sperm, and flagella axonemes, consist of a thin 'stalk' and a bulbous 'head' that form a signal transduction scaffold between the central pair of microtubules and dynein.
# Clinical significance
Mutations in the RSPH4A gene are associated with primary ciliary dyskinesia. | RSPH4A
Radial spoke head protein 4 homolog A, also known as radial spoke head-like protein 3, is a protein that in humans is encoded by the RSPH4A gene.[1][2]
# Function
TRadial spoke head protein 4 homolog A appears to be a component the radial spoke head, as determined by homology to similar proteins in the biflagellate alga Chlamydomonas reinhardtii and other ciliates. Radial spokes, which are regularly spaced along cilia, sperm, and flagella axonemes, consist of a thin 'stalk' and a bulbous 'head' that form a signal transduction scaffold between the central pair of microtubules and dynein.[1]
# Clinical significance
Mutations in the RSPH4A gene are associated with primary ciliary dyskinesia.[2] | https://www.wikidoc.org/index.php/RSPH4A | |
39d9fec7b3ca1686c30d652e5f44ab42b1230085 | wikidoc | RSPH6A | RSPH6A
Radial spoke head protein 6 homolog A (RSPH6A) also known as radial spoke head-like protein 1 (RSHL1) is a protein that in humans is encoded by the RSPH6A gene.
# Function
Radial spoke head protein 6 homolog A is similar to a sea urchin radial spoke head protein. Radial spoke protein complexes form part of the axoneme of eukaryotic flagella and are located between the axoneme's outer ring of doublet microtubules and central pair of microtubules. In Chlamydomonas, radial spoke proteins are thought to regulate the activity of dynein and the symmetry of flagellar bending patterns.
# Clinical significance
The RSPH6A gene maps to a region of chromosome 19 that is linked to primary ciliary dyskinesia-2 (CILD2). | RSPH6A
Radial spoke head protein 6 homolog A (RSPH6A) also known as radial spoke head-like protein 1 (RSHL1) is a protein that in humans is encoded by the RSPH6A gene.[1][2]
# Function
Radial spoke head protein 6 homolog A is similar to a sea urchin radial spoke head protein. Radial spoke protein complexes form part of the axoneme of eukaryotic flagella and are located between the axoneme's outer ring of doublet microtubules and central pair of microtubules. In Chlamydomonas, radial spoke proteins are thought to regulate the activity of dynein and the symmetry of flagellar bending patterns.[2]
# Clinical significance
The RSPH6A gene maps to a region of chromosome 19 that is linked to primary ciliary dyskinesia-2 (CILD2).[2] | https://www.wikidoc.org/index.php/RSPH6A | |
d7f2a97d9364d4b7c5f191e5e891bce31003ee93 | wikidoc | RUVBL2 | RUVBL2
RuvB-like 2 (E. coli), also known as RUVBL2, is a human gene coding for a protein belonging to the AAA+ family of proteins.
# Function
This gene encodes the second human homologue of the bacterial RuvB gene. Bacterial RuvB protein is a DNA helicase essential for homologous recombination and DNA double-strand break repair. However, the evidence for whether RUVBL2 has DNA helicase activity is contradictory. This gene is physically linked to the CGB/LHB gene cluster on chromosome 19q13.3, and is very close (55 nt) to the LHB gene, in the opposite orientation.
# Interactions
RUVBL2 has been shown to interact with RuvB-like 1 and Activating transcription factor 2. | RUVBL2
RuvB-like 2 (E. coli), also known as RUVBL2, is a human gene coding for a protein belonging to the AAA+ family of proteins.
# Function
This gene encodes the second human homologue of the bacterial RuvB gene. Bacterial RuvB protein is a DNA helicase essential for homologous recombination and DNA double-strand break repair. However, the evidence for whether RUVBL2 has DNA helicase activity is contradictory.[1] This gene is physically linked to the CGB/LHB gene cluster on chromosome 19q13.3, and is very close (55 nt) to the LHB gene, in the opposite orientation.[2]
# Interactions
RUVBL2 has been shown to interact with RuvB-like 1[3] and Activating transcription factor 2.[4] | https://www.wikidoc.org/index.php/RUVBL2 | |
9d4938698e041fcfd7f900106aa0bdffd9aab9e1 | wikidoc | Radish | Radish
The radish (Raphanus sativus) is an edible root vegetable of the Brassicaceae family that is grown and consumed throughout the world.
# History
Although the radish was a well-established crop in Hellenistic and Roman times, which leads to the assumption that it was brought into cultivation at an earlier time, Zohary and Hopf note that "there are almost no archeological records available" to help determine its earlier history and domestication. Wild forms of the radish and its relatives the mustards and turnip can be found over west Asia and Europe, suggesting that their domestication took place somewhere in that area. However Zohary and Hopf conclude, "Suggestions as to the origins of these plants are necessarily based on linguistic considerations."
# Cultivation
Summer radishes mature rapidly, with many varieties germinating in 3-7 days, and reaching maturity in three to four weeks. A common garden crop in the U.S., the fast harvest cycle makes them a popular choice for children's gardens. Harvesting periods can be extended through repeated plantings, spaced a week or two apart.
Radishes grow best in full sun and fertile, acidic to neutral soil. They are in season from April to as late as October in the northern hemisphere. As with other root crops, tilling the soil helps the roots grow. Most soil types will work, though sandy loams are particularly good for winter and spring crops, while soils that form a hard crust can impair growth. The depth at which seeds are planted affects the size of the root, from 1 cm deep recommended for small radishes to 4 cm for large radishes.
# Varieties
Broadly speaking, radishes can be categorized into four main types (summer, fall, winter, and spring) and a variety of shapes, colours, and sizes, such as black or multi-coloured radishes, with round or elongated roots that can grow longer than a parsnip.
## Spring or summer radishes
Sometimes referred to as European radishes, or as spring radishes if they're typically planted in cooler weather, summer radishes are generally small and have a relatively short 3-4 week cultivation time.
- Cherry Belle is a bright red-skinned round variety with a white interior. It is familiar in North American supermarkets.
- Champion is round and red-skinned like the Cherry Belle, but with slightly larger roots, up to about 5 cm, and a milder flavor.
- Red King has a mild flavor, with good resistance to club foot, a problem that can arise from poor drainage.
- Snow Belle is an all-white variety of radish, also round like the Cherry Belle.
- White Icicle or just Icicle is a white carrot-shaped variety, around 10-12 cm long, dating back to the 16th century. It slices easily, and is has better than average resistance to pithiness.
- French Breakfast is an elongated red-skinned radish with a white splash at the root end. It is typically slightly milder than other summer varieties, but is among the quickest to turn pithy.
- Plum Purple a purple-fuchsia radish that tends to stay crisp longer than the average radish.
- Gala and Roodbol are two varieties popular in the Netherlands in a breakfast dish, thinly sliced on buttered bread.
- Easter Egg is not an actual variety, but a mix of varieties with different skin colors, typically including white, pink, red, and purple radishes. Sold in markets or seed packets under the name, the seed mixes can extend harvesting duration from a single planting, as different varieties may mature at different times.
## Winter varieties
Various winter varieties can actually be grown throughout the growing season, from early spring to fall, but take their name from their ability to be stored during the non-growing winter months. Sizes are generally than the summer varieties, and cultivation often takes six to eight weeks.
Black Spanish or Black Spanish Round are occur in both round and elongated forms, and is sometimes simply called the black radish or known by the French Gros Noir d'Hiver. It dates in Europe to 1548, and was a common garden variety in England and France the early 19th century. It has a rough black skin with hot-flavored white flesh, is round or irregularly pear shaped, and grows to around 10cm in diameter.
Daikon refers to a wide variety of winter radishes from east Asia. While the Japanese name daikon has been adopted in English, it is also sometimes called the Japanese radish, Chinese radish, or Oriental radish. Daikon commonly have elongated white roots, although many varieties of daikon exist. One well known variety is April Cross, with smooth white roots. The New York Times describes Masato Red and Masato Green varieties as extremely long, well suited for fall planting and winter storage. The Sakurajima daikon is a hot flavored variety which is typically grown to around 10 kg when harvested, but which has grown as heavy as 30 kg when left in the ground.
## Seed pod varieties
The seeds of radishes grow in pods, following flowering that happens when left to grow past their normal harvesting period. The seeds are edible, and are sometimes used as a crunchy, spicy addition to salads. Some varieties are grown specifically for their seeds or seed pods, rather than their roots. The Rat-tailed radish, an old European variety, has long, thin, curly pods. In the 17th century, the pods were often pickled and served with meat. The München Bier variety supplies spicy seeds that are sometimes served raw as an accompaniment to beer in Germany.
# Nutritional value
Radishes are rich in ascorbic acid, folic acid, and potassium. They are a good source of vitamin B6, riboflavin, magnesium, copper, and calcium. One cup of sliced red radish bulbs provides approximately 20 Calories or less, coming largely from carbohydrates, making radishes, relative to their size, a very filling food for their caloric value.
# Uses
## In cooking
The most popular part for eating is the napiform taproot, although the entire plant is edible and the tops can be used as a leaf vegetable. The skin comes in a variety of colours. Most commonly known is the round, red-skinned variety but other varieties may have a pink, white or gray-black skin, and there is a yellow-skinned variety.
The bulb of the radish is usually eaten raw, but tougher specimens can be steamed. The raw flesh has a crisp texture and a pungent, peppery flavor, caused by chewing glucosinolates and the enzyme myrosinase in the radish, that, when brought together form allyl isothiocyanates , also present in mustard, horseradish and wasabi.
## In medicine
Radishes are suggested as an alternative treatment for a variety of ailments including whooping cough, cancer, coughs, gastric discomfort, liver problems, constipation, dyspepsia, gallbladder problems, arthritis, gallstones, kidney stones and intestinal parasites.
## In industry
The seeds of the Raphanus sativus species can be pressed to extract seed oil. Wild radish seeds contain up to 48% oil content, and while not suitable for human consumption the oil has promise as a source of biofuel.
The oilseed radish grows well in cool climates.
# Radishes in popular culture
- Radishes were the staple food of the three main races of the Fraggle Rock universe - the Fraggles, Doozers and Gorgs.
- In 2005 in Japan, a giant radish grew through a section of pavement. Named Dokonjo Daikon, the vegetable received considerable interest from the public, and toy shops began stocking giant radish dolls.
- Murder, She Wrote protagonist Jessica Fletcher was revealed to be severely allergic to radishes.
- Luna Lovegood, a character from the Harry Potter series, wears radish earrings.
- In The Simpsons episode The Wife Aquatic local bully Jimbo Jones wonders what a radish is, saying "It's like an apple did it with an onion," referring to procreative copulation and hybridization.
- The Nepalese word for radish is "mulaa" and is a euphemism for penis. In Nepal, the large, long Asian radish is the common variety.
- An early Homestar Runner cartoon, called "The Reddest Radish" features Strong Bad stealing Marzipan's prize radish.
- In the French Revolutionary Calendar, April 8 was dedicated to radishes.
- Radishes is the name of the comic strip Peanuts in Denmark.
- The character of Raditz in Dragonball Z is a name pun on Radish.
# Notes
- ↑ Daniel Zohary and Maria Hopf, Domestication of plants in the Old World, third edition (Oxford: University Press, 2000), p. 139
- ↑ Jump up to: 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 Faust, Joan Lee. (1996-03-03.) "Hail the Speedy Radish, in All Its Forms." The New York Times, via nytimes.com archives. Retrieved on 2007-09-27.
- ↑ Jump up to: 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 Peterson, Cass. (1999-05-02.) "Radishes: Easy to Sprout, Hard to Grow Right." The New York Times, via nytimes.com archives. Retrieved on 2007-09-27.
- ↑ Jump up to: 4.0 4.1 4.2 Beattie, J. H. and W. R. Beattie. (March 1938.) "Production of Radishes." U.S. Department of Agriculture, leaflet no. 57, via University of North Texas Government Documents A to Z Digitization Project website. Retrieved on 2007-09-27.
- ↑ Aiton, William Townsend. (1812.) "Hortus Kewensis; Or, A Catalogue of the Plants Cultivated in the Royal Botanic Garden at Kew, Second Edition, Vol. IV" Longman, Hurst, Rees, Orme, and Brown: London. Page 129. Retrieved on 2007-09-28.
- ↑ Lindley, George. (1831.) "A Guide to the Orchard and Kitchen Garden: Or, an Account of the Most Valuable Fruit and Vegetables Cultivated in Great Britain." Longman, Rees, Orme, Brown, and Green: London. Retrieved on 2007-09-28.
- ↑ McIntosh, Charles. (1828.) "The Practical Gardener, and Modern Horticulturist." Thomas Kelly: London. Page 288.
- ↑ (2004.) "Daikon." The American Heritage Dictionary of the English Language, Fourth Edition, Houghton Mifflin Company, via dictionary.com. Retrieved on 2007-09-28.
- ↑ (2002-02-10.) "29 kg radish wins contest." Kyodo World News Service, via highbeam.com (fee for full access.) Retrieved on 2007-09-28.
- ↑ Healing foods page for radishes
- ↑ Plants for the Future page on radishes
- ↑ "Plant Oils as Fuel: Radish oil"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ "Oilseed radish".
- ↑ Giant radish grows through pavement in Japan | Radish
Template:Otheruses4
The radish (Raphanus sativus) is an edible root vegetable of the Brassicaceae family that is grown and consumed throughout the world.
# History
Template:Refimprovesect
Although the radish was a well-established crop in Hellenistic and Roman times, which leads to the assumption that it was brought into cultivation at an earlier time, Zohary and Hopf note that "there are almost no archeological records available" to help determine its earlier history and domestication. Wild forms of the radish and its relatives the mustards and turnip can be found over west Asia and Europe, suggesting that their domestication took place somewhere in that area. However Zohary and Hopf conclude, "Suggestions as to the origins of these plants are necessarily based on linguistic considerations."[1]
# Cultivation
Summer radishes mature rapidly, with many varieties germinating in 3-7 days, and reaching maturity in three to four weeks.[2][3] A common garden crop in the U.S., the fast harvest cycle makes them a popular choice for children's gardens.[2] Harvesting periods can be extended through repeated plantings, spaced a week or two apart.[4]
Radishes grow best in full sun and fertile, acidic to neutral soil.[citation needed] They are in season from April to as late as October in the northern hemisphere.[citation needed] As with other root crops, tilling the soil helps the roots grow.[4] Most soil types will work, though sandy loams are particularly good for winter and spring crops, while soils that form a hard crust can impair growth.[4] The depth at which seeds are planted affects the size of the root, from 1 cm deep recommended for small radishes to 4 cm for large radishes.[3]
# Varieties
Broadly speaking, radishes can be categorized into four main types (summer, fall, winter, and spring) and a variety of shapes, colours, and sizes, such as black or multi-coloured radishes, with round or elongated roots that can grow longer than a parsnip.
## Spring or summer radishes
Sometimes referred to as European radishes, or as spring radishes if they're typically planted in cooler weather, summer radishes are generally small and have a relatively short 3-4 week cultivation time.[citation needed]
- Cherry Belle is a bright red-skinned round variety with a white interior.[2] It is familiar in North American supermarkets.
- Champion is round and red-skinned like the Cherry Belle, but with slightly larger roots, up to about 5 cm, and a milder flavor.[2]
- Red King has a mild flavor, with good resistance to club foot, a problem that can arise from poor drainage.[2]
- Snow Belle is an all-white variety of radish, also round like the Cherry Belle.[2]
- White Icicle or just Icicle is a white carrot-shaped variety, around 10-12 cm long, dating back to the 16th century. It slices easily, and is has better than average resistance to pithiness.[2][3]
- French Breakfast is an elongated red-skinned radish with a white splash at the root end. It is typically slightly milder than other summer varieties, but is among the quickest to turn pithy.[3]
- Plum Purple a purple-fuchsia radish that tends to stay crisp longer than the average radish.[3]
- Gala and Roodbol are two varieties popular in the Netherlands in a breakfast dish, thinly sliced on buttered bread.[2]
- Easter Egg is not an actual variety, but a mix of varieties with different skin colors,[3] typically including white, pink, red, and purple radishes. Sold in markets or seed packets under the name, the seed mixes can extend harvesting duration from a single planting, as different varieties may mature at different times.[3]
## Winter varieties
Various winter varieties can actually be grown throughout the growing season, from early spring to fall, but take their name from their ability to be stored during the non-growing winter months. Sizes are generally than the summer varieties, and cultivation often takes six to eight weeks.[citation needed]
Black Spanish or Black Spanish Round are occur in both round and elongated forms, and is sometimes simply called the black radish or known by the French Gros Noir d'Hiver. It dates in Europe to 1548,[5] and was a common garden variety in England and France the early 19th century.[6] It has a rough black skin with hot-flavored white flesh, is round or irregularly pear shaped,[7] and grows to around 10cm in diameter.
Daikon refers to a wide variety of winter radishes from east Asia. While the Japanese name daikon has been adopted in English, it is also sometimes called the Japanese radish, Chinese radish, or Oriental radish.[8] Daikon commonly have elongated white roots, although many varieties of daikon exist. One well known variety is April Cross, with smooth white roots.[2][3] The New York Times describes Masato Red and Masato Green varieties as extremely long, well suited for fall planting and winter storage.[2] The Sakurajima daikon is a hot flavored variety which is typically grown to around 10 kg when harvested, but which has grown as heavy as 30 kg when left in the ground.[2][9]
## Seed pod varieties
The seeds of radishes grow in pods, following flowering that happens when left to grow past their normal harvesting period. The seeds are edible, and are sometimes used as a crunchy, spicy addition to salads.[3] Some varieties are grown specifically for their seeds or seed pods, rather than their roots. The Rat-tailed radish, an old European variety, has long, thin, curly pods. In the 17th century, the pods were often pickled and served with meat.[3] The München Bier variety supplies spicy seeds that are sometimes served raw as an accompaniment to beer in Germany.[citation needed]
# Nutritional value
Template:Nutritionalvalue
Radishes are rich in ascorbic acid, folic acid, and potassium. They are a good source of vitamin B6, riboflavin, magnesium, copper, and calcium. One cup of sliced red radish bulbs provides approximately 20 Calories or less, coming largely from carbohydrates, making radishes, relative to their size, a very filling food for their caloric value.
# Uses
## In cooking
The most popular part for eating is the napiform taproot, although the entire plant is edible and the tops can be used as a leaf vegetable. The skin comes in a variety of colours. Most commonly known is the round, red-skinned variety but other varieties may have a pink, white or gray-black skin, and there is a yellow-skinned variety.
The bulb of the radish is usually eaten raw, but tougher specimens can be steamed. The raw flesh has a crisp texture and a pungent, peppery flavor, caused by chewing glucosinolates and the enzyme myrosinase in the radish, that, when brought together form allyl isothiocyanates , also present in mustard, horseradish and wasabi.
## In medicine
Radishes are suggested as an alternative treatment for a variety of ailments including whooping cough, cancer, coughs, gastric discomfort, liver problems, constipation, dyspepsia, gallbladder problems, arthritis, gallstones, kidney stones[10] and intestinal parasites.[11]
## In industry
The seeds of the Raphanus sativus species can be pressed to extract seed oil. Wild radish seeds contain up to 48% oil content, and while not suitable for human consumption the oil has promise as a source of biofuel.[12]
The oilseed radish grows well in cool climates.[13]
# Radishes in popular culture
Template:Trivia
- Radishes were the staple food of the three main races of the Fraggle Rock universe - the Fraggles, Doozers and Gorgs.
- In 2005 in Japan, a giant radish grew through a section of pavement. Named Dokonjo Daikon, the vegetable received considerable interest from the public, and toy shops began stocking giant radish dolls.[14]
- Murder, She Wrote protagonist Jessica Fletcher was revealed to be severely allergic to radishes.
- Luna Lovegood, a character from the Harry Potter series, wears radish earrings.
- In The Simpsons episode The Wife Aquatic local bully Jimbo Jones wonders what a radish is, saying "It's like an apple did it with an onion," referring to procreative copulation and hybridization.
- The Nepalese word for radish is "mulaa" and is a euphemism for penis. In Nepal, the large, long Asian radish is the common variety.
- An early Homestar Runner cartoon, called "The Reddest Radish" features Strong Bad stealing Marzipan's prize radish.
- In the French Revolutionary Calendar, April 8 was dedicated to radishes.
- Radishes is the name of the comic strip Peanuts in Denmark.
- The character of Raditz in Dragonball Z is a name pun on Radish.
# Notes
- ↑ Daniel Zohary and Maria Hopf, Domestication of plants in the Old World, third edition (Oxford: University Press, 2000), p. 139
- ↑ Jump up to: 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 Faust, Joan Lee. (1996-03-03.) "Hail the Speedy Radish, in All Its Forms." The New York Times, via nytimes.com archives. Retrieved on 2007-09-27.
- ↑ Jump up to: 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 Peterson, Cass. (1999-05-02.) "Radishes: Easy to Sprout, Hard to Grow Right." The New York Times, via nytimes.com archives. Retrieved on 2007-09-27.
- ↑ Jump up to: 4.0 4.1 4.2 Beattie, J. H. and W. R. Beattie. (March 1938.) "Production of Radishes." U.S. Department of Agriculture, leaflet no. 57, via University of North Texas Government Documents A to Z Digitization Project website. Retrieved on 2007-09-27.
- ↑ Aiton, William Townsend. (1812.) "Hortus Kewensis; Or, A Catalogue of the Plants Cultivated in the Royal Botanic Garden at Kew, Second Edition, Vol. IV" Longman, Hurst, Rees, Orme, and Brown: London. Page 129. Retrieved on 2007-09-28.
- ↑ Lindley, George. (1831.) "A Guide to the Orchard and Kitchen Garden: Or, an Account of the Most Valuable Fruit and Vegetables Cultivated in Great Britain." Longman, Rees, Orme, Brown, and Green: London. Retrieved on 2007-09-28.
- ↑ McIntosh, Charles. (1828.) "The Practical Gardener, and Modern Horticulturist." Thomas Kelly: London. Page 288.
- ↑ (2004.) "Daikon." The American Heritage Dictionary of the English Language, Fourth Edition, Houghton Mifflin Company, via dictionary.com. Retrieved on 2007-09-28.
- ↑ (2002-02-10.) "29 kg radish wins contest." Kyodo World News Service, via highbeam.com (fee for full access.) Retrieved on 2007-09-28.
- ↑ Healing foods page for radishes
- ↑ Plants for the Future page on radishes
- ↑ "Plant Oils as Fuel: Radish oil"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ "Oilseed radish".
- ↑ Giant radish grows through pavement in Japan [Japanese wikipedia article]
# External links
- Multilingual taxonomic information from the University of Melbourne
- Production of radishes hosted by the UNT Government Documents Department
ar:فجل
bg:Репичка
da:Radise
de:Radieschen
el:Ρεπάνι
it:Raphanus sativus
he:צנון
lt:Ridikas
nl:radijs
fi:Retiisi
sv:rädisa
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Radish | |
2270cdfe9d28a1e3329a20692b6b8b960d7e0fe3 | wikidoc | Ranula | Ranula
# Overview
A ranula is a type of mucocele found on the floor of the mouth. Ranulas present as a swelling of connective tissue consisting of collected mucin from a ruptured salivary gland duct, which is usually caused by local trauma.
# Etymology
The latin rana means frog, and a ranula is so named because its appearance is sometimes compared to a frog's underbelly.
# Locations
The gland that most likely causes a ranula is the sublingual gland. Nonetheless, the submandibular gland and minor salivary glands may be involved.
# Appearance
An oral ranula is a fluctuant swelling with a bluish translucent color that somewhat resembles the underbelly of a frog "Rana". If it is deeper it does not have this bluish appearance. If it is large ( 2 or more cm.), it may hide the salivary gland and affect the location of the tongue. Most frequently it stems from the sublingual salivary gland, but also from the submandibular gland.
Though normally above the mylohyoid muscle, if a ranula is found deeper in the floor of the mouth, it can appear to have a normal color. A ranula below the mylohyoid muscle is referred to as a "plunging or cervical ranula", and produces swelling of the neck with or without swelling in the floor of the mouth.
Ranulas measure several centimeters in diameter and are usually larger than mucoceles. As a result, when ranulas are present the tongue may be elevated. As with mucoceles, ranulas may be subject to recurrent swelling with occasional rupturing of its contents. When pressed, they may not blanch.
# Symptoms
Ranulas are usually asymptomatic, although they may change gradually in size, shrinking and swelling. The overlying skin is usually intact. The mass is not fixed and is also not tender. The mass is not connected to the thyroid gland or lymph nodes. The mass may not be well defined. If it gets large enough it may interfere with swallowing, and cervical ranulas may even interfere with breathing. Some pain may be connected with very larrge ranulas.
# CT
Cystic mass in the sublingual area.
- CT demonstrates a Ranula Image courtesy of RadsWiki and copylefted
- CT demonstrates a Ranula Image courtesy of RadsWiki and copylefted
- CT demonstrates a Ranula Image courtesy of RadsWiki and copylefted
- CT demonstrates a Ranula Image courtesy of RadsWiki and copylefted
- CT demonstrates a Ranula Image courtesy of RadsWiki and copylefted
# Histology
Microscopically, ranulas are cystic saliva filled distensions of salivary gland ducts on the floor of the mouth along side the tongue, and are lined by epithelium. A salivary mucocele, in contrast is not lined by epithelium.
# Treatment
Treatment of ranulas involves excision of the top of the lesion in a procedure known as "marsupialization". Ranulas may reoccur if the sublingual gland or other gland causing them is not removed. There is little morbidity or mortality connected with treatment. | Ranula
Template:DiseaseDisorder infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Associate Editor-In-Chief: Berna Zorkun DMD [2]
# Overview
A ranula is a type of mucocele found on the floor of the mouth. Ranulas present as a swelling of connective tissue consisting of collected mucin from a ruptured salivary gland duct, which is usually caused by local trauma.
# Etymology
The latin rana means frog, and a ranula is so named because its appearance is sometimes compared to a frog's underbelly.
# Locations
The gland that most likely causes a ranula is the sublingual gland. Nonetheless, the submandibular gland and minor salivary glands may be involved.
# Appearance
An oral ranula is a fluctuant swelling with a bluish translucent color that somewhat resembles the underbelly of a frog "Rana". If it is deeper it does not have this bluish appearance. If it is large ( 2 or more cm.), it may hide the salivary gland and affect the location of the tongue. Most frequently it stems from the sublingual salivary gland, but also from the submandibular gland.
Though normally above the mylohyoid muscle, if a ranula is found deeper in the floor of the mouth, it can appear to have a normal color. A ranula below the mylohyoid muscle is referred to as a "plunging or cervical ranula", and produces swelling of the neck with or without swelling in the floor of the mouth.
Ranulas measure several centimeters in diameter and are usually larger than mucoceles. As a result, when ranulas are present the tongue may be elevated. As with mucoceles, ranulas may be subject to recurrent swelling with occasional rupturing of its contents. When pressed, they may not blanch.
# Symptoms
Ranulas are usually asymptomatic, although they may change gradually in size, shrinking and swelling. The overlying skin is usually intact. The mass is not fixed and is also not tender. The mass is not connected to the thyroid gland or lymph nodes. The mass may not be well defined. If it gets large enough it may interfere with swallowing, and cervical ranulas may even interfere with breathing. Some pain may be connected with very larrge ranulas.
# CT
Cystic mass in the sublingual area.
- CT demonstrates a Ranula Image courtesy of RadsWiki and copylefted
- CT demonstrates a Ranula Image courtesy of RadsWiki and copylefted
- CT demonstrates a Ranula Image courtesy of RadsWiki and copylefted
- CT demonstrates a Ranula Image courtesy of RadsWiki and copylefted
- CT demonstrates a Ranula Image courtesy of RadsWiki and copylefted
# Histology
Microscopically, ranulas are cystic saliva filled distensions of salivary gland ducts on the floor of the mouth along side the tongue, and are lined by epithelium. A salivary mucocele, in contrast is not lined by epithelium.
# Treatment
Treatment of ranulas involves excision of the top of the lesion in a procedure known as "marsupialization". Ranulas may reoccur if the sublingual gland or other gland causing them is not removed. There is little morbidity or mortality connected with treatment. | https://www.wikidoc.org/index.php/Ranula | |
eb75569b1c09860efa8ca4c5fc49327c6d4f6a58 | wikidoc | RasMol | RasMol
# Overview
RasMol is a computer program written for molecular graphics visualization intended and used primarily for the depiction and exploration of biological macromolecule structures, such as those found in the Protein Data Bank. It was originally developed by Roger Sayle in the early 90s.
Historically, it was an important tool for molecular biologists since the extremely optimized program allowed the software to run on (then) modestly powerful personal computers. Before RasMol, visualization software ran on graphics workstations that, due to their expense, were less accessible to scholars. RasMol has become an important educational tool as well as continuing to be an important tool for research in structural biology.
RasMol has a complex version history. Starting with the series of 2.7 versions, RasMol is licensed under a dual license (GPL or custom license RASLIC). Thus, RasMol is (along with Molekel, Jmol and PyMOL), among the few open source molecular visualization programs available.
RasMol includes a language (for selecting certain protein chains, or changing colors etc). Jmol has incorporated the RasMol scripting language into its commands.
Protein Databank (PDB) files can be downloaded for visualization from the Research Collaboratory for Structural Bioinformatics (RCSB) bank. These have been uploaded by researchers who have characterized the structure of molecules usually by X-ray crystallography or NMR spectroscopy.
# Inter-process Communication
On UNIX platforms Rasmol can communicate with other programs via TCL/TK.
Under MS-Windows, Dynamic Data Exchange (DDE) is used.
- multiple alignment program. The responsible Java class can be freely used in other applications. | RasMol
# Overview
RasMol is a computer program written for molecular graphics visualization intended and used primarily for the depiction and exploration of biological macromolecule structures, such as those found in the Protein Data Bank. It was originally developed by Roger Sayle in the early 90s.
Historically, it was an important tool for molecular biologists since the extremely optimized program allowed the software to run on (then) modestly powerful personal computers. Before RasMol, visualization software ran on graphics workstations that, due to their expense, were less accessible to scholars. RasMol has become an important educational tool as well as continuing to be an important tool for research in structural biology.
RasMol has a complex version history. Starting with the series of 2.7 versions, RasMol is licensed under a dual license (GPL or custom license RASLIC[1]). Thus, RasMol is (along with Molekel, Jmol and PyMOL), among the few open source molecular visualization programs available.
RasMol includes a language (for selecting certain protein chains, or changing colors etc). Jmol has incorporated the RasMol scripting language into its commands.
Protein Databank (PDB) files can be downloaded for visualization from the Research Collaboratory for Structural Bioinformatics (RCSB) bank. These have been uploaded by researchers who have characterized the structure of molecules usually by X-ray crystallography or NMR spectroscopy.
# Inter-process Communication
On UNIX platforms Rasmol can communicate with other programs via TCL/TK.
Under MS-Windows, Dynamic Data Exchange (DDE) is used.
- multiple alignment program. The responsible Java class can be freely used in other applications. | https://www.wikidoc.org/index.php/RasMol | |
1e075983daa94dcac479cd89873027e7899bb735 | wikidoc | RecLOH | RecLOH
RecLOH is a term in genetics that is an abbreviation for "Recombinational Loss of Heterozygosity".
This is a type of mutation which occurs with DNA by recombination. From a pair of equivalent ("homologous"), but slightly different genes, a pair of identical genes results. In this case there is an unreciprocal exchange of genetic code between the chromosomes, in contrast to chromosomal crossover, because genetic information is lost.
# For Y chromosome
In genetic genealogy, the term is used particularly concerning similar seeming events in Y chromosome DNA. This type of mutation happens within one chromosome, and does not involve a reciprocal transfer. Rather, one homologous segment "writes over" the other. The mechanism is presumed to be different from RecLOH events in autosomal chromosomes, since the target is the very same chromosome instead of the homologous one.
During the mutation one of these copies overwrites the other. Thus the differences between the two are lost. Because differences are lost, heterozygosity is lost.
Recombination on the Y chromosome does not only take place during meiosis, but virtually at every mitosis when the Y chromosome condenses, because it doesn't require pairing between chromosomes. Recombination frequency even exceeds the frame shift mutation frequency (slipped strand mispairing) of (average fast) Y-STRs, however many recombination products may lead to infertile germ cells and "daughter out".
Recombination events (RecLOH) can be observed if YSTR databases are searched for twin alleles at 3 or more duplicated markers on the same palindrome (hairpin).
E.g. DYS459, DYS464 and DYS724 (CDY) are located on the same palindrome P1. A high proportion of 9-9, 15-15-17-17, 36-36 combinations and similar twin allelic patterns will be found. PCR typing technologies have been developed (e.g. DYS464X) that are able to verify that there are most frequently really two alleles of each, so we can be sure that there is no gene deletion. Family genealogies have proven many times, that parallel changes on all markers located on the same palindrome are frequently observed and the result of those changes are always twin alleles. So a 9-10, 15-16-17-17, 36-38 haplotype can change in one recombination event to the one mentioned above, because all three markers (DYS459, DYS464 and DYS724) are affected by one and the same recLOH event. | RecLOH
RecLOH is a term in genetics that is an abbreviation for "Recombinational Loss of Heterozygosity".
This is a type of mutation which occurs with DNA by recombination. From a pair of equivalent ("homologous"), but slightly different genes, a pair of identical genes results. In this case there is an unreciprocal exchange of genetic code between the chromosomes, in contrast to chromosomal crossover, because genetic information is lost.
# For Y chromosome
In genetic genealogy, the term is used particularly concerning similar seeming events in Y chromosome DNA. This type of mutation happens within one chromosome, and does not involve a reciprocal transfer. Rather, one homologous segment "writes over" the other. The mechanism is presumed to be different from RecLOH events in autosomal chromosomes, since the target is the very same chromosome instead of the homologous one.
During the mutation one of these copies overwrites the other. Thus the differences between the two are lost. Because differences are lost, heterozygosity is lost.
Recombination on the Y chromosome does not only take place during meiosis, but virtually at every mitosis when the Y chromosome condenses, because it doesn't require pairing between chromosomes. Recombination frequency even exceeds the frame shift mutation frequency (slipped strand mispairing) of (average fast) Y-STRs, however many recombination products may lead to infertile germ cells and "daughter out".
Recombination events (RecLOH) can be observed if YSTR databases are searched for twin alleles at 3 or more duplicated markers on the same palindrome (hairpin).
E.g. DYS459, DYS464 and DYS724 (CDY) are located on the same palindrome P1. A high proportion of 9-9, 15-15-17-17, 36-36 combinations and similar twin allelic patterns will be found. PCR typing technologies have been developed (e.g. DYS464X) that are able to verify that there are most frequently really two alleles of each, so we can be sure that there is no gene deletion. Family genealogies have proven many times, that parallel changes on all markers located on the same palindrome are frequently observed and the result of those changes are always twin alleles. So a 9-10, 15-16-17-17, 36-38 haplotype can change in one recombination event to the one mentioned above, because all three markers (DYS459, DYS464 and DYS724) are affected by one and the same recLOH event. | https://www.wikidoc.org/index.php/RecLOH | |
f728aad3ea127d9629955334927487934eaa1f96 | wikidoc | Rectal | Rectal
# Overview
The rectum (from the Latin rectum intestinum, meaning straight intestine) is the final straight portion of the large intestine in some mammals, and the gut in others, terminating in the anus. The human rectum is about 12 cm long. At its commencement its caliber is similar to that of the sigmoid colon, but near its termination it is dilated, forming the rectal ampulla.
# Role in human defecation
The rectum intestinum acts as a temporary storage facility for feces. As the rectal walls expand due to the materials filling it from within, stretch receptors from the nervous system located in the rectal walls stimulate the desire to defecate. If the urge is not acted upon, the material in the rectum is often returned to the colon where more water is absorbed. If defecation is delayed for a prolonged period, constipation and hardened feces results.
When the rectum becomes full the increase in intrarectal pressure forces the walls of the anal canal apart allowing the fecal matter to enter the canal. The rectum shortens as material is forced into the anal canal and peristaltic waves propel the feces out of the rectum. The internal and external sphincter allow the faeces to be passed by muscles pulling the anus up over the exiting feces.
# Medical procedures
For the diagnosis of certain ailments, a rectal exam may be done.
Suppositories may be inserted into the rectum as a route of administration for medicine.
The endoscopic procedures colonoscopy and sigmoidoscopy are performed to diagnose diseases such as cancer.
## Temperature taking
Body temperature can also be taken in the rectum. Rectal temperature can be taken by inserting a mercury thermometer for 3 to 5 minutes, or a digital thermometer until it "beeps", not more than 25 mm (1 inch) into the rectum via the anus. Due to recent concerns related to mercury poisoning, the use of mercury thermometers is now discouraged. Normal rectal temperature generally ranges from 36 to 38 °C (97.6 to 100.4 °F) and is about 0.5 °C (1 °F) above oral (mouth) temperature and about 1 °C (2 °F) above axillary (armpit) temperature.
Many pediatricians recommend that parents take infants and toddler's temperature in the rectum for two reasons:
- (1) Rectal temperature is the closest to core body temperature and in children that young, accuracy is critical.
- (2) Younger children are unable to cooperate when having their temperature taken by mouth (oral) which is recommended for children, ages 6 and above and for adults.
In recent years, the introduction of ear (tympanic) thermometers and changing attitudes on privacy and modesty have led some parents and doctors to discontinue taking rectal temperatures.
# Sexual stimulation
Due to the proximity of the anterior wall of the rectum to the vagina in females or to the prostate in males and the shared nerves thereof, rectal stimulation or penetration can result in sexual arousal. For further information on this aspect, see anal sex.
# Additional images
- Organs of the female reproductive system.
- Median sagittal section of pelvis, showing arrangement of fasciæ.
- The arteries of the pelvis.
- Section of mucous membrane of human rectum. X 60.
- The blood vessels of the rectum and anus.
- Median sagittal section of male pelvis.
- Median sagittal section of female pelvis.
- Sagittal section of the lower part of a female trunk, right segment.
- Error creating thumbnail: File missing
The rectum can be seen the left of this illustration.
- Cross section microscopic shot of the rectal wall. | Rectal
# Overview
Template:Infobox Anatomy
The rectum (from the Latin rectum intestinum, meaning straight intestine) is the final straight portion of the large intestine in some mammals, and the gut in others, terminating in the anus. The human rectum is about 12 cm long. At its commencement its caliber is similar to that of the sigmoid colon, but near its termination it is dilated, forming the rectal ampulla.
# Role in human defecation
The rectum intestinum acts as a temporary storage facility for feces. As the rectal walls expand due to the materials filling it from within, stretch receptors from the nervous system located in the rectal walls stimulate the desire to defecate. If the urge is not acted upon, the material in the rectum is often returned to the colon where more water is absorbed. If defecation is delayed for a prolonged period, constipation and hardened feces results.
When the rectum becomes full the increase in intrarectal pressure forces the walls of the anal canal apart allowing the fecal matter to enter the canal. The rectum shortens as material is forced into the anal canal and peristaltic waves propel the feces out of the rectum. The internal and external sphincter allow the faeces to be passed by muscles pulling the anus up over the exiting feces.
# Medical procedures
For the diagnosis of certain ailments, a rectal exam may be done.
Suppositories may be inserted into the rectum as a route of administration for medicine.
The endoscopic procedures colonoscopy and sigmoidoscopy are performed to diagnose diseases such as cancer.
## Temperature taking
Body temperature can also be taken in the rectum. Rectal temperature can be taken by inserting a mercury thermometer for 3 to 5 minutes, or a digital thermometer until it "beeps", not more than 25 mm (1 inch) into the rectum via the anus. Due to recent concerns related to mercury poisoning, the use of mercury thermometers is now discouraged. Normal rectal temperature generally ranges from 36 to 38 °C (97.6 to 100.4 °F) and is about 0.5 °C (1 °F) above oral (mouth) temperature and about 1 °C (2 °F) above axillary (armpit) temperature.
Many pediatricians recommend that parents take infants and toddler's temperature in the rectum for two reasons:
- (1) Rectal temperature is the closest to core body temperature and in children that young, accuracy is critical.
- (2) Younger children are unable to cooperate when having their temperature taken by mouth (oral) which is recommended for children, ages 6 and above and for adults.
In recent years, the introduction of ear (tympanic) thermometers and changing attitudes on privacy and modesty have led some parents and doctors to discontinue taking rectal temperatures.
# Sexual stimulation
Due to the proximity of the anterior wall of the rectum to the vagina in females or to the prostate in males and the shared nerves thereof, rectal stimulation or penetration can result in sexual arousal. For further information on this aspect, see anal sex.
# Additional images
- Organs of the female reproductive system.
- Median sagittal section of pelvis, showing arrangement of fasciæ.
- The arteries of the pelvis.
- Section of mucous membrane of human rectum. X 60.
- The blood vessels of the rectum and anus.
- Median sagittal section of male pelvis.
- Median sagittal section of female pelvis.
- Sagittal section of the lower part of a female trunk, right segment.
- Error creating thumbnail: File missing
The rectum can be seen the left of this illustration.
- Cross section microscopic shot of the rectal wall. | https://www.wikidoc.org/index.php/Rectal | |
e16a6e55985e61b23392984910ddef2809e74234 | wikidoc | Red 2G | Red 2G
Red 2G is a synthetic red azo dye. It is soluble in water and slightly soluble in ethanol. It usually comes as a disodium salt of 8-actamido-1-hydroxy-2-phenylazonaphthalene-3,6 disulphonate.
# Uses
## Food dye
In the European Union, Red 2G is used as a food dye (E number E128). However, it is only permitted for use in breakfast sausages with a minimum cereal content of 6% and burger meat with a minimum vegetable and/or cereal content of 4%.
Following safety concerns raised by EFSA in its opinion of 5 July 2007 , the European Commission has prepared a draft Regulation to suspend use of E128 as a food colouring. This proposed course of action was unanimously approved by European Union Member States at a meeting of the Standing Committee of the Food Chain and Animal Health (Section Toxicological Safety of the Food Chain) on 20 July 2007 .
Red 2G is banned in Australia, Austria, Canada, Japan, Norway, Sweden, Malaysia and the United States. It was banned in Ireland, Israel and Greece in July 2007. .
It is relatively insensitive to the bleaching effect of sulfur dioxide (E220) and sodium metabisulfite (E223). In the intestines, Red 2G can be converted to the toxic compound aniline , so there are concerns Red 2G may ultimately interfere with blood haemoglobin, as well as cause cancer.
## Inks
It is also used as a dye for coatings, inks, paper, crepe paper, and fine tissue.
## Histology
Red 2G can be also used for staining in histology, though rarely, e.g. as a component of Masson's trichrome.
# Health risks
It is one of the colourants that the Hyperactive Children's Support Group recommends be eliminated from the diet of children.
The EU agency EFSA recently established E128 is potentially is carcinogenic as it forms aniline in the body when consumed.
The pressure group The Food Commission, said there had been concerns about Red 2G going back decades and it was suspected of being a carcinogen in the 1980s | Red 2G
Template:Chembox new
Red 2G is a synthetic red azo dye. It is soluble in water and slightly soluble in ethanol. It usually comes as a disodium salt of 8-actamido-1-hydroxy-2-phenylazonaphthalene-3,6 disulphonate.
# Uses
## Food dye
In the European Union, Red 2G is used as a food dye (E number E128). However, it is only permitted for use in breakfast sausages with a minimum cereal content of 6% and burger meat with a minimum vegetable and/or cereal content of 4%. [1]
Following safety concerns raised by EFSA in its opinion of 5 July 2007 [2], the European Commission has prepared a draft Regulation to suspend use of E128 as a food colouring. This proposed course of action was unanimously approved by European Union Member States at a meeting of the Standing Committee of the Food Chain and Animal Health (Section Toxicological Safety of the Food Chain) on 20 July 2007 [3].
Red 2G is banned in Australia, Austria, Canada, Japan, Norway[4], Sweden, Malaysia[5] and the United States. It was banned in Ireland, Israel and Greece in July 2007. [6] [7].
It is relatively insensitive to the bleaching effect of sulfur dioxide (E220) and sodium metabisulfite (E223). In the intestines, Red 2G can be converted to the toxic compound aniline [8], so there are concerns Red 2G may ultimately interfere with blood haemoglobin, as well as cause cancer.
## Inks
It is also used as a dye for coatings, inks, paper, crepe paper, and fine tissue.
## Histology
Red 2G can be also used for staining in histology, though rarely, e.g. as a component of Masson's trichrome.
# Health risks
It is one of the colourants that the Hyperactive Children's Support Group recommends be eliminated from the diet of children.
The EU agency EFSA recently established E128 is potentially is carcinogenic as it forms aniline in the body when consumed.[9]
The pressure group The Food Commission, said there had been concerns about Red 2G going back decades and it was suspected of being a carcinogen in the 1980s[10] | https://www.wikidoc.org/index.php/Red_2G | |
b679b5d0fdd68201a5a422dd53d982ea606bbe76 | wikidoc | Reelin | Reelin
Reelin (RELN) is a large secreted extracellular matrix glycoprotein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell-cell interactions. Besides this important role in early development, reelin continues to work in the adult brain. It modulates synaptic plasticity by enhancing the induction and maintenance of long-term potentiation. It also stimulates dendrite and dendritic spine development and regulates the continuing migration of neuroblasts generated in adult neurogenesis sites like subventricular and subgranular zones. It is found not only in the brain, but also in the liver, thyroid gland, adrenal gland, Fallopian tube, breast, and in comparatively lower levels across a range of anatomical regions.
Reelin has been suggested to be implicated in pathogenesis of several brain diseases. The expression of the protein has been found to be significantly lower in schizophrenia and psychotic bipolar disorder, but the cause of this observation remains uncertain as studies show that psychotropic medication itself affects reelin expression. Moreover, epigenetic hypotheses aimed at explaining the changed levels of reelin expression are controversial. Total lack of reelin causes a form of lissencephaly. Reelin may also play a role in Alzheimer's disease, temporal lobe epilepsy and autism.
Reelin's name comes from the abnormal reeling gait of reeler mice, which were later found to have a deficiency of this brain protein and were homozygous for mutation of the RELN gene.
The primary phenotype associated with loss of reelin function is a failure of neuronal positioning throughout the developing central nervous system (CNS). The mice heterozygous for the reelin gene, while having little neuroanatomical defects, display the endophenotypic traits linked to psychotic disorders.
# Discovery
Mutant mice have provided insight into the underlying molecular mechanisms of the development of the central nervous system. Useful spontaneous mutations were first identified by scientists who were interested in motor behavior, and it proved relatively easy to screen littermates for mice that showed difficulties moving around the cage. A number of such mice were found and given descriptive names such as reeler, weaver, lurcher, nervous, and staggerer.
The "reeler" mouse was described for the first time in 1951 by D.S.Falconer in Edinburgh University as a spontaneous variant arising in a colony of mice maintained by geneticist Charlotte Auerbach. Histopathological studies in the 1960s revealed that the cerebellum of reeler mice is dramatically decreased in size while the normal laminar organization found in several brain regions is disrupted. The 1970s brought about the discovery of cellular layer inversion in the mouse neocortex, which attracted more attention to the reeler mutation.
In 1994, a new allele of reeler was obtained by means of insertional mutagenesis. This provided the first molecular marker of the locus, permitting the RELN gene to be mapped to chromosome 7q22 and subsequently cloned and identified. Japanese scientists at Kochi Medical School successfully raised antibodies against normal brain extracts in reeler mice, later these antibodies were found to be specific monoclonal antibodies for reelin, and were termed CR-50 (Cajal-Retzius marker 50). They noted that CR-50 reacted specifically with Cajal-Retzius neurons, whose functional role was unknown until then.
The Reelin receptors, apolipoprotein E receptor 2 (ApoER2) and very-low-density lipoprotein receptor (VLDLR), were discovered by Trommsdorff, Herz and colleagues, who initially found that the cytosolic adaptor protein Dab1 interacts with the cytoplasmic domain of LDL receptor family members. They then went on to show that the double knockout mice for ApoER2 and VLDLR, which both interact with Dab1, had cortical layering defects similar to those in reeler.
The downstream pathway of reelin was further clarified with the help of other mutant mice, including yotari and scrambler. These mutants have phenotypes similar to that of reeler mice, but without mutation in reelin. It was then demonstrated that the mouse disabled homologue 1 (Dab1) gene is responsible for the phenotypes of these mutant mice, as Dab1 protein was absent (yotari) or only barely detectable (scrambler) in these mutants. Targeted disruption of Dab1 also caused a phenotype similar to that of reeler. Pinpointing the DAB1 as a pivotal regulator of the reelin signaling cascade started the tedious process of deciphering its complex interactions.
There followed a series of speculative reports linking reelin's genetic variation and interactions to schizophrenia, Alzheimer's disease, autism and other highly complex dysfunctions. These and other discoveries, coupled with the perspective of unraveling the evolutionary changes that allowed for the creation of human brain, highly intensified the research. As of 2008, some 13 years after the gene coding the protein was discovered, hundreds of scientific articles address the multiple aspects of its structure and functioning.
# Tissue distribution and secretion
Studies show that reelin is absent from synaptic vesicles and is secreted via constitutive secretory pathway, being stored in Golgi secretory vesicles. Reelin's release rate is not regulated by depolarization, but strictly depends on its synthesis rate. This relationship is similar to that reported for the secretion of other extracellular matrix proteins.
During the brain development, reelin is secreted in the cortex and hippocampus by the so-called Cajal-Retzius cells, Cajal cells, and Retzius cells. Reelin-expressing cells in the prenatal and early postnatal brain are predominantly found in the marginal zone (MZ) of the cortex and in the temporary subpial granular layer (SGL), which is manifested to the highest extent in human, and in the hippocampal stratum lacunosum-moleculare and the upper marginal layer of the dentate gyrus.
In the developing cerebellum, reelin is expressed first in the external granule cell layer (EGL), before the granule cell migration to the internal granule cell layer (IGL) takes place.
Having peaked just after the birth, the synthesis of reelin subsequently goes down sharply, becoming more diffuse compared with the distinctly laminar expression in the developing brain. In the adult brain, reelin is expressed by GABA-ergic interneurons of the cortex and glutamatergic cerebellar neurons, and by the few extant Cajal-Retzius cells. Among GABAergic interneurons, reelin seems to be detected predominantly in those expressing calretinin and calbindin, like bitufted, horizontal, and Martinotti cells, but not parvalbumin-expressing cells, like chandelier or basket neurons. In the white matter, a minute proportion of interstitial neurons has also been found to stain positive for reelin expression.
Outside the brain, reelin is found in adult mammalian blood, liver, pituitary pars intermedia, and adrenal chromaffin cells. In the liver, reelin is localized in hepatic stellate cells. The expression of reelin increases when the liver is damaged, and returns to normal following its repair.
In the eyes, reelin is secreted by retinal ganglion cells and is also found in the endothelial layer of the cornea. Just as in the liver, its expression increases after an injury has taken place.
The protein is also produced by the odontoblasts, which are cells at the margins of the dental pulp. Reelin is found here both during odontogenesis and in the mature tooth. Some authors suggest that odontoblasts play an additional role as sensory cells able to transduce pain signals to the nerve endings. According to the hypothesis, reelin participates in the process by enhancing the contact between odontoblasts and the nerve terminals.
# Structure
Reelin is composed of 3461 amino acids with a relative molecular mass of 388 kDa. It also has serine protease activity. Murine RELN gene consists of 65 exons spanning approximately 450 kb. One exon, coding for only two amino acids near the protein's C-terminus, undergoes alternative splicing, but the exact functional impact of this is unknown. Two transcription initiation sites and two polyadenylation sites are identified in the gene structure.
The reelin protein starts with a signaling peptide 27 amino acids in length, followed by a region bearing similarity to F-spondin (the reeler domain), marked as "SP" on the scheme, and by a region unique to reelin, marked as "H". Next comes 8 repeats of 300–350 amino acids. These are called reelin repeats and have an epidermal growth factor motif at their center, dividing each repeat into two subrepeats, A (the BNR/Asp-box repeat) and B (the EGF-like domain). Despite this interruption, the two subdomains make direct contact, resulting in a compact overall structure.
The final reelin domain contains a highly basic and short C-terminal region (CTR, marked "+") with a length of 32 amino acids. This region is highly conserved, being 100% identical in all investigated mammals. It was thought that CTR is necessary for reelin secretion, because the Orleans reeler mutation, which lacks a part of 8th repeat and the whole CTR, is unable to secrete the misshaped protein, leading to its concentration in cytoplasm. However, other studies have shown that the CTR is not essential for secretion itself, but mutants lacking the CTR were much less efficient in activating downstream signaling events.
Reelin is cleaved in vivo at two sites located after domains 2 and 6 – approximately between repeats 2 and 3 and between repeats 6 and 7, resulting in the production of three fragments. This splitting does not decrease the protein's activity, as constructs made of the predicted central fragments (repeats 3–6) bind to lipoprotein receptors, trigger Dab1 phosphorylation and mimic functions of reelin during cortical plate development. Moreover, the processing of reelin by embryonic neurons may be necessary for proper corticogenesis.
# Function
The primary functions of Reelin are the regulation of corticogenesis and neuronal cell positioning in the prenatal period, but the protein also continues to play a role in adults. Reelin is found in numerous tissues and organs, and one could roughly subdivide its functional roles by the time of expression and by localisation of its action.
## During development
A number of non-nervous tissues and organs express reelin during development, with the expression sharply going down after organs have been formed. The role of the protein here is largely unexplored, because the knockout mice show no major pathology in these organs. Reelin's role in the growing central nervous system has been extensively characterized. It promotes the differentiation of progenitor cells into radial glia and affects the orientation of its fibers, which serve as the guides for the migrating neuroblasts. The position of reelin-secreting cell layer is important, because the fibers orient themselves in the direction of its higher concentration. For example, reelin regulates the development of layer-specific connections in hippocampus and entorhinal cortex.
Mammalian corticogenesis is another process where reelin plays a major role. In this process the temporary layer called preplate is split into the marginal zone on the top and subplate below, and the space between them is populated by neuronal layers in the inside-out pattern. Such an arrangement, where the newly created neurons pass through the settled layers and position themselves one step above, is a distinguishing feature of mammalian brain, in contrast to the evolutionary older reptile cortex, in which layers are positioned in an "outside-in" fashion. When reelin is absent, like in the mutant reeler mouse, the order of cortical layering becomes roughly inverted, with younger neurons finding themselves to be unable to pass the settled layers. Subplate neurons fail to stop and invade the upper most layer, creating the so-called superplate in which they mix with Cajal-Retzius cells and some cells normally destined for the second layer.
There is no agreement concerning the role of reelin in the proper positioning of cortical layers. The original hypothesis, that the protein is a stop signal for the migrating cells, is supported by its ability to induce the dissociation, its role in asserting the compact granule cell layer in the hippocampus, and by the fact that migrating neuroblasts evade the reelin-rich areas. But an experiment in which murine corticogenesis went normally despite the malpositioned reelin secreting layer, and lack of evidence that reelin affects the growth cones and leading edges of neurons, caused some additional hypotheses to be proposed. According to one of them, reelin makes the cells more susceptible to some yet undescribed positional signaling cascade.
Reelin may also ensure correct neuronal positioning in the spinal cord: according to one study, location and level of its expression affects the movement of sympathetic preganglionic neurons.
The protein is thought to act on migrating neuronal precursors and thus controls correct cell positioning in the cortex and other brain structures. The proposed role is one of a dissociation signal for neuronal groups, allowing them to separate and go from tangential chain-migration to radial individual migration. Dissociation detaches migrating neurons from the glial cells that are acting as their guides, converting them into individual cells that can strike out alone to find their final position.
Reelin takes part in the developmental change of NMDA receptor configuration, increasing mobility of NR2B-containing receptors and thus decreasing the time they spend at the synapse. It has been hypothesized that this may be a part of the mechanism behind the "NR2B-NR2A switch" that is observed in the brain during its postnatal development. Ongoing reelin secretion by GABAergic hippocampal neurons is necessary to keep NR2B-containing NMDA receptors at a low level.
## In adults
In the adult nervous system, reelin plays an eminent role at the two most active neurogenesis sites, the subventricular zone and the dentate gyrus. In some species, the neuroblasts from the subventricular zone migrate in chains in the rostral migratory stream (RMS) to reach the olfactory bulb, where reelin dissociates them into individual cells that are able to migrate further individually. They change their mode of migration from tangential to radial, and begin using the radial glia fibers as their guides. There are studies showing that along the RMS itself the two receptors, ApoER2 and VLDLR, and their intracellular adapter DAB1 function independently of Reelin, most likely by the influence of a newly proposed ligand, thrombospondin-1. In the adult dentate gyrus, reelin provides guidance cues for new neurons that are constantly arriving to the granule cell layer from subgranular zone, keeping the layer compact.
Reelin also plays an important role in the adult brain by modulating cortical pyramidal neuron dendritic spine expression density, the branching of dendrites, and the expression of long-term potentiation as its secretion is continued diffusely by the GABAergic cortical interneurons those origin is traced to the medial ganglionic eminence.
In the adult organism the non-neural expression is much less widespread, but goes up sharply when some organs are injured. The exact function of reelin upregulation following an injury is still being researched.
# Evolutionary significance
Reelin-DAB1 interactions could have played a key role in the structural evolution of the cortex that evolved from a single layer in the common predecessor of the amniotes into multiple-layered cortex of contemporary mammals. Research shows that reelin expression goes up as the cortex becomes more complex, reaching the maximum in the human brain in which the reelin-secreting Cajal-Retzius cells have significantly more complex axonal arbour. Reelin is present in the telencephalon of all the vertebrates studied so far, but the pattern of expression differs widely. For example, zebrafish have no Cajal-Retzius cells at all; instead, the protein is being secreted by other neurons. These cells do not form a dedicated layer in amphibians, and radial migration in their brains is very weak.
As the cortex becomes more complex and convoluted, migration along the radial glia fibers becomes more important for the proper lamination. The emergence of a distinct reelin-secreting layer is thought to play an important role in this evolution. There are conflicting data concerning the importance of this layer, and these are explained in the literature either by the existence of an additional signaling positional mechanism that interacts with the reelin cascade, or by the assumption that mice that are used in such experiments have redundant secretion of reelin compared with more localized synthesis in the human brain.
Cajal-Retzius cells, most of which disappear around the time of birth, coexpress reelin with the HAR1 gene that is thought to have undergone the most significant evolutionary change in humans compared with chimpanzee, being the most "evolutionary accelerated" of the genes from the human accelerated regions. There is also evidence of that variants in the DAB1 gene have been included in a recent selective sweep in Chinese populations.
# Mechanism of action
## Receptors
Reelin's control of cell-cell interactions is thought to be mediated by binding of reelin to the two members of low density lipoprotein receptor gene family: VLDLR and the ApoER2. The two main reelin receptors seem to have slightly different roles: VLDLR conducts the stop signal, while ApoER2 is essential for the migration of late-born neocortical neurons. It also has been shown that the N-terminal region of reelin, a site distinct from the region of reelin shown to associate with VLDLR/ApoER2 binds to the alpha-3-beta-1 integrin receptor. The proposal that the protocadherin CNR1 behaves as a Reelin receptor has been disproven.
As members of lipoprotein receptor superfamily, both VLDLR and ApoER2 have in their structure an internalization domain called NPxY motif. After binding to the receptors reelin is internalized by endocytosis, and the N-terminal fragment of the protein is re-secreted. This fragment may serve postnatally to prevent apical dendrites of cortical layer II/III pyramidal neurons from overgrowth, acting via a pathway independent of canonical reelin receptors.
Reelin receptors are present on both neurons and glial cells. Furthermore, radial glia express the same amount of ApoER2 but being ten times less rich in VLDLR. beta-1 integrin receptors on glial cells play more important role in neuronal layering than the same receptors on the migrating neuroblasts.
Reelin-dependent strengthening of long-term potentiation is caused by ApoER2 interaction with NMDA receptor. This interaction happens when ApoER2 has a region coded by exon 19. ApoER2 gene is alternatively spliced, with the exon 19-containing variant more actively produced during periods of activity. According to one study, the hippocampal reelin expression rapidly goes up when there is need to store a memory, as demethylases open up the RELN gene. The activation of dendrite growth by reelin is apparently conducted through Src family kinases and is dependent upon the expression of Crk family proteins, consistent with the interaction of Crk and CrkL with tyrosine-phosphorylated Dab1. Moreover, a Cre-loxP recombination mouse model that lacks Crk and CrkL in most neurons was reported to have the reeler phenotype, indicating that Crk/CrkL lie between DAB1 and Akt in the reelin signaling chain.
## Signaling cascades
Reelin activates the signaling cascade of Notch-1, inducing the expression of FABP7 and prompting progenitor cells to assume radial glial phenotype. In addition, corticogenesis in vivo is highly dependent upon reelin being processed by embrionic neurons, which are thought to secrete some as yet unidentified metalloproteinases that free the central signal-competent part of the protein. Some other unknown proteolytic mechanisms may also play a role. It is supposed that full-sized reelin sticks to the extracellular matrix fibers on the higher levels, and the central fragments, as they are being freed up by the breaking up of reelin, are able to permeate into the lower levels. It is possible that as neuroblasts reach the higher levels they stop their migration either because of the heightened combined expression of all forms of reelin, or due to the peculiar mode of action of the full-sized reelin molecules and its homodimers.
The intracellular adaptor DAB1 binds to the VLDLR and ApoER2 through an NPxY motif and is involved in transmission of Reelin signals through these lipoprotein receptors. It becomes phosphorylated by Src and Fyn kinases and apparently stimulates the actin cytoskeleton to change its shape, affecting the proportion of integrin receptors on the cell surface, which leads to the change in adhesion. Phosphorylation of DAB1 leads to its ubiquitination and subsequent degradation, and this explains the heightened levels of DAB1 in the absence of reelin. Such negative feedback is thought to be important for proper cortical lamination. Activated by two antibodies, VLDLR and ApoER2 cause DAB1 phosphorylation but seemingly without the subsequent degradation and without rescuing the reeler phenotype, and this may indicate that a part of the signal is conducted independently of DAB1.
A protein having an important role in lissencephaly and accordingly called LIS1 (PAFAH1B1), was shown to interact with the intracellular segment of VLDLR, thus reacting to the activation of reelin pathway.
## Complexes
Reelin molecules have been shown to form a large protein complex, a disulfide-linked homodimer. If the homodimer fails to form, efficient tyrosine phosphorylation of DAB1 in vitro fails. Moreover, the two main receptors of reelin are able to form clusters that most probably play a major role in the signaling, causing the intracellular adaptor DAB1 to dimerize or oligomerize in its turn. Such clustering has been shown in the study to activate the signaling chain even in the absence of Reelin itself. In addition, reelin itself can cut the peptide bonds holding other proteins together, being a serine protease, and this may affect the cellular adhesion and migration processes. Reelin signaling leads to phosphorylation of actin-interacting protein cofilin 1 at ser3; this may stabilize the actin cytoskeleton and anchor the leading processes of migrating neuroblasts, preventing their further growth.
## Interaction with Cdk5
Cyclin-dependent kinase 5 (Cdk5), a major regulator of neuronal migration and positioning, is known to phosphorylate DAB1 and other cytosolic targets of reelin signaling, such as Tau, which could be activated also via reelin-induced deactivation of GSK3B, and NUDEL, associated with Lis1, one of the DAB1 targets. LTP induction by reelin in hippocampal slices fails in p35 knockouts. P35 is a key Cdk5 activator, and double p35/Dab1, p35/RELN, p35/ApoER2, p35/VLDLR knockouts display increased neuronal migration deficits, indicating a synergistic action of reelin → ApoER2/VLDLR → DAB1 and p35/p39 → Cdk5 pathways in the normal corticogenesis.
# Possible pathological role
## Lissencephaly/Microlissencephaly
Disruptions of the RELN gene are considered to be the cause of the rare form of lissencephaly with cerebellar hypoplasia called Norman-Roberts syndrome. The mutations disrupt splicing of the RELN mRNA transcript, resulting in low or undetectable amounts of reelin protein. The phenotype in these patients was characterized by hypotonia, ataxia, and developmental delay, with lack of unsupported sitting and profound mental retardation with little or no language development. Seizures and congenital lymphedema are also present. A novel chromosomal translocation causing the syndrome was described in 2007. The mutations affecting reelin in human are usually associated with consanguineous marriage.
## Schizophrenia
Reduced expression of reelin and its mRNA levels in the brains of schizophrenia sufferers had been reported in 1998 and 2000 and independently confirmed in the postmortem studies of hippocampus, cerebellum, basal ganglia, and in the cortex studies. The reduction may reach up to 50% in some brain regions and is coupled with reduced expression of GAD-67 enzyme, which catalyses the transition of glutamate to GABA. Blood levels of reelin and its isoforms are also altered in schizophrenia, along with mood disorders, according to one study. Reduced reelin mRNA prefrontal expression in schizophrenia was found to be the most statistically relevant disturbance found in the multicenter study conducted in 14 separate laboratories in 2001 by Stanley Foundation Neuropathology Consortium.
Epigenetic hypermethylation of DNA in schizophrenia patients is proposed as a cause of the reduction, in agreement with the observations dating from the 1960s that administration of methionine to schizophrenic patients results in a profound exacerbation of schizophrenia symptoms in sixty to seventy percent of patients. The proposed mechanism is a part of the "epigenetic hypothesis for schizophrenia pathophysiology" formulated by a group of scientists in 2008 (D. Grayson; A. Guidotti; E. Costa). A postmortem study comparing a DNA methyltransferase (DNMT1) and Reelin mRNA expression in cortical layers I and V of schizophrenic patients and normal controls demonstrated that in the layer V both DNMT1 and Reelin levels were normal, while in the layer I DNMT1 was threefold higher, probably leading to the twofold decrease in the Reelin expression. There is evidence that the change is selective, and DNMT1 is overexpressed in reelin-secreting GABAergic neurons but not in their glutamatergic neighbours. Methylation inhibitors and histone deacetylase inhibitors, such as valproic acid, increase reelin mRNA levels, while L-methionine treatment downregulates the phenotypic expression of reelin. One study indicated the upregulation of histone deacetylase HDAC1 in the hippocampi of patients. Histone deacetylases suppress gene promoters; hyperacetylation of hystones was shown in murine models to demethylate the promoters of both reelin and GAD67. DNMT1 inhibitors in animals have been shown to increase the expression of both reelin and GAD67, and both DNMT inhibitors and HDAC inhibitors shown in one study to activate both genes with comparable dose- and time-dependence. As one study shows, S-adenosyl methionine (SAM) concentration in patients' prefrontal cortex is twice as high as in the cortices of non-affected people. SAM, being a methyl group donor necessary for DNMT activity, could further shift epigenetic control of gene expression.
The factors mentioned above serve to corroborate the epigenetic hypothesis. But it is worth mentioning that in contrast with initial data, two recent studies have failed to confirm the RELN hypermethylation, and psychotropic medication could in itself affect the reelin expression in the brain, as animal studies show (see below).
Other interesting findings probably linking reelin pathway to developmental hypotheses of schizophrenia are noted in the studies on mice that are either prenatally infected with influenza virus or have their immune system activated artificially during pregnancy. The Cajal-Retzius cells in the newborns secrete significantly less reelin despite keeping their expression of calretinin and nNos within normal range. These data run in parallel with the findings of increased risk of schizophrenia in humans after a prenatal infection during the second trimester.
Chromosome region 7q22 that harbours the RELN gene is associated with schizophrenia, and the gene itself was associated with the disease in a large study that found the polymorphism rs7341475 to increase the risk of the disease in women, but not in men. The women that have the single-nucleotide polymorphism (SNP) are about 1.4 times more likely to get ill, according to the study. Allelic variations of RELN have also been correlated with working memory, memory and executive functioning in nuclear families where one of the members suffers from schizophrenia. The association with working memory was later replicated. In one small study, nonsynonymous polymorphism Val997Leu of the gene was associated with left and right ventricular enlargement in patients.
One study showed that patients have decreased levels of one of reelin receptors, VLDLR, in the peripheral lymphocytes. After six months of antipsychotic therapy the expression went up; according to authors, peripheral VLRLR levels may serve as a reliable peripheral biomarker of schizophrenia.
Considering the role of reelin in promoting dendritogenesis, suggestions were made that the localized dendritic spine deficit observed in schizophrenia could be in part connected with the downregulation of reelin.
Reelin pathway could also be linked to schizophrenia and other psychotic disorders through its interaction with risk genes. One example is the neuronal transcription factor NPAS3, disruption of which is linked to schizophrenia and learning disability. Knockout mice lacking NPAS3 or the similar protein NPAS1 have significantly lower levels of reelin; the precise mechanism behind this is unknown. Another example is the schizophrenia-linked gene MTHFR, with murine knockouts showing decreased levels of reelin in the cerebellum. Along the same line, it is worth noting that the gene coding for the subunit NR2B that is presumably affected by reelin in the process of NR2B->NR2A developmental change of NMDA receptor composition, stands as one of the strongest risk gene candidates. Another shared aspect between NR2B and RELN is that they both can be regulated by the TBR1 transcription factor.
The heterozygous reeler mouse, which is haploinsufficient for the RELN gene, shares several neurochemical and behavioral abnormalities with schizophrenia and bipolar disorder, but the exact relevance of these murine behavioral changes to the pathophysiology of schizophrenia remains debatable.
As previously described, reelin plays a crucial role in modulating early neuroblast migration during brain development. Evidences of altered neural cell positioning in post-mortem schizophrenia patient brains and changes to gene regulatory networks that control cell migration suggests a potential link between altered reelin expression in patient brain tissue to disrupted cell migration during brain development. To model the role of reelin in the context of schizophrenia at a cellular level, olfactory neurosphere-derived cells were generated from the nasal biopsies of schizophrenia patients, and compared to cells from healthy controls. Schizophrenia patient-derived cells have reduced levels of reelin mRNA and protein when compared to healthy control cells, but expresses the key reelin receptors and DAB1 accessory protein. When grown in vitro, schizophrenia patient-derived cells were unable to respond to reelin coated onto tissue culture surfaces; In contrast, cells derived from healthy controls were able to alter their cell migration when exposed to reelin. This work went on to show that the lack of cell migration response in patient-derived cells were caused by the cell's inability to produce enough focal adhesions of the appropriate size when in contact with extracellular reelin. More research into schizophrenia cell-based models are needed to look at the function of reelin, or lack of, in the pathophysiology of schizophrenia.
## Bipolar disorder
Decrease in RELN expression with concurrent upregulation of DNMT1 is typical of bipolar disorder with psychosis, but is not characteristic of patients with major depression without psychosis, which could speak of specific association of the change with psychoses. One study suggests that unlike in schizophrenia, such changes are found only in the cortex and do not affect the deeper structures in psychotic bipolar patients, as their basal ganglia were found to have the normal levels of DNMT1 and subsequently both the reelin and GAD67 levels were within the normal range.
In a genetic study conducted in 2009, preliminary evidence requiring further DNA replication suggested that variation of the RELN gene (SNP rs362719) may be associated with susceptibility to bipolar disorder in women.
## Autism
Autism is a neurodevelopmental disorder that is generally believed to be caused by mutations in several locations, likely triggered by environmental factors. The role of reelin in autism is not decided yet.
Reelin was originally in 2001 implicated in a study finding associations between autism and a polymorphic GGC/CGG repeat preceding the 5' ATG initiator codon of the RELN gene in an Italian population. Longer triplet repeats in the 5’ region were associated with an increase in autism susceptibility. However, another study of 125 multiple-incidence families and 68 single-incidence families from the subsequent year found no significant difference between the length of the polymorphic repeats in affected and controls. Although, using a family based association test larger reelin alleles were found to be transmitted more frequently than expected to affected children. An additional study examining 158 subjects with German lineage likewise found no evidence of triplet repeat polymorphisms associated with autism. And a larger study from 2004 consisting of 395 families found no association between autistic subjects and the CGG triplet repeat as well as the allele size when compared to age of first word.
In 2010 a large study using data from 4 European cohorts would find some evidence for an association between autism and the rs362780 RELN polymorphism.
Studies of transgenic mice have been suggestive of an association, but not definitive.
## Temporal lobe epilepsy: granule cell dispersion
Decreased reelin expression in the hippocampal tissue samples from patients with temporal lobe epilepsy was found to be directly correlated with the extent of granule cell dispersion (GCD), a major feature of the disease that is noted in 45%–73% of patients. The dispersion, according to a small study, is associated with the RELN promoter hypermethylation. According to one study, prolonged seizures in a rat model of mesial temporal lobe epilepsy have led to the loss of reelin-expressing interneurons and subsequent ectopic chain migration and aberrant integration of newborn dentate granule cells. Without reelin, the chain-migrating neuroblasts failed to detach properly. Moreover, in a kainate-induced mouse epilepsy model, exogenous reelin had prevented GCD, according to one study.
## Alzheimer's disease
The Reelin receptors ApoER2 and VLDLR belong to the LDL receptor gene family. All members of this family are receptors for Apolipoprotein E (ApoE). Therefore, they are often synonymously referred to as 'ApoE receptors'. ApoE occurs in 3 common isoforms (E2, E3, E4) in the human population. ApoE4 is the primary genetic risk factor for late-onset Alzheimer's disease. This strong genetic association has led to the proposal that ApoE receptors play a central role in the pathogenesis of Alzheimer's Disease. According to one study, reelin expression and glycosylation patterns are altered in Alzheimer's disease. In the cortex of the patients, reelin levels were 40% higher compared with controls, but the cerebellar levels of the protein remain normal in the same patients. This finding is in agreement with an earlier study showing the presence of Reelin associated with amyloid plaques in a transgenic AD mouse model. A large genetic study of 2008 showed that RELN gene variation is associated with an increased risk of Alzheimer's disease in women. The number of reelin-producing Cajal-Retzius cells is significantly decreased in the first cortical layer of patients. Reelin has been shown to interact with amyloid precursor protein, and, according to one in-vitro study, is able to counteract the Aβ-induced dampening of NMDA-receptor activity. This is modulated by ApoE isoforms, which selectively alter the recycling of ApoER2 as well as AMPA and NMDA receptors.
## Cancer
DNA methylation patterns are often changed in tumours, and the RELN gene could be affected: according to one study, in the pancreatic cancer the expression is suppressed, along with other reelin pathway components In the same study, cutting the reelin pathway in cancer cells that still expressed reelin resulted in increased motility and invasiveness. On the contrary, in prostate cancer the RELN expression is excessive and correlates with Gleason score. Retinoblastoma presents another example of RELN overexpression. This gene has also been seen recurrently mutated in cases of acute lymphoblastic leukaemia.
## Other conditions
One genome-wide association study indicates a possible role for RELN gene variation in otosclerosis, an abnormal growth of bone of the middle ear. In a statistical search for the genes that are differentially expressed in the brains of cerebral malaria-resistant versus cerebral malaria-susceptible mice, Delahaye et al. detected a significant upregulation of both RELN and DAB1 and speculated on possible protective effects of such over-expression.
# Factors affecting reelin expression
The expression of reelin is controlled by a number of factors besides the sheer number of Cajal-Retzius cells. For example, TBR1 transcription factor regulates RELN along with other T-element-containing genes. On a higher level, increased maternal care was found to correlate with reelin expression in rat pups; such correlation was reported in hippocampus and in the cortex. According to one report, prolonged exposure to corticosterone significantly decreased reelin expression in murine hippocampi, a finding possibly pertinent to the hypothetical role of corticosteroids in depression. One small postmortem study has found increased methylation of RELN gene in the neocortex of persons past their puberty compared with those that had yet to enter the period of maturation.
## Psychotropic medication
As reelin is being implicated in a number of brain disorders and its expression is usually measured posthumously, assessing the possible medication effects is important.
According to the epigenetic hypothesis, drugs that shift the balance in favour of demethylation have a potential to alleviate the proposed methylation-caused downregulation of RELN and GAD67. In one study, clozapine and sulpiride but not haloperidol and olanzapine were shown to increase the demethylation of both genes in mice pretreated with l-methionine. Valproic acid, a histone deacetylase inhibitor, when taken in combination with antipsychotics, is proposed to have some benefits. But there are studies conflicting the main premise of the epigenetic hypothesis, and a study by Fatemi et al. shows no increase in RELN expression by valproic acid; that indicates the need for further investigation.
Fatemi et al. conducted the study in which RELN mRNA and reelin protein levels were measured in rat prefrontal cortex following a 21-day of intraperitoneal injections of the following drugs:
In 2009, Fatemi et al. published the more detailed work on rats using the same medication. Here, cortical expression of several participants (VLDLR, DAB1, GSK3B) of the signaling chain was measured besides reelin itself, and also the expression of GAD65 and GAD67. | Reelin
Reelin (RELN)[1] is a large secreted extracellular matrix glycoprotein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell-cell interactions. Besides this important role in early development, reelin continues to work in the adult brain.[2] It modulates synaptic plasticity by enhancing the induction and maintenance of long-term potentiation.[3][4] It also stimulates dendrite[5] and dendritic spine[6] development and regulates the continuing migration of neuroblasts generated in adult neurogenesis sites like subventricular and subgranular zones. It is found not only in the brain, but also in the liver, thyroid gland, adrenal gland, Fallopian tube, breast, and in comparatively lower levels across a range of anatomical regions.[7]
Reelin has been suggested to be implicated in pathogenesis of several brain diseases. The expression of the protein has been found to be significantly lower in schizophrenia and psychotic bipolar disorder,[8] but the cause of this observation remains uncertain as studies show that psychotropic medication itself affects reelin expression. Moreover, epigenetic hypotheses aimed at explaining the changed levels of reelin expression[9] are controversial.[10][11] Total lack of reelin causes a form of lissencephaly. Reelin may also play a role in Alzheimer's disease, temporal lobe epilepsy and autism.[citation needed]
Reelin's name comes from the abnormal reeling gait of reeler mice,[12] which were later found to have a deficiency of this brain protein and were homozygous for mutation of the RELN gene.
The primary phenotype associated with loss of reelin function is a failure of neuronal positioning throughout the developing central nervous system (CNS). The mice heterozygous for the reelin gene, while having little neuroanatomical defects, display the endophenotypic traits linked to psychotic disorders.[13]
# Discovery
Mutant mice have provided insight into the underlying molecular mechanisms of the development of the central nervous system. Useful spontaneous mutations were first identified by scientists who were interested in motor behavior, and it proved relatively easy to screen littermates for mice that showed difficulties moving around the cage. A number of such mice were found and given descriptive names such as reeler, weaver, lurcher, nervous, and staggerer.[citation needed]
The "reeler" mouse was described for the first time in 1951 by D.S.Falconer in Edinburgh University as a spontaneous variant arising in a colony of mice maintained by geneticist Charlotte Auerbach.[12] Histopathological studies in the 1960s revealed that the cerebellum of reeler mice is dramatically decreased in size while the normal laminar organization found in several brain regions is disrupted.[14] The 1970s brought about the discovery of cellular layer inversion in the mouse neocortex,[15] which attracted more attention to the reeler mutation.
In 1994, a new allele of reeler was obtained by means of insertional mutagenesis.[16] This provided the first molecular marker of the locus, permitting the RELN gene to be mapped to chromosome 7q22 and subsequently cloned and identified.[17] Japanese scientists at Kochi Medical School successfully raised antibodies against normal brain extracts in reeler mice, later these antibodies were found to be specific monoclonal antibodies for reelin, and were termed CR-50 (Cajal-Retzius marker 50).[18] They noted that CR-50 reacted specifically with Cajal-Retzius neurons, whose functional role was unknown until then.[citation needed]
The Reelin receptors, apolipoprotein E receptor 2 (ApoER2) and very-low-density lipoprotein receptor (VLDLR), were discovered by Trommsdorff, Herz and colleagues, who initially found that the cytosolic adaptor protein Dab1 interacts with the cytoplasmic domain of LDL receptor family members.[19] They then went on to show that the double knockout mice for ApoER2 and VLDLR, which both interact with Dab1, had cortical layering defects similar to those in reeler.[20]
The downstream pathway of reelin was further clarified with the help of other mutant mice, including yotari and scrambler. These mutants have phenotypes similar to that of reeler mice, but without mutation in reelin. It was then demonstrated that the mouse disabled homologue 1 (Dab1) gene is responsible for the phenotypes of these mutant mice, as Dab1 protein was absent (yotari) or only barely detectable (scrambler) in these mutants.[21] Targeted disruption of Dab1 also caused a phenotype similar to that of reeler. Pinpointing the DAB1 as a pivotal regulator of the reelin signaling cascade started the tedious process of deciphering its complex interactions.[citation needed]
There followed a series of speculative reports linking reelin's genetic variation and interactions to schizophrenia, Alzheimer's disease, autism and other highly complex dysfunctions. These and other discoveries, coupled with the perspective of unraveling the evolutionary changes that allowed for the creation of human brain, highly intensified the research. As of 2008, some 13 years after the gene coding the protein was discovered, hundreds of scientific articles address the multiple aspects of its structure and functioning.[22][23]
# Tissue distribution and secretion
Studies show that reelin is absent from synaptic vesicles and is secreted via constitutive secretory pathway, being stored in Golgi secretory vesicles.[24] Reelin's release rate is not regulated by depolarization, but strictly depends on its synthesis rate. This relationship is similar to that reported for the secretion of other extracellular matrix proteins.[citation needed]
During the brain development, reelin is secreted in the cortex and hippocampus by the so-called Cajal-Retzius cells, Cajal cells, and Retzius cells.[25] Reelin-expressing cells in the prenatal and early postnatal brain are predominantly found in the marginal zone (MZ) of the cortex and in the temporary subpial granular layer (SGL), which is manifested to the highest extent in human,[26] and in the hippocampal stratum lacunosum-moleculare and the upper marginal layer of the dentate gyrus.
In the developing cerebellum, reelin is expressed first in the external granule cell layer (EGL), before the granule cell migration to the internal granule cell layer (IGL) takes place.[27]
Having peaked just after the birth, the synthesis of reelin subsequently goes down sharply, becoming more diffuse compared with the distinctly laminar expression in the developing brain. In the adult brain, reelin is expressed by GABA-ergic interneurons of the cortex and glutamatergic cerebellar neurons,[28] and by the few extant Cajal-Retzius cells. Among GABAergic interneurons, reelin seems to be detected predominantly in those expressing calretinin and calbindin, like bitufted, horizontal, and Martinotti cells, but not parvalbumin-expressing cells, like chandelier or basket neurons.[29][30] In the white matter, a minute proportion of interstitial neurons has also been found to stain positive for reelin expression.[31]
Outside the brain, reelin is found in adult mammalian blood, liver, pituitary pars intermedia, and adrenal chromaffin cells.[32] In the liver, reelin is localized in hepatic stellate cells.[33] The expression of reelin increases when the liver is damaged, and returns to normal following its repair.[34]
In the eyes, reelin is secreted by retinal ganglion cells and is also found in the endothelial layer of the cornea.[35] Just as in the liver, its expression increases after an injury has taken place.[citation needed]
The protein is also produced by the odontoblasts, which are cells at the margins of the dental pulp. Reelin is found here both during odontogenesis and in the mature tooth.[36] Some authors suggest that odontoblasts play an additional role as sensory cells able to transduce pain signals to the nerve endings.[37] According to the hypothesis, reelin participates in the process[23] by enhancing the contact between odontoblasts and the nerve terminals.[38]
# Structure
Reelin is composed of 3461 amino acids with a relative molecular mass of 388 kDa. It also has serine protease activity.[40] Murine RELN gene consists of 65 exons spanning approximately 450 kb.[41] One exon, coding for only two amino acids near the protein's C-terminus, undergoes alternative splicing, but the exact functional impact of this is unknown.[23] Two transcription initiation sites and two polyadenylation sites are identified in the gene structure.[41]
The reelin protein starts with a signaling peptide 27 amino acids in length, followed by a region bearing similarity to F-spondin (the reeler domain), marked as "SP" on the scheme, and by a region unique to reelin, marked as "H". Next comes 8 repeats of 300–350 amino acids. These are called reelin repeats and have an epidermal growth factor motif at their center, dividing each repeat into two subrepeats, A (the BNR/Asp-box repeat) and B (the EGF-like domain). Despite this interruption, the two subdomains make direct contact, resulting in a compact overall structure.[42]
The final reelin domain contains a highly basic and short C-terminal region (CTR, marked "+") with a length of 32 amino acids. This region is highly conserved, being 100% identical in all investigated mammals. It was thought that CTR is necessary for reelin secretion, because the Orleans reeler mutation, which lacks a part of 8th repeat and the whole CTR, is unable to secrete the misshaped protein, leading to its concentration in cytoplasm. However, other studies have shown that the CTR is not essential for secretion itself, but mutants lacking the CTR were much less efficient in activating downstream signaling events.[43]
Reelin is cleaved in vivo at two sites located after domains 2 and 6 – approximately between repeats 2 and 3 and between repeats 6 and 7, resulting in the production of three fragments.[44] This splitting does not decrease the protein's activity, as constructs made of the predicted central fragments (repeats 3–6) bind to lipoprotein receptors, trigger Dab1 phosphorylation and mimic functions of reelin during cortical plate development.[45] Moreover, the processing of reelin by embryonic neurons may be necessary for proper corticogenesis.[46]
# Function
The primary functions of Reelin are the regulation of corticogenesis and neuronal cell positioning in the prenatal period, but the protein also continues to play a role in adults. Reelin is found in numerous tissues and organs, and one could roughly subdivide its functional roles by the time of expression and by localisation of its action.[7]
## During development
A number of non-nervous tissues and organs express reelin during development, with the expression sharply going down after organs have been formed. The role of the protein here is largely unexplored, because the knockout mice show no major pathology in these organs. Reelin's role in the growing central nervous system has been extensively characterized. It promotes the differentiation of progenitor cells into radial glia and affects the orientation of its fibers, which serve as the guides for the migrating neuroblasts.[49] The position of reelin-secreting cell layer is important, because the fibers orient themselves in the direction of its higher concentration.[50] For example, reelin regulates the development of layer-specific connections in hippocampus and entorhinal cortex.[51][52]
Mammalian corticogenesis is another process where reelin plays a major role. In this process the temporary layer called preplate is split into the marginal zone on the top and subplate below, and the space between them is populated by neuronal layers in the inside-out pattern. Such an arrangement, where the newly created neurons pass through the settled layers and position themselves one step above, is a distinguishing feature of mammalian brain, in contrast to the evolutionary older reptile cortex, in which layers are positioned in an "outside-in" fashion. When reelin is absent, like in the mutant reeler mouse, the order of cortical layering becomes roughly inverted, with younger neurons finding themselves to be unable to pass the settled layers. Subplate neurons fail to stop and invade the upper most layer, creating the so-called superplate in which they mix with Cajal-Retzius cells and some cells normally destined for the second layer.[citation needed]
There is no agreement concerning the role of reelin in the proper positioning of cortical layers. The original hypothesis, that the protein is a stop signal for the migrating cells, is supported by its ability to induce the dissociation,[53] its role in asserting the compact granule cell layer in the hippocampus, and by the fact that migrating neuroblasts evade the reelin-rich areas. But an experiment in which murine corticogenesis went normally despite the malpositioned reelin secreting layer,[54] and lack of evidence that reelin affects the growth cones and leading edges of neurons, caused some additional hypotheses to be proposed. According to one of them, reelin makes the cells more susceptible to some yet undescribed positional signaling cascade.[citation needed]
Reelin may also ensure correct neuronal positioning in the spinal cord: according to one study, location and level of its expression affects the movement of sympathetic preganglionic neurons.[55]
The protein is thought to act on migrating neuronal precursors and thus controls correct cell positioning in the cortex and other brain structures. The proposed role is one of a dissociation signal for neuronal groups, allowing them to separate and go from tangential chain-migration to radial individual migration.[53] Dissociation detaches migrating neurons from the glial cells that are acting as their guides, converting them into individual cells that can strike out alone to find their final position.[citation needed]
Reelin takes part in the developmental change of NMDA receptor configuration, increasing mobility of NR2B-containing receptors and thus decreasing the time they spend at the synapse.[57][dead link][58][59] It has been hypothesized that this may be a part of the mechanism behind the "NR2B-NR2A switch" that is observed in the brain during its postnatal development.[60] Ongoing reelin secretion by GABAergic hippocampal neurons is necessary to keep NR2B-containing NMDA receptors at a low level.[56]
## In adults
In the adult nervous system, reelin plays an eminent role at the two most active neurogenesis sites, the subventricular zone and the dentate gyrus. In some species, the neuroblasts from the subventricular zone migrate in chains in the rostral migratory stream (RMS) to reach the olfactory bulb, where reelin dissociates them into individual cells that are able to migrate further individually. They change their mode of migration from tangential to radial, and begin using the radial glia fibers as their guides. There are studies showing that along the RMS itself the two receptors, ApoER2 and VLDLR, and their intracellular adapter DAB1 function independently of Reelin,[61] most likely by the influence of a newly proposed ligand, thrombospondin-1.[47] In the adult dentate gyrus, reelin provides guidance cues for new neurons that are constantly arriving to the granule cell layer from subgranular zone, keeping the layer compact.[62]
Reelin also plays an important role in the adult brain by modulating cortical pyramidal neuron dendritic spine expression density, the branching of dendrites, and the expression of long-term potentiation[4] as its secretion is continued diffusely by the GABAergic cortical interneurons those origin is traced to the medial ganglionic eminence.
In the adult organism the non-neural expression is much less widespread, but goes up sharply when some organs are injured.[34][35] The exact function of reelin upregulation following an injury is still being researched.[citation needed]
# Evolutionary significance
Reelin-DAB1 interactions could have played a key role in the structural evolution of the cortex that evolved from a single layer in the common predecessor of the amniotes into multiple-layered cortex of contemporary mammals.[63] Research shows that reelin expression goes up as the cortex becomes more complex, reaching the maximum in the human brain in which the reelin-secreting Cajal-Retzius cells have significantly more complex axonal arbour.[64] Reelin is present in the telencephalon of all the vertebrates studied so far, but the pattern of expression differs widely. For example, zebrafish have no Cajal-Retzius cells at all; instead, the protein is being secreted by other neurons.[65][66] These cells do not form a dedicated layer in amphibians, and radial migration in their brains is very weak.[65]
As the cortex becomes more complex and convoluted, migration along the radial glia fibers becomes more important for the proper lamination. The emergence of a distinct reelin-secreting layer is thought to play an important role in this evolution.[50] There are conflicting data concerning the importance of this layer,[54] and these are explained in the literature either by the existence of an additional signaling positional mechanism that interacts with the reelin cascade,[54] or by the assumption that mice that are used in such experiments have redundant secretion of reelin[67] compared with more localized synthesis in the human brain.[26]
Cajal-Retzius cells, most of which disappear around the time of birth, coexpress reelin with the HAR1 gene that is thought to have undergone the most significant evolutionary change in humans compared with chimpanzee, being the most "evolutionary accelerated" of the genes from the human accelerated regions.[68] There is also evidence of that variants in the DAB1 gene have been included in a recent selective sweep in Chinese populations.[69][70]
# Mechanism of action
## Receptors
Reelin's control of cell-cell interactions is thought to be mediated by binding of reelin to the two members of low density lipoprotein receptor gene family: VLDLR and the ApoER2.[72][73][74][75] The two main reelin receptors seem to have slightly different roles: VLDLR conducts the stop signal, while ApoER2 is essential for the migration of late-born neocortical neurons.[76] It also has been shown that the N-terminal region of reelin, a site distinct from the region of reelin shown to associate with VLDLR/ApoER2 binds to the alpha-3-beta-1 integrin receptor.[77] The proposal that the protocadherin CNR1 behaves as a Reelin receptor[78] has been disproven.[45]
As members of lipoprotein receptor superfamily, both VLDLR and ApoER2 have in their structure an internalization domain called NPxY motif. After binding to the receptors reelin is internalized by endocytosis, and the N-terminal fragment of the protein is re-secreted.[79] This fragment may serve postnatally to prevent apical dendrites of cortical layer II/III pyramidal neurons from overgrowth, acting via a pathway independent of canonical reelin receptors.[80]
Reelin receptors are present on both neurons and glial cells. Furthermore, radial glia express the same amount of ApoER2 but being ten times less rich in VLDLR.[49] beta-1 integrin receptors on glial cells play more important role in neuronal layering than the same receptors on the migrating neuroblasts.[81]
Reelin-dependent strengthening of long-term potentiation is caused by ApoER2 interaction with NMDA receptor. This interaction happens when ApoER2 has a region coded by exon 19. ApoER2 gene is alternatively spliced, with the exon 19-containing variant more actively produced during periods of activity.[82] According to one study, the hippocampal reelin expression rapidly goes up when there is need to store a memory, as demethylases open up the RELN gene.[83] The activation of dendrite growth by reelin is apparently conducted through Src family kinases and is dependent upon the expression of Crk family proteins,[84] consistent with the interaction of Crk and CrkL with tyrosine-phosphorylated Dab1.[85] Moreover, a Cre-loxP recombination mouse model that lacks Crk and CrkL in most neurons[86] was reported to have the reeler phenotype, indicating that Crk/CrkL lie between DAB1 and Akt in the reelin signaling chain.
## Signaling cascades
Reelin activates the signaling cascade of Notch-1, inducing the expression of FABP7 and prompting progenitor cells to assume radial glial phenotype.[87] In addition, corticogenesis in vivo is highly dependent upon reelin being processed by embrionic neurons,[46] which are thought to secrete some as yet unidentified metalloproteinases that free the central signal-competent part of the protein. Some other unknown proteolytic mechanisms may also play a role.[88] It is supposed that full-sized reelin sticks to the extracellular matrix fibers on the higher levels, and the central fragments, as they are being freed up by the breaking up of reelin, are able to permeate into the lower levels.[46] It is possible that as neuroblasts reach the higher levels they stop their migration either because of the heightened combined expression of all forms of reelin, or due to the peculiar mode of action of the full-sized reelin molecules and its homodimers.[23]
The intracellular adaptor DAB1 binds to the VLDLR and ApoER2 through an NPxY motif and is involved in transmission of Reelin signals through these lipoprotein receptors. It becomes phosphorylated by Src[89] and Fyn[90] kinases and apparently stimulates the actin cytoskeleton to change its shape, affecting the proportion of integrin receptors on the cell surface, which leads to the change in adhesion. Phosphorylation of DAB1 leads to its ubiquitination and subsequent degradation, and this explains the heightened levels of DAB1 in the absence of reelin.[91] Such negative feedback is thought to be important for proper cortical lamination.[92] Activated by two antibodies, VLDLR and ApoER2 cause DAB1 phosphorylation but seemingly without the subsequent degradation and without rescuing the reeler phenotype, and this may indicate that a part of the signal is conducted independently of DAB1.[45]
A protein having an important role in lissencephaly and accordingly called LIS1 (PAFAH1B1), was shown to interact with the intracellular segment of VLDLR, thus reacting to the activation of reelin pathway.[71]
## Complexes
Reelin molecules have been shown[93][94] to form a large protein complex, a disulfide-linked homodimer. If the homodimer fails to form, efficient tyrosine phosphorylation of DAB1 in vitro fails. Moreover, the two main receptors of reelin are able to form clusters[95] that most probably play a major role in the signaling, causing the intracellular adaptor DAB1 to dimerize or oligomerize in its turn. Such clustering has been shown in the study to activate the signaling chain even in the absence of Reelin itself.[95] In addition, reelin itself can cut the peptide bonds holding other proteins together, being a serine protease,[40] and this may affect the cellular adhesion and migration processes. Reelin signaling leads to phosphorylation of actin-interacting protein cofilin 1 at ser3; this may stabilize the actin cytoskeleton and anchor the leading processes of migrating neuroblasts, preventing their further growth.[96][97]
## Interaction with Cdk5
Cyclin-dependent kinase 5 (Cdk5), a major regulator of neuronal migration and positioning, is known to phosphorylate DAB1[98][99][100] and other cytosolic targets of reelin signaling, such as Tau,[101] which could be activated also via reelin-induced deactivation of GSK3B,[102] and NUDEL,[103] associated with Lis1, one of the DAB1 targets. LTP induction by reelin in hippocampal slices fails in p35 knockouts.[104] P35 is a key Cdk5 activator, and double p35/Dab1, p35/RELN, p35/ApoER2, p35/VLDLR knockouts display increased neuronal migration deficits,[104][105] indicating a synergistic action of reelin → ApoER2/VLDLR → DAB1 and p35/p39 → Cdk5 pathways in the normal corticogenesis.
# Possible pathological role
## Lissencephaly/Microlissencephaly
Disruptions of the RELN gene are considered to be the cause of the rare form of lissencephaly with cerebellar hypoplasia called Norman-Roberts syndrome.[106][107] The mutations disrupt splicing of the RELN mRNA transcript, resulting in low or undetectable amounts of reelin protein. The phenotype in these patients was characterized by hypotonia, ataxia, and developmental delay, with lack of unsupported sitting and profound mental retardation with little or no language development. Seizures and congenital lymphedema are also present. A novel chromosomal translocation causing the syndrome was described in 2007.[108] The mutations affecting reelin in human are usually associated with consanguineous marriage.[citation needed]
## Schizophrenia
Reduced expression of reelin and its mRNA levels in the brains of schizophrenia sufferers had been reported in 1998[109] and 2000[110] and independently confirmed in the postmortem studies of hippocampus,[8] cerebellum,[111] basal ganglia,[112] and in the cortex studies.[113][114] The reduction may reach up to 50% in some brain regions and is coupled with reduced expression of GAD-67 enzyme,[111] which catalyses the transition of glutamate to GABA. Blood levels of reelin and its isoforms are also altered in schizophrenia, along with mood disorders, according to one study.[115] Reduced reelin mRNA prefrontal expression in schizophrenia was found to be the most statistically relevant disturbance found in the multicenter study conducted in 14 separate laboratories in 2001 by Stanley Foundation Neuropathology Consortium.[116]
Epigenetic hypermethylation of DNA in schizophrenia patients is proposed as a cause of the reduction,[117][118] in agreement with the observations dating from the 1960s that administration of methionine to schizophrenic patients results in a profound exacerbation of schizophrenia symptoms in sixty to seventy percent of patients.[119][120][121][122] The proposed mechanism is a part of the "epigenetic hypothesis for schizophrenia pathophysiology" formulated by a group of scientists in 2008 (D. Grayson; A. Guidotti; E. Costa).[9][123] A postmortem study comparing a DNA methyltransferase (DNMT1) and Reelin mRNA expression in cortical layers I and V of schizophrenic patients and normal controls demonstrated that in the layer V both DNMT1 and Reelin levels were normal, while in the layer I DNMT1 was threefold higher, probably leading to the twofold decrease in the Reelin expression.[124] There is evidence that the change is selective, and DNMT1 is overexpressed in reelin-secreting GABAergic neurons but not in their glutamatergic neighbours.[125][126] Methylation inhibitors and histone deacetylase inhibitors, such as valproic acid, increase reelin mRNA levels,[127][128][129] while L-methionine treatment downregulates the phenotypic expression of reelin.[130] One study indicated the upregulation of histone deacetylase HDAC1 in the hippocampi of patients.[131] Histone deacetylases suppress gene promoters; hyperacetylation of hystones was shown in murine models to demethylate the promoters of both reelin and GAD67.[132] DNMT1 inhibitors in animals have been shown to increase the expression of both reelin and GAD67,[133] and both DNMT inhibitors and HDAC inhibitors shown in one study[134] to activate both genes with comparable dose- and time-dependence. As one study shows, S-adenosyl methionine (SAM) concentration in patients' prefrontal cortex is twice as high as in the cortices of non-affected people.[135] SAM, being a methyl group donor necessary for DNMT activity, could further shift epigenetic control of gene expression.[citation needed]
The factors mentioned above serve to corroborate the epigenetic hypothesis. But it is worth mentioning that in contrast with initial data, two recent studies have failed to confirm the RELN hypermethylation,[10][11] and psychotropic medication could in itself affect the reelin expression in the brain, as animal studies show (see below).
Other interesting findings probably linking reelin pathway to developmental hypotheses of schizophrenia are noted in the studies on mice that are either prenatally infected with influenza virus[136] or have their immune system activated artificially during pregnancy.[137] The Cajal-Retzius cells in the newborns secrete significantly less reelin despite keeping their expression of calretinin and nNos within normal range. These data run in parallel with the findings of increased risk of schizophrenia in humans after a prenatal infection during the second trimester.[citation needed]
Chromosome region 7q22 that harbours the RELN gene is associated with schizophrenia,[138] and the gene itself was associated with the disease in a large study that found the polymorphism rs7341475 to increase the risk of the disease in women, but not in men. The women that have the single-nucleotide polymorphism (SNP) are about 1.4 times more likely to get ill, according to the study.[139] Allelic variations of RELN have also been correlated with working memory, memory and executive functioning in nuclear families where one of the members suffers from schizophrenia.[138] The association with working memory was later replicated.[140] In one small study, nonsynonymous polymorphism Val997Leu of the gene was associated with left and right ventricular enlargement in patients.[141]
One study showed that patients have decreased levels of one of reelin receptors, VLDLR, in the peripheral lymphocytes.[142] After six months of antipsychotic therapy the expression went up; according to authors, peripheral VLRLR levels may serve as a reliable peripheral biomarker of schizophrenia.[142]
Considering the role of reelin in promoting dendritogenesis,[5][84] suggestions were made that the localized dendritic spine deficit observed in schizophrenia[143][144] could be in part connected with the downregulation of reelin.[145][146]
Reelin pathway could also be linked to schizophrenia and other psychotic disorders through its interaction with risk genes. One example is the neuronal transcription factor NPAS3, disruption of which is linked to schizophrenia[147] and learning disability. Knockout mice lacking NPAS3 or the similar protein NPAS1 have significantly lower levels of reelin;[148] the precise mechanism behind this is unknown. Another example is the schizophrenia-linked gene MTHFR, with murine knockouts showing decreased levels of reelin in the cerebellum.[149] Along the same line, it is worth noting that the gene coding for the subunit NR2B that is presumably affected by reelin in the process of NR2B->NR2A developmental change of NMDA receptor composition,[59] stands as one of the strongest risk gene candidates.[150] Another shared aspect between NR2B and RELN is that they both can be regulated by the TBR1 transcription factor.[151]
The heterozygous reeler mouse, which is haploinsufficient for the RELN gene, shares several neurochemical and behavioral abnormalities with schizophrenia and bipolar disorder,[152] but the exact relevance of these murine behavioral changes to the pathophysiology of schizophrenia remains debatable.[153]
As previously described, reelin plays a crucial role in modulating early neuroblast migration during brain development. Evidences of altered neural cell positioning in post-mortem schizophrenia patient brains[154][155] and changes to gene regulatory networks that control cell migration[156][157] suggests a potential link between altered reelin expression in patient brain tissue to disrupted cell migration during brain development. To model the role of reelin in the context of schizophrenia at a cellular level, olfactory neurosphere-derived cells were generated from the nasal biopsies of schizophrenia patients, and compared to cells from healthy controls.[156] Schizophrenia patient-derived cells have reduced levels of reelin mRNA[156] and protein[158] when compared to healthy control cells, but expresses the key reelin receptors and DAB1 accessory protein.[158] When grown in vitro, schizophrenia patient-derived cells were unable to respond to reelin coated onto tissue culture surfaces; In contrast, cells derived from healthy controls were able to alter their cell migration when exposed to reelin.[158] This work went on to show that the lack of cell migration response in patient-derived cells were caused by the cell's inability to produce enough focal adhesions of the appropriate size when in contact with extracellular reelin.[158] More research into schizophrenia cell-based models are needed to look at the function of reelin, or lack of, in the pathophysiology of schizophrenia.
## Bipolar disorder
Decrease in RELN expression with concurrent upregulation of DNMT1 is typical of bipolar disorder with psychosis, but is not characteristic of patients with major depression without psychosis, which could speak of specific association of the change with psychoses.[110] One study suggests that unlike in schizophrenia, such changes are found only in the cortex and do not affect the deeper structures in psychotic bipolar patients, as their basal ganglia were found to have the normal levels of DNMT1 and subsequently both the reelin and GAD67 levels were within the normal range.[112]
In a genetic study conducted in 2009, preliminary evidence requiring further DNA replication suggested that variation of the RELN gene (SNP rs362719) may be associated with susceptibility to bipolar disorder in women.[159]
## Autism
Autism is a neurodevelopmental disorder that is generally believed to be caused by mutations in several locations, likely triggered by environmental factors. The role of reelin in autism is not decided yet.[160]
Reelin was originally in 2001 implicated in a study finding associations between autism and a polymorphic GGC/CGG repeat preceding the 5' ATG initiator codon of the RELN gene in an Italian population. Longer triplet repeats in the 5’ region were associated with an increase in autism susceptibility.[161] However, another study of 125 multiple-incidence families and 68 single-incidence families from the subsequent year found no significant difference between the length of the polymorphic repeats in affected and controls. Although, using a family based association test larger reelin alleles were found to be transmitted more frequently than expected to affected children.[162] An additional study examining 158 subjects with German lineage likewise found no evidence of triplet repeat polymorphisms associated with autism.[163] And a larger study from 2004 consisting of 395 families found no association between autistic subjects and the CGG triplet repeat as well as the allele size when compared to age of first word.[164]
In 2010 a large study using data from 4 European cohorts would find some evidence for an association between autism and the rs362780 RELN polymorphism.[165]
Studies of transgenic mice have been suggestive of an association, but not definitive.[166]
## Temporal lobe epilepsy: granule cell dispersion
Decreased reelin expression in the hippocampal tissue samples from patients with temporal lobe epilepsy was found to be directly correlated with the extent of granule cell dispersion (GCD), a major feature of the disease that is noted in 45%–73% of patients.[167][168] The dispersion, according to a small study, is associated with the RELN promoter hypermethylation.[169] According to one study, prolonged seizures in a rat model of mesial temporal lobe epilepsy have led to the loss of reelin-expressing interneurons and subsequent ectopic chain migration and aberrant integration of newborn dentate granule cells. Without reelin, the chain-migrating neuroblasts failed to detach properly.[170] Moreover, in a kainate-induced mouse epilepsy model, exogenous reelin had prevented GCD, according to one study.[171]
## Alzheimer's disease
The Reelin receptors ApoER2 and VLDLR belong to the LDL receptor gene family.[172] All members of this family are receptors for Apolipoprotein E (ApoE). Therefore, they are often synonymously referred to as 'ApoE receptors'. ApoE occurs in 3 common isoforms (E2, E3, E4) in the human population. ApoE4 is the primary genetic risk factor for late-onset Alzheimer's disease. This strong genetic association has led to the proposal that ApoE receptors play a central role in the pathogenesis of Alzheimer's Disease.[172][173] According to one study, reelin expression and glycosylation patterns are altered in Alzheimer's disease. In the cortex of the patients, reelin levels were 40% higher compared with controls, but the cerebellar levels of the protein remain normal in the same patients.[174] This finding is in agreement with an earlier study showing the presence of Reelin associated with amyloid plaques in a transgenic AD mouse model.[175] A large genetic study of 2008 showed that RELN gene variation is associated with an increased risk of Alzheimer's disease in women.[176] The number of reelin-producing Cajal-Retzius cells is significantly decreased in the first cortical layer of patients.[177][178] Reelin has been shown to interact with amyloid precursor protein,[179] and, according to one in-vitro study, is able to counteract the Aβ-induced dampening of NMDA-receptor activity.[180] This is modulated by ApoE isoforms, which selectively alter the recycling of ApoER2 as well as AMPA and NMDA receptors.[181]
## Cancer
DNA methylation patterns are often changed in tumours, and the RELN gene could be affected: according to one study, in the pancreatic cancer the expression is suppressed, along with other reelin pathway components[182] In the same study, cutting the reelin pathway in cancer cells that still expressed reelin resulted in increased motility and invasiveness. On the contrary, in prostate cancer the RELN expression is excessive and correlates with Gleason score.[183] Retinoblastoma presents another example of RELN overexpression.[184] This gene has also been seen recurrently mutated in cases of acute lymphoblastic leukaemia.[185]
## Other conditions
One genome-wide association study indicates a possible role for RELN gene variation in otosclerosis, an abnormal growth of bone of the middle ear.[186] In a statistical search for the genes that are differentially expressed in the brains of cerebral malaria-resistant versus cerebral malaria-susceptible mice, Delahaye et al. detected a significant upregulation of both RELN and DAB1 and speculated on possible protective effects of such over-expression.[187]
# Factors affecting reelin expression
The expression of reelin is controlled by a number of factors besides the sheer number of Cajal-Retzius cells. For example, TBR1 transcription factor regulates RELN along with other T-element-containing genes.[151] On a higher level, increased maternal care was found to correlate with reelin expression in rat pups; such correlation was reported in hippocampus[189] and in the cortex.[188] According to one report, prolonged exposure to corticosterone significantly decreased reelin expression in murine hippocampi, a finding possibly pertinent to the hypothetical role of corticosteroids in depression.[190] One small postmortem study has found increased methylation of RELN gene in the neocortex of persons past their puberty compared with those that had yet to enter the period of maturation.[191]
## Psychotropic medication
As reelin is being implicated in a number of brain disorders and its expression is usually measured posthumously, assessing the possible medication effects is important.[citation needed]
According to the epigenetic hypothesis, drugs that shift the balance in favour of demethylation have a potential to alleviate the proposed methylation-caused downregulation of RELN and GAD67. In one study, clozapine and sulpiride but not haloperidol and olanzapine were shown to increase the demethylation of both genes in mice pretreated with l-methionine.[192] Valproic acid, a histone deacetylase inhibitor, when taken in combination with antipsychotics, is proposed to have some benefits. But there are studies conflicting the main premise of the epigenetic hypothesis, and a study by Fatemi et al. shows no increase in RELN expression by valproic acid; that indicates the need for further investigation.[citation needed]
Fatemi et al. conducted the study in which RELN mRNA and reelin protein levels were measured in rat prefrontal cortex following a 21-day of intraperitoneal injections of the following drugs:[23]
In 2009, Fatemi et al. published the more detailed work on rats using the same medication. Here, cortical expression of several participants (VLDLR, DAB1, GSK3B) of the signaling chain was measured besides reelin itself, and also the expression of GAD65 and GAD67.[193] | https://www.wikidoc.org/index.php/Reelin | |
d7e83d0f99b3b0ab9ae5efc272f435ab3ec0962a | wikidoc | Reflux | Reflux
# Overview
Reflux is a technique used in industrial and laboratory distillations. It is also used in chemistry to apply energy to reactions over a long time.
# Reflux in industrial distillation
The term reflux is very widely used in industries that utilize large-scale distillation columns and fractionators such as petroleum refineries, petrochemical and chemical plants, and natural gas processing plants.
In that context, reflux refers to the portion of the overhead liquid product from a distillation column or fractionator that is returned to the upper part of the column as shown in the schematic diagram of a typical industrial distillation column. Inside the column, the downflowing reflux liquid provides cooling and condensation of the upflowing vapors thereby increasing the efficacy of the distillation column. The more reflux provided for a given number of theoretical plates, the better is the column's separation of lower boiling materials from higher boiling materials. Conversely, for a given desired separation, the more reflux is provided, the fewer theoretical plates are required.
# Reflux in laboratory distillation
The apparatus shown in the diagram represents a batch distillation as opposed to a continuous distillation. The liquid feed mixture to be distilled is placed into the round-bottomed flask along with a few anti-bumping granules, and the fractionating column is fitted into the top. As the mixture is heated and boils, vapor rises up the column. The vapor condenses on the glass platforms (known as plates or trays) inside the column and runs back down into the liquid below, thereby refluxing the upflowing distillate vapor. The hottest tray is at the bottom of the column and the coolest tray is at the top. At steady state conditions, the vapor and liquid on each tray is at equilibrium. Only the most volatile of the vapors stays in gaseous form all the way to the top. The vapor at the top of the column then passes into the condenser, where it cools until it condenses into a liquid. The separation can be enhanced with the addition of more trays (to a practical limitation of heat, flow, etc.). The process continues until all the most volatile components in the liquid feed boil out of the mixture. This point can be recognized by the rise in temperature shown on the thermometer. For continuous distillation, the feed mixture enters in the middle of the column.
# Reflux to apply energy to chemical reactions
A liquid reaction mixture is placed in a vessel open only at the top. This vessel is connected to a Liebig condenser, such that any vapours given off are cooled back to liquid, and fall back into the reaction vessel. The vessel is then heated vigorously for the course of the reaction. The purpose is to thermally accelerate the reaction by conducting it at an elevated temperature (i.e. the solvent's boiling point.)
The advantage of this technique is that it can be left for a long period of time without the need to add more solvent or fear of the reaction vessel boiling dry as any vapour is immediately condensed in the condenser. In addition, as a given solvent will always boil at a certain temperature, one can be sure that the reaction will proceed at a constant temperature. By careful choice of solvent, one can control the temperature within a very narrow range. The constant boiling action also serves to continuously mix the solution, although a magnetic stirring rod mechanism is often used to achieve a uniform solution. This technique is useful for performing chemical reactions under controlled conditions that require substantial time for completion.
The diagram shows a typical reflux apparatus for applying energy to chemical reactions. It includes an optional beaker of water between the reactants and the heat. This is often used as a safety precaution when using flammable reactants and a Bunsen burner in order to keep the flame away from the reactants. In modern laboratories, open flames are avoided due to the many flammable solvents often in use, and electrical heating, (i.e., with a hot plate or mantle) is preferred. Furthermore, a high boiling, thermally stable silicone oil is generally used to immerse the reaction vessel, rather than water which evaporates too readily to be useful for lengthy reactions. Using an oil bath, temperatures of up to several hundred degrees can easily be achieved, which is higher than the boiling point of most commonly used solvents. If even higher temperatures are required, the oil bath can be replaced with a sand bath.
# Reflux in beverage distillation
By controlling the temperature of the condenser, a reflux still may be used to ensure that higher boiling point components (which are also of higher molecular weight) are returned to the flask while lighter elements are passed out to a secondary condenser. This is useful in producing high quality alcoholic beverages, while ensuring that less desirable components (such as fusel alcohols) are returned to the primary flask. This is particularly effective in the production of alcoholic beverages in which it is appropriate to retain the flavors and aromas of the source fruit - such as applejack. For high quality neutral spirits (such as vodka), or post distillation flavored spirits, a process of multiple distillations or charcoal filtering may be applied to obtain a product lacking in any suggestion of its original source material for fermentation. | Reflux
# Overview
Reflux is a technique used in industrial and laboratory distillations. It is also used in chemistry to apply energy to reactions over a long time.
# Reflux in industrial distillation
The term reflux [1][2] is very widely used in industries that utilize large-scale distillation columns and fractionators such as petroleum refineries, petrochemical and chemical plants, and natural gas processing plants.
In that context, reflux refers to the portion of the overhead liquid product from a distillation column or fractionator that is returned to the upper part of the column as shown in the schematic diagram of a typical industrial distillation column. Inside the column, the downflowing reflux liquid provides cooling and condensation of the upflowing vapors thereby increasing the efficacy of the distillation column. The more reflux provided for a given number of theoretical plates, the better is the column's separation of lower boiling materials from higher boiling materials. Conversely, for a given desired separation, the more reflux is provided, the fewer theoretical plates are required.
# Reflux in laboratory distillation
The apparatus shown in the diagram represents a batch distillation as opposed to a continuous distillation. The liquid feed mixture to be distilled is placed into the round-bottomed flask along with a few anti-bumping granules, and the fractionating column is fitted into the top. As the mixture is heated and boils, vapor rises up the column. The vapor condenses on the glass platforms (known as plates or trays) inside the column and runs back down into the liquid below, thereby refluxing the upflowing distillate vapor. The hottest tray is at the bottom of the column and the coolest tray is at the top. At steady state conditions, the vapor and liquid on each tray is at equilibrium. Only the most volatile of the vapors stays in gaseous form all the way to the top. The vapor at the top of the column then passes into the condenser, where it cools until it condenses into a liquid. The separation can be enhanced with the addition of more trays (to a practical limitation of heat, flow, etc.). The process continues until all the most volatile components in the liquid feed boil out of the mixture. This point can be recognized by the rise in temperature shown on the thermometer. For continuous distillation, the feed mixture enters in the middle of the column.
# Reflux to apply energy to chemical reactions
A liquid reaction mixture is placed in a vessel open only at the top. This vessel is connected to a Liebig condenser, such that any vapours given off are cooled back to liquid, and fall back into the reaction vessel. The vessel is then heated vigorously for the course of the reaction. The purpose is to thermally accelerate the reaction by conducting it at an elevated temperature (i.e. the solvent's boiling point.)
The advantage of this technique is that it can be left for a long period of time without the need to add more solvent or fear of the reaction vessel boiling dry as any vapour is immediately condensed in the condenser. In addition, as a given solvent will always boil at a certain temperature, one can be sure that the reaction will proceed at a constant temperature. By careful choice of solvent, one can control the temperature within a very narrow range. The constant boiling action also serves to continuously mix the solution, although a magnetic stirring rod mechanism is often used to achieve a uniform solution. This technique is useful for performing chemical reactions under controlled conditions that require substantial time for completion.
The diagram shows a typical reflux apparatus for applying energy to chemical reactions. It includes an optional beaker of water between the reactants and the heat. This is often used as a safety precaution when using flammable reactants and a Bunsen burner in order to keep the flame away from the reactants. In modern laboratories, open flames are avoided due to the many flammable solvents often in use, and electrical heating, (i.e., with a hot plate or mantle) is preferred. Furthermore, a high boiling, thermally stable silicone oil is generally used to immerse the reaction vessel, rather than water which evaporates too readily to be useful for lengthy reactions. Using an oil bath, temperatures of up to several hundred degrees can easily be achieved, which is higher than the boiling point of most commonly used solvents. If even higher temperatures are required, the oil bath can be replaced with a sand bath.
# Reflux in beverage distillation
By controlling the temperature of the condenser, a reflux still may be used to ensure that higher boiling point components (which are also of higher molecular weight) are returned to the flask while lighter elements are passed out to a secondary condenser. This is useful in producing high quality alcoholic beverages, while ensuring that less desirable components (such as fusel alcohols) are returned to the primary flask. This is particularly effective in the production of alcoholic beverages in which it is appropriate to retain the flavors and aromas of the source fruit - such as applejack. For high quality neutral spirits (such as vodka), or post distillation flavored spirits, a process of multiple distillations or charcoal filtering may be applied to obtain a product lacking in any suggestion of its original source material for fermentation. | https://www.wikidoc.org/index.php/Reflux | |
cceeb09cee8348b7dd463908a92e38637b5df52f | wikidoc | Remedy | Remedy
Def. "a medicine, application, or treatment that relieves or cures a disease" is called a remedy.
# Cures
Def. a "method, device or medication that restores good health" or an act "of healing or state of being healed; restoration to health after a disease, or to soundness after injury" is called a cure.
# Medicines
Def. a "substance which specifically promotes healing ingested or consumed in some way", a "treatment or cure", or the "study of the cause, diagnosis, prognosis and treatment of disease or illness" is called a medicine or medicine.
# Nutraceuticals
Def. a "nutrient or food believed to have curative properties" or a "food used as a drug" is called a nutraceutical.
A nutraceutical or 'bioceutical' is a pharmaceutical alternative which claims physiological benefits.
In the US, "nutraceuticals" are largely unregulated, as they exist in the same category as dietary supplements and food additives by the Food and Drug Administration (FDA), under the authority of the Federal Food, Drug, and Cosmetic Act. | Remedy
Associate Editor(s)-in-Chief: Henry A. Hoff
Def. "a medicine, application, or treatment that relieves or cures a disease"[1] is called a remedy.
# Cures
Def. a "method, device or medication that restores good health"[2] or an act "of healing or state of being healed; restoration to health after a disease, or to soundness after injury"[3] is called a cure.
# Medicines
Def. a "substance which specifically promotes healing [when][4] ingested or consumed in some way"[5], a "treatment or cure"[4], or the "study of the cause, diagnosis, prognosis and treatment of disease or illness"[4] is called a medicine or medicine.
# Nutraceuticals
Def. a "nutrient or food believed to have curative properties"[6] or a "food used as a drug"[6] is called a nutraceutical.
A nutraceutical or 'bioceutical' is a pharmaceutical alternative which claims physiological benefits.[7][8]
In the US, "nutraceuticals" are largely unregulated, as they exist in the same category as dietary supplements and food additives by the Food and Drug Administration (FDA), under the authority of the Federal Food, Drug, and Cosmetic Act.[9][10] | https://www.wikidoc.org/index.php/Remedy | |
d0740ef1cb0afb66bdbee94eb1b8fd7cc8ee7e50 | wikidoc | Rennet | Rennet
Rennet (Template:PronEng) is a natural complex of enzymes produced in any mammalian stomach to digest the mother's milk. Rennet contains a proteolytic enzyme (protease) that coagulates the milk, causing it to separate into solids (curds) and liquid (whey). The active enzyme in rennet is called rennin or chymosin (EC 3.4.23.4) but there are also other important enzymes in it, e.g., pepsin or lipase. There are non-animal sources for rennet substitutes.
# Uses
The chief use of rennet is in the making of cheese, curd, and junket. Chymosin reacts specifically with κ-casein, cleaving the protein between the amino acids phenylalanine(105) and methionine (106), producing two fragments. The soluble fragment (residues 106-169), which becomes part of the whey, is known as glyco macro peptide and contains the glycosylation sites for κ-casein. The other component (residues 1-105) is insoluble, and in the presence of calcium ions causes the coagulation of the casein micelles to form a curd.
# Production of natural calf rennet
Natural calf rennet is extracted from the inner mucosa of the fourth stomach chamber (the abomasum) of young calves. These stomachs are a by-product of veal production. If rennet is extracted from older calves (grass-fed or grain-fed) the rennet contains less or no chymosin but a high level of pepsin and can only be used for special types of milk and cheeses. As each ruminant produces a special kind of rennet to digest the milk of its own mother, there are milk-specific rennets available, such as kid-goat rennet especially for goat's milk and lamb-rennet for sheep-milk. Rennet or digestion enzymes from other animals, like swine-pepsin, are not used in cheese production. (Swine-pepsin is, however, used in the analysis of disulfide bonds of proteins.)
## Traditional method
Dried and cleaned stomachs of young calves are sliced into small pieces and then put into saltwater or whey, together with some vinegar or wine to lower the pH of the solution. After some time, (overnight or several days) the solution is filtered. The crude rennet that remains in the filtered solution can then be used to coagulate milk. About 1 gram of this solution can normally coagulate 2000 to 4000 grams of milk.
Today this method is used only by traditional cheese-makers in central Europe: Switzerland, Jura, France, Romania and Alp-Sennereien in Austria.
## Modern method
Deep-frozen stomachs are milled and put into an enzyme-extracting solution. The crude rennet extract is then activated by adding acid – the enzymes in the stomach are produced in an inactive pre-form and are activated by the stomach acid. After neutralisation of the acid, the rennet extract is filtered in several stages and concentrated until reaching the required potency: about 1:15000 (1 kg of rennet would have the ability to coagulate 15000 litres of milk).
In 1 kg of rennet extract there are about 0.7 grams of active enzymes and no other organic material – the rest is water and salt and sometimes sodium benzoate, E211,
0.5% - 1% for preservation. Typically, 1 kg of cheese contains about 0.0003 grams of rennet enzymes.
# Alternative coagulants
Because of the limited availability of proper stomachs for rennet production, cheesemakers have always looked for other ways to coagulate the milk. Artificial coagulants are a useful alternative, especially for cheap or lower-quality cheeses.
As the proper coagulation is done by enzymatic activity, the task was to find enzymes for cleaving the casein that would result in a taste and texture similar to animal-based rennet.
## Vegetable rennet
Many plants have coagulating properties. Some examples include fig tree bark, nettles, thistles, mallow, and Creeping Charlie. Enzymes from thistle or cynara is used in some traditional cheese production in the Mediterranean.
These real vegetable rennets are also suitable for vegetarians. Vegetable rennet might be used in the production of kosher cheeses but nearly all kosher cheeses are produced with either microbial rennet or GM rennet. Worldwide, there is no industrial production for vegetable rennet. Commercial so-called vegetable rennets usually contain rennet from the mold Mucor miehei - see microbial rennet below.
## Microbial rennet
Some molds, such as Rhizomucor miehei are able to produce proteolytic enzymes. These molds are produced in a fermenter and then especially concentrated and purified to avoid contamination with unpleasant side products of the mold growth. At the present state of scientific research, governmental food safety organizations such as the EFSA deny QPS (Qualified Presumption of Safety) status to enzymes produced especially by these molds.
The flavor and taste of cheeses produced with microbial rennets tend towards some bitterness, especially after longer maturation periods. These so-called "microbial rennets" are suitable for vegetarians, provided no animal-based alimentation was used during the production.
## Genetically engineered rennet
Because of the above imperfections of microbial rennets, some producers sought further replacements of natural rennet. With the development of genetic engineering, it suddenly became possible to use calf-genes to modify some bacteria, fungus or yeast to make them produce chymosin. Chymosin produced by genetically modified organisms was the first artificially produced enzyme to be registered and allowed by the FDA in the USA. In 1999, about 60% of U.S. hard cheese was made with genetically engineered chymosin. One example of a commercially available genetically engineered rennet is Chymax, created by Pfizer.
Today the most widely-used genetically engineered rennet is produced by the fungus Aspergillus niger. The problems of destroying the aflatoxins or the antibiotic-resistant marker genes seem to be solved.
Cheese production with genetically engineered rennet is similar to production with natural calf rennet. Genetic rennet contains only one of the known main chymosin types – either type A or type B. Other chymosin types found in natural rennet do not exist in genetic rennet. This is also the reason why special analysis can determine what kind of coagulant has been used by analyzing what bonds have and haven't been cleaved.
Often a mixture of genetically engineered chymosin and natural pepsin is used to imitate the complexity of natural rennet and to get the same results in coagulation and in development of flavour and taste.
The so-called "GM rennets" are suitable for vegetarians if there was no animal based alimentation used during the production in the fermenter—but only for vegetarians who are not opposed to GM-derived foods.
## Acid coagulation
Milk can also be coagulated by adding some acid, e.g. citric acid. This form of coagulation is sometimes used in cheap mozzarella production without maturation of the cheese. Paneer is also made this way. The acidification can also come from bacterial fermentation such as in cultured milk. | Rennet
Rennet (Template:PronEng) is a natural complex of enzymes produced in any mammalian stomach to digest the mother's milk. Rennet contains a proteolytic enzyme (protease) that coagulates the milk, causing it to separate into solids (curds) and liquid (whey). The active enzyme in rennet is called rennin or chymosin (EC 3.4.23.4) but there are also other important enzymes in it, e.g., pepsin or lipase. There are non-animal sources for rennet substitutes.
# Uses
The chief use of rennet is in the making of cheese, curd, and junket. Chymosin reacts specifically with κ-casein, cleaving the protein between the amino acids phenylalanine(105) and methionine (106), producing two fragments. The soluble fragment (residues 106-169), which becomes part of the whey, is known as glyco macro peptide and contains the glycosylation sites for κ-casein. The other component (residues 1-105) is insoluble, and in the presence of calcium ions causes the coagulation of the casein micelles to form a curd.
# Production of natural calf rennet
Natural calf rennet is extracted from the inner mucosa of the fourth stomach chamber (the abomasum) of young calves. These stomachs are a by-product of veal production. If rennet is extracted from older calves (grass-fed or grain-fed) the rennet contains less or no chymosin but a high level of pepsin and can only be used for special types of milk and cheeses. As each ruminant produces a special kind of rennet to digest the milk of its own mother, there are milk-specific rennets available, such as kid-goat rennet especially for goat's milk and lamb-rennet for sheep-milk. Rennet or digestion enzymes from other animals, like swine-pepsin, are not used in cheese production. (Swine-pepsin is, however, used in the analysis of disulfide bonds of proteins.)
## Traditional method
Dried and cleaned stomachs of young calves are sliced into small pieces and then put into saltwater or whey, together with some vinegar or wine to lower the pH of the solution. After some time, (overnight or several days) the solution is filtered. The crude rennet that remains in the filtered solution can then be used to coagulate milk. About 1 gram of this solution can normally coagulate 2000 to 4000 grams of milk.
Today this method is used only by traditional cheese-makers in central Europe: Switzerland, Jura, France, Romania and Alp-Sennereien in Austria.
## Modern method
Deep-frozen stomachs are milled and put into an enzyme-extracting solution. The crude rennet extract is then activated by adding acid – the enzymes in the stomach are produced in an inactive pre-form and are activated by the stomach acid. After neutralisation of the acid, the rennet extract is filtered in several stages and concentrated until reaching the required potency: about 1:15000 (1 kg of rennet would have the ability to coagulate 15000 litres of milk).
In 1 kg of rennet extract there are about 0.7 grams of active enzymes and no other organic material – the rest is water and salt and sometimes sodium benzoate, E211,
0.5% - 1% for preservation. Typically, 1 kg of cheese contains about 0.0003 grams of rennet enzymes.
# Alternative coagulants
Because of the limited availability of proper stomachs for rennet production, cheesemakers have always looked for other ways to coagulate the milk. Artificial coagulants are a useful alternative, especially for cheap or lower-quality cheeses.
As the proper coagulation is done by enzymatic activity, the task was to find enzymes for cleaving the casein that would result in a taste and texture similar to animal-based rennet.
## Vegetable rennet
Many plants have coagulating properties. Some examples include fig tree bark, nettles, thistles, mallow, and Creeping Charlie. Enzymes from thistle or cynara is used in some traditional cheese production in the Mediterranean.
These real vegetable rennets are also suitable for vegetarians. Vegetable rennet might be used in the production of kosher cheeses but nearly all kosher cheeses are produced with either microbial rennet or GM rennet. Worldwide, there is no industrial production for vegetable rennet. Commercial so-called vegetable rennets usually contain rennet from the mold Mucor miehei - see microbial rennet below.
## Microbial rennet
Some molds, such as Rhizomucor miehei are able to produce proteolytic enzymes. These molds are produced in a fermenter and then especially concentrated and purified to avoid contamination with unpleasant side products of the mold growth. At the present state of scientific research, governmental food safety organizations such as the EFSA deny QPS (Qualified Presumption of Safety) status to enzymes produced especially by these molds.
The flavor and taste of cheeses produced with microbial rennets tend towards some bitterness, especially after longer maturation periods.[1] These so-called "microbial rennets" are suitable for vegetarians, provided no animal-based alimentation was used during the production.
## Genetically engineered rennet
Because of the above imperfections of microbial rennets, some producers sought further replacements of natural rennet. With the development of genetic engineering, it suddenly became possible to use calf-genes to modify some bacteria, fungus or yeast to make them produce chymosin. Chymosin produced by genetically modified organisms was the first artificially produced enzyme to be registered and allowed by the FDA in the USA. In 1999, about 60% of U.S. hard cheese was made with genetically engineered chymosin[2]. One example of a commercially available genetically engineered rennet is Chymax, created by Pfizer.
Today the most widely-used genetically engineered rennet is produced by the fungus Aspergillus niger. The problems of destroying the aflatoxins or the antibiotic-resistant marker genes seem to be solved.
Cheese production with genetically engineered rennet is similar to production with natural calf rennet. Genetic rennet contains only one of the known main chymosin types – either type A or type B. Other chymosin types found in natural rennet do not exist in genetic rennet. This is also the reason why special analysis can determine what kind of coagulant has been used by analyzing what bonds have and haven't been cleaved.
Often a mixture of genetically engineered chymosin and natural pepsin is used to imitate the complexity of natural rennet and to get the same results in coagulation and in development of flavour and taste.
The so-called "GM rennets" are suitable for vegetarians if there was no animal based alimentation used during the production in the fermenter—but only for vegetarians who are not opposed to GM-derived foods.
## Acid coagulation
Milk can also be coagulated by adding some acid, e.g. citric acid. This form of coagulation is sometimes used in cheap mozzarella production without maturation of the cheese. Paneer is also made this way. The acidification can also come from bacterial fermentation such as in cultured milk. | https://www.wikidoc.org/index.php/Rennet | |
f45a22995725a29e1444c43f3249add62003bb19 | wikidoc | Result | Result
A result is the final consequence of a sequence of actions or events (broadly incidents and accidents) expressed qualitatively or quantitatively, being a loss, injury, disadvantage, advantage, gain, victory or simply a value. There may be a range of possible outcomes associated with an event possibly depending on the point of view, historical distance or relevance.
Reaching no result proves that actions are inefficient, ineffective, meaningless or flawed.
- in general any kind of research, action or phenomenon can lead to one or more results.
- in games (e.g. cricket, lotteries) or wars the result describes the victorious party and possibly effects on the environment.
- in mathematics: the final value of a calculation (e.g. arithmetic operation), function or statistical expression
- statistics uses polls, tests and logs to analyze, extract and interpolate information.
- in computer sciences: the return value of a function, state of a system or list of records matching a query (e.g. web search). The result type is the data type of the data returned by a function.
- in physics: the outcome of an experiment
- in forensics and justice: the proof of guilt or innocence of a suspect after evaluating evidence in a criminal investigation.
- in economics/accounting: the profit or loss at the end of a fiscal period. (see also: NOR)
- in democracy : the election of a representative or vote on a subject.
# Result Properties
As with any other piece of information results have certain properties in absolute terms or in relation to previous results or settings:
different meanings result, results, resulted
# Quality
In many cases the following formula is used:
result = quality - acceptance
A product, service or activity can be delivered with a high (technical) quality, but if the acceptance is small, the end-result is also small.
This formula is commonly used to explain junior technical engineers that more needs to be done to reach a (project) target than just implement a good technical solution.
The acceptance in the formula is most of the time increased by involving end-users/customers in the specification of the targets and assigning end-user-tests to them. | Result
Click here for the drug result.
A result is the final consequence of a sequence of actions or events (broadly incidents and accidents) expressed qualitatively or quantitatively, being a loss, injury, disadvantage, advantage, gain, victory or simply a value. There may be a range of possible outcomes associated with an event possibly depending on the point of view, historical distance or relevance.
Reaching no result proves that actions are inefficient, ineffective, meaningless or flawed.
- in general any kind of research, action or phenomenon can lead to one or more results.
- in games (e.g. cricket, lotteries) or wars the result describes the victorious party and possibly effects on the environment.
- in mathematics: the final value of a calculation (e.g. arithmetic operation), function or statistical expression
- statistics uses polls, tests and logs to analyze, extract and interpolate information.
- in computer sciences: the return value of a function, state of a system or list of records matching a query (e.g. web search). The result type is the data type of the data returned by a function.
- in physics: the outcome of an experiment
- in forensics and justice: the proof of guilt or innocence of a suspect after evaluating evidence in a criminal investigation.
- in economics/accounting: the profit or loss at the end of a fiscal period. (see also: NOR)
- in democracy : the election of a representative or vote on a subject.
## Result Properties
As with any other piece of information results have certain properties in absolute terms or in relation to previous results or settings:
different meanings result, results, resulted
## Quality
In many cases the following formula is used:
result = quality * acceptance
A product, service or activity can be delivered with a high (technical) quality, but if the acceptance is small, the end-result is also small.
This formula is commonly used to explain junior technical engineers that more needs to be done to reach a (project) target than just implement a good technical solution.
The acceptance in the formula is most of the time increased by involving end-users/customers in the specification of the targets and assigning end-user-tests to them. | https://www.wikidoc.org/index.php/Result | |
c99dcde304a681dc0529bcdb669a70292d20cb6a | wikidoc | RhoBTB | RhoBTB
The RhoBTB family is a subgroup of the Rho family of small GTPases. They are a highly divergent class and are all characterized by an N-terminal Rho-related domain followed by at least one C-terminal BTB domain.
# Discovery
The RhoBTB family of molecules was unknowingly discovered in 1993 by analyzing the Dictyostelium genome looking for members of the Ras superfamily of GTPases. The authors began by doing Southern blots looking for cDNAs that cross-hybridize with a very conservative probe from hRas. They identified 19 new genes that belonged to the Ras superfamily and sequenced approximately 600 nucleotides from the start of the transcript. If they were looking for a normal Ras-like GTPase, this would have been sufficient. One of their clones, they called RacA, was more divergent than most of the others and the transcript didn’t terminate in a stop codon like the rest. The authors, however, didn’t comment on this and RhoBTB went undiscovered for another eight years.
A very careful analysis by Francisco Rivero and coworkers ensued to find all of the Rho GTPases in Dictyostelium. During their endeavor, they found that the open reading frame of RacA was actually 400 amino acids longer than what Bush had published 8 years earlier. Instead of a 168 amino acid protein, RacA encoded a 598 residue protein with a Rho GTPase domain at the N-terminus and two BTB domains toward the C-terminus. BTB (Broad-Complex, Tramtrack and Bric-a-Brac) domains are known to involve hetero and homo associations with other BTB domain-containing proteins. Because this novel RhoBTB protein was in Dictostelium, the authors were curious if any homologous proteins exist in humans. They found three and called them RhoBTB1, RhoBTB2, and RhoBTB3.
# Localization and expression
RhoBTB1 and RhoBTB2 are much more homologous than RhoBTB3. Further analysis revealed that the intron-exon structure of RhoBTB1 and 2 are also quite similar and have only one common intron with RhoBTB3.
RhoBTB1 and 2 were not detected during mouse development, but RhoBTB3 was detected strongly between embryonic days 11.5 through 17.5. Additionally, RhoBTB1 and 2 are localized to vesicular structures, while RhoBTB3 is localized to the trans-Golgi network. | RhoBTB
The RhoBTB family is a subgroup of the Rho family of small GTPases. They are a highly divergent class and are all characterized by an N-terminal Rho-related domain followed by at least one C-terminal BTB domain.
# Discovery
The RhoBTB family of molecules was unknowingly discovered in 1993 by analyzing the Dictyostelium genome looking for members of the Ras superfamily of GTPases. The authors began by doing Southern blots looking for cDNAs that cross-hybridize with a very conservative probe from hRas.[1] They identified 19 new genes that belonged to the Ras superfamily and sequenced approximately 600 nucleotides from the start of the transcript.[1] If they were looking for a normal Ras-like GTPase, this would have been sufficient. One of their clones, they called RacA, was more divergent than most of the others and the transcript didn’t terminate in a stop codon like the rest.[1] The authors, however, didn’t comment on this and RhoBTB went undiscovered for another eight years.
A very careful analysis by Francisco Rivero and coworkers ensued to find all of the Rho GTPases in Dictyostelium. During their endeavor, they found that the open reading frame of RacA was actually 400 amino acids longer than what Bush had published 8 years earlier.[2] Instead of a 168 amino acid protein, RacA encoded a 598 residue protein with a Rho GTPase domain at the N-terminus and two BTB domains toward the C-terminus. BTB (Broad-Complex, Tramtrack and Bric-a-Brac) domains are known to involve hetero and homo associations with other BTB domain-containing proteins.[3][4] Because this novel RhoBTB protein was in Dictostelium, the authors were curious if any homologous proteins exist in humans. They found three and called them RhoBTB1, RhoBTB2, and RhoBTB3.[2]
# Localization and expression
RhoBTB1 and RhoBTB2 are much more homologous than RhoBTB3.[2] Further analysis revealed that the intron-exon structure of RhoBTB1 and 2 are also quite similar and have only one common intron with RhoBTB3.[5]
RhoBTB1 and 2 were not detected during mouse development, but RhoBTB3 was detected strongly between embryonic days 11.5 through 17.5.[5] Additionally, RhoBTB1 and 2 are localized to vesicular structures,[6] while RhoBTB3 is localized to the trans-Golgi network.[7] | https://www.wikidoc.org/index.php/RhoBTB | |
ba87b08e08a181f72b5a3c67b1c47ccd61b1deaa | wikidoc | Ribose | Ribose
Ribose (ɹˈaɪbəʊs, ɹˈaɪbəɹʊs), primarily seen as D-ribose, is an aldopentose — a monosaccharide containing five carbon atoms, and including an aldehyde functional group in its linear form. It has the chemical formula Template:Carbon5Template:Hydrogen10Template:Oxygen5, and was discovered in 1905 by Phoebus Levene.
As a component of the RNA that is used for genetic transcription, ribose is critical to living creatures. It is related to deoxyribose, which is a component of DNA. It is also a component of ATP, NADH, and several other chemicals that are critical to metabolism.
Refer to the article on deoxyribose for more information on both sugars, how they relate to each other, and how they relate to genetic material.
# Isomerism
D-Ribose has the same configuration at its penultimate carbon atom as D-glyceraldehyde. | Ribose
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Ribose (ɹˈaɪbəʊs[1], ɹˈaɪbəɹʊs[2]), primarily seen as D-ribose, is an aldopentose — a monosaccharide containing five carbon atoms, and including an aldehyde functional group in its linear form. It has the chemical formula Template:Carbon5Template:Hydrogen10Template:Oxygen5, and was discovered in 1905 by Phoebus Levene.
As a component of the RNA that is used for genetic transcription, ribose is critical to living creatures. It is related to deoxyribose, which is a component of DNA. It is also a component of ATP, NADH, and several other chemicals that are critical to metabolism.
Refer to the article on deoxyribose for more information on both sugars, how they relate to each other, and how they relate to genetic material.
# Isomerism
D-Ribose has the same configuration at its penultimate carbon atom as D-glyceraldehyde. | https://www.wikidoc.org/index.php/Ribose | |
0c4f066ace95ee545735351900204f7d36ef876c | wikidoc | Ricola | Ricola
Ricola AG is a well known manufacturer of cough drops and breath mints in Switzerland. The company focuses primarily on using herbal ingredients.
# History
The company was founded by Emil Wilhelm Richterich in 1930. Today 2007, it is managed by Felix Richterich. The company's name is an abbreviation of the words - Richterich & Compagnie Laufen. The headquarter of Ricola is located in the Swiss town Laufen.
# Herbs
While the active ingredient in most Ricola products is menthol, an important part of Ricola products is the herb mixture. Sixteen herbs are mentioned on Ricola's U.S. website:
- Elder (Sambucus nigra)
- Horehound (Marrubium vulgare)
- Mallow (Malva silvestris)
- Peppermint (Mentha × piperita)
- Sage (Salvia officinalis)
- Thyme (Thymus vulgaris)
- Cowslip (Primula veris)
- Burnet (Pimpinella saxifraga)
- Yarrow (Achillea millefolium)
- Marsh Mallow (Althaea officinalis)
- Lady's Mantle (Alchemilla vulgaris)
- Speedwell, aka Veronica (Veronica officinalis)
- Plantain (Plantago lanceolata)
- Hyssop (Hyssopus officinalis)
- Lemon Balm, aka Lemon Mint, Melissa (Melissa officinalis)
- "Orange-Mint" (Mentha citrata)
Of these, the first thirteen are noted as Ricola's classic herbal mixture. Note also that while only ten herbs are listed on packages of Ricola cough drops sold in the U.S., two of these are not mentioned at all on Ricola's website. These are Linden Flowers and Wild Thyme.
# Business culture
Ricola holds assets of 245 Million CHF (Swiss Francs) (2004) and employs 400 workers. Around 200 independent produce companies in the surrounding area service Ricola. In order to obtain enough herbs for the different production of herbal drops, the firm also owns five private herbal gardens in Zermatt, Kandersteg, Pontresina, and Nenzlingen.
Ricola are well-known for their commercials featuring mountaineers shouting "Ri-co-la!" and blowing through a large Alphorn.
# Products
Ricola has various kinds of different products along with different flavors for each product.
- Cough Drops
Original Herb
Honey Lemon with Echinacea
Orange Spice with Echinacea.
- Original Herb
- Honey Lemon with Echinacea
- Orange Spice with Echinacea.
- Sugar Free Cough Drops
Sugar Free Mountain Herb
Sugar Free Green Tea with Echinacea
- Sugar Free Mountain Herb
- Sugar Free Green Tea with Echinacea
- Throat Drops
Lemon Mint
Cherry Honey
Honey Herb
- Lemon Mint
- Cherry Honey
- Honey Herb
- Sugar Free Throat Drops
Sugar Free Lemon Mint
Sugar Free Cherry
- Sugar Free Lemon Mint
- Sugar Free Cherry
- Nature's Protection: contains daily value of Vitamin C
Cranberry
Elderberry
Orange Mint
- Cranberry
- Elderberry
- Orange Mint
- Ricola Refreshers
Lemon Mint
Elderflower
- Lemon Mint
- Elderflower
- Ricola Breath Mints
Spearmint
Peppermint
LemonMint
- Spearmint
- Peppermint
- LemonMint
# Ricola Herb Gardens
The company promotes natural earth gardens for cultivation in Swiss Mountain regions. These areas include:
- Nenzlingen
- Trogberg
- Kandersteg
- Zermatt
- Pontresina | Ricola
Template:Expand
Ricola AG is a well known manufacturer of cough drops and breath mints in Switzerland. The company focuses primarily on using herbal ingredients.
### History
The company was founded by Emil Wilhelm Richterich in 1930. Today 2007, it is managed by Felix Richterich. The company's name is an abbreviation of the words - Richterich & Compagnie Laufen. The headquarter of Ricola is located in the Swiss town Laufen.
### Herbs
While the active ingredient in most Ricola products is menthol, an important part of Ricola products is the herb mixture. Sixteen herbs are mentioned on Ricola's U.S. website:
- Elder (Sambucus nigra)
- Horehound (Marrubium vulgare)
- Mallow (Malva silvestris)
- Peppermint (Mentha × piperita)
- Sage (Salvia officinalis)
- Thyme (Thymus vulgaris)
- Cowslip (Primula veris)
- Burnet (Pimpinella saxifraga)
- Yarrow (Achillea millefolium)
- Marsh Mallow (Althaea officinalis)
- Lady's Mantle (Alchemilla vulgaris)
- Speedwell, aka Veronica (Veronica officinalis)
- Plantain (Plantago lanceolata)
- Hyssop (Hyssopus officinalis)
- Lemon Balm, aka Lemon Mint, Melissa (Melissa officinalis)
- "Orange-Mint" (Mentha citrata)
Of these, the first thirteen are noted as Ricola's classic herbal mixture. Note also that while only ten herbs are listed on packages of Ricola cough drops sold in the U.S., two of these are not mentioned at all on Ricola's website. These are Linden Flowers and Wild Thyme.
### Business culture
Ricola holds assets of 245 Million CHF (Swiss Francs) (2004) and employs 400 workers. Around 200 independent produce companies in the surrounding area service Ricola. In order to obtain enough herbs for the different production of herbal drops, the firm also owns five private herbal gardens in Zermatt, Kandersteg, Pontresina, and Nenzlingen.
Ricola are well-known for their commercials featuring mountaineers shouting "Ri-co-la!" and blowing through a large Alphorn.
### Products
Ricola has various kinds of different products along with different flavors for each product.
- Cough Drops
Original Herb
Honey Lemon with Echinacea
Orange Spice with Echinacea.
- Original Herb
- Honey Lemon with Echinacea
- Orange Spice with Echinacea.
- Sugar Free Cough Drops
Sugar Free Mountain Herb
Sugar Free Green Tea with Echinacea
- Sugar Free Mountain Herb
- Sugar Free Green Tea with Echinacea
- Throat Drops
Lemon Mint
Cherry Honey
Honey Herb
- Lemon Mint
- Cherry Honey
- Honey Herb
- Sugar Free Throat Drops
Sugar Free Lemon Mint
Sugar Free Cherry
- Sugar Free Lemon Mint
- Sugar Free Cherry
- Nature's Protection: contains daily value of Vitamin C
Cranberry
Elderberry
Orange Mint
- Cranberry
- Elderberry
- Orange Mint
- Ricola Refreshers
Lemon Mint
Elderflower
- Lemon Mint
- Elderflower
- Ricola Breath Mints
Spearmint
Peppermint
LemonMint
- Spearmint
- Peppermint
- LemonMint
[1]
### Ricola Herb Gardens
The company promotes natural earth gardens for cultivation in Swiss Mountain regions. These areas include:
- Nenzlingen
- Trogberg
- Kandersteg
- Zermatt
- Pontresina
[2]
# External links
- Ricola Website
- Ricola USA Website
de:Ricola
no:Ricola
nn:Ricola | https://www.wikidoc.org/index.php/Ricola | |
402f05c73cdcb7143c5e1590e44348b26c68207b | wikidoc | Rodent | Rodent
Rodentia is an order of mammals also known as rodents, characterised by two continuously-growing incisors in the upper and lower jaws which must be kept short by gnawing.
Forty percent of mammal species are rodents, and they are found in vast numbers on all continents other than Antarctica. Common rodents include mice, rats, squirrels, chipmunks, gophers, porcupines, beavers, hamsters, gerbils, guinea pigs, chinchillas and degus. Rodents have sharp incisors that they use to gnaw wood, break into food, and bite predators. Most eat seeds or plants, though some have more varied diets. Some species have historically been pests, eating human seed stores and spreading disease.
# Size and range of order
In terms of number of species — although not necessarily in terms of number of organisms (population) or biomass — rodents make up the largest order of mammals. There are about 2,277 species of rodents (Wilson and Reeder, 2005), with over 40 percent of mammalian species belonging to the order. Their success is probably due to their small size, short breeding cycle, and ability to gnaw and eat a wide variety of foods. (Lambert, 2000)
Rodents are found in vast numbers on all continents except Antarctica, most islands, and in all habitats except oceans. They are the only placental order, other than bats (Chiroptera) and Pinnipeds, to reach Australia without human introduction.
# Characteristics
Many rodents are small; the tiny African pygmy mouse is only 6 cm in length and 7 grams in weight. On the other hand, the capybara can weigh up to 65 (Expression error: Missing operand for *. ), and the largest known rodent, the extinct Josephoartigasia monesi, is estimated to weigh about 1,000 (Expression error: Missing operand for *. ), and possibly up to 1,534 (Expression error: Missing operand for *. ) or 2,586 (Expression error: Missing operand for *. ).
Rodents have two incisors in the upper as well as in the lower jaw which grow continuously and must be kept worn down by gnawing; this is the origin of the name, from the Latin rodere, to gnaw, and dens, dentis, tooth. These teeth are used for cutting wood, biting through the skin of fruit, or for defense. The teeth have enamel on the outside and exposed dentine on the inside, so they self-sharpen during gnawing. Rodents lack canines, and have a space between their incisors and premolars. Nearly all rodents feed on plants, seeds in particular, but there are a few exceptions which eat insects or fish. Some squirrels are known to eat passerine birds like cardinals and blue jays.
Rodents are important in many ecosystems because they reproduce rapidly, and can function as food sources for predators, mechanisms for seed dispersal, and as disease vectors. Humans use rodents as a source of fur, as pets, as model organisms in animal testing, for food, and even in detecting landmines.
Members of non-rodent orders such as Chiroptera (bats), Scandentia (treeshrews), Insectivora (moles, shrews and hedgehogs), Lagomorpha (hares, rabbits and pikas) and mustelid carnivores such as weasels and mink are sometimes confused with rodents.
# Evolution
The fossil record of rodent-like mammals begins shortly after the extinction of the non-avian dinosaurs 65 million years ago, as early as the Paleocene. Some molecular clock data, however, suggests that modern rodents (members of the order Rodentia) already appeared in the late Cretaceous, although other molecular divergence estimations are in agreement with the fossil record. By the end of the Eocene epoch, relatives of beavers, dormouse, squirrels, and other groups appeared in the fossil record. They originated in Laurasia, the formerly joined continents of North America, Europe, and Asia. Some species colonized Africa, giving rise to the earliest hystricognaths. There is, however, a minority belief in the scientific community that evidence from mitochondrial DNA indicates that the Hystricognathi may belong to a different evolutionary offshoot and therefore a different order. From there hystricognaths rafted to South America, an isolated continent during the Oligocene and Miocene epochs. By the Miocene, Africa collided with Asia, allowing rodents such as the porcupine to spread into Eurasia. During the Pliocene, rodent fossils appeared in Australia. Even though marsupials are the prominent mammals in Australia, rodents make up almost 25% of the mammals on the continent. Meanwhile, the Americas became joined and some rodents expanded into new territory; mice headed south and porcupines headed north.
# Classification
## Standard classification
The rodents are part of the clades: Glires (along with lagomorphs), Euarchontoglires (along with lagomorphs, primates, treeshrews, and colugos), and Boreoeutheria (along with most other placental mammals). The order Rodentia may be divided into suborders, infraorders, superfamilies and families.
Classification scheme:
ORDER RODENTIA (from Latin, rodere, to gnaw)
- Suborder Anomaluromorpha
Family Anomaluridae: scaly-tailed squirrels
Family Pedetidae: springhares
- Family Anomaluridae: scaly-tailed squirrels
- Family Pedetidae: springhares
- Suborder Castorimorpha
Superfamily Castoroidea
Family Castoridae: beavers
Superfamily Geomyoidea
Family Geomyidae: pocket gophers (true gophers)
Family Heteromyidae: kangaroo rats and kangaroo mice
- Superfamily Castoroidea
Family Castoridae: beavers
- Family Castoridae: beavers
- Superfamily Geomyoidea
Family Geomyidae: pocket gophers (true gophers)
Family Heteromyidae: kangaroo rats and kangaroo mice
- Family Geomyidae: pocket gophers (true gophers)
- Family Heteromyidae: kangaroo rats and kangaroo mice
- Suborder Hystricomorpha
Family incertae sedis Diatomyidae: Laotian rock rat
Infraorder Ctenodactylomorphi
Family Ctenodactylidae: gundis
Infraorder Hystricognathi
Family Bathyergidae: African mole rats
Family Hystricidae: Old World porcupines
Family Petromuridae: dassie rat
Family Thryonomyidae: cane rats
Parvorder Caviomorpha
Family †Heptaxodontidae: giant hutias
Family Abrocomidae: chinchilla rats
Family Capromyidae: hutias
Family Caviidae: cavies, including guinea pigs and the capybara
Family Chinchillidae: chinchillas and viscachas
Family Ctenomyidae: tuco-tucos
Family Dasyproctidae: agoutis
Family Dinomyidae: pacaranas
Family Echimyidae: spiny rats
Family Erethizontidae: New World porcupines
Family Myocastoridae: nutria
Family Octodontidae: octodonts
- Family incertae sedis Diatomyidae: Laotian rock rat
- Infraorder Ctenodactylomorphi
Family Ctenodactylidae: gundis
- Family Ctenodactylidae: gundis
- Infraorder Hystricognathi
Family Bathyergidae: African mole rats
Family Hystricidae: Old World porcupines
Family Petromuridae: dassie rat
Family Thryonomyidae: cane rats
Parvorder Caviomorpha
Family †Heptaxodontidae: giant hutias
Family Abrocomidae: chinchilla rats
Family Capromyidae: hutias
Family Caviidae: cavies, including guinea pigs and the capybara
Family Chinchillidae: chinchillas and viscachas
Family Ctenomyidae: tuco-tucos
Family Dasyproctidae: agoutis
Family Dinomyidae: pacaranas
Family Echimyidae: spiny rats
Family Erethizontidae: New World porcupines
Family Myocastoridae: nutria
Family Octodontidae: octodonts
- Family Bathyergidae: African mole rats
- Family Hystricidae: Old World porcupines
- Family Petromuridae: dassie rat
- Family Thryonomyidae: cane rats
- Parvorder Caviomorpha
Family †Heptaxodontidae: giant hutias
Family Abrocomidae: chinchilla rats
Family Capromyidae: hutias
Family Caviidae: cavies, including guinea pigs and the capybara
Family Chinchillidae: chinchillas and viscachas
Family Ctenomyidae: tuco-tucos
Family Dasyproctidae: agoutis
Family Dinomyidae: pacaranas
Family Echimyidae: spiny rats
Family Erethizontidae: New World porcupines
Family Myocastoridae: nutria
Family Octodontidae: octodonts
- Family †Heptaxodontidae: giant hutias
- Family Abrocomidae: chinchilla rats
- Family Capromyidae: hutias
- Family Caviidae: cavies, including guinea pigs and the capybara
- Family Chinchillidae: chinchillas and viscachas
- Family Ctenomyidae: tuco-tucos
- Family Dasyproctidae: agoutis
- Family Dinomyidae: pacaranas
- Family Echimyidae: spiny rats
- Family Erethizontidae: New World porcupines
- Family Myocastoridae: nutria
- Family Octodontidae: octodonts
- Suborder Myomorpha
Superfamily Dipodoidea
Family Dipodidae: jerboas and jumping mice
Superfamily Muroidea
Family Calomyscidae: mouse-like hamsters
Family Cricetidae: hamsters, New World rats and mice, voles
Family Muridae: true mice and rats, gerbils, spiny mice, crested rat
Family Nesomyidae: climbing mice, rock mice, white-tailed rat, Malagasy rats and mice
Family Platacanthomyidae: spiny dormice
Family Spalacidae: mole rats, bamboo rats, and zokors
- Superfamily Dipodoidea
Family Dipodidae: jerboas and jumping mice
- Family Dipodidae: jerboas and jumping mice
- Superfamily Muroidea
Family Calomyscidae: mouse-like hamsters
Family Cricetidae: hamsters, New World rats and mice, voles
Family Muridae: true mice and rats, gerbils, spiny mice, crested rat
Family Nesomyidae: climbing mice, rock mice, white-tailed rat, Malagasy rats and mice
Family Platacanthomyidae: spiny dormice
Family Spalacidae: mole rats, bamboo rats, and zokors
- Family Calomyscidae: mouse-like hamsters
- Family Cricetidae: hamsters, New World rats and mice, voles
- Family Muridae: true mice and rats, gerbils, spiny mice, crested rat
- Family Nesomyidae: climbing mice, rock mice, white-tailed rat, Malagasy rats and mice
- Family Platacanthomyidae: spiny dormice
- Family Spalacidae: mole rats, bamboo rats, and zokors
- Suborder Sciuromorpha
Family Aplodontiidae: mountain beaver
Family Gliridae (also Myoxidae, Muscardinidae): dormice
Family Sciuridae: squirrels, including chipmunks, prairie dogs, & marmots
- Family Aplodontiidae: mountain beaver
- Family Gliridae (also Myoxidae, Muscardinidae): dormice
- Family Sciuridae: squirrels, including chipmunks, prairie dogs, & marmots
## Alternate classifications
The above taxonomy uses the shape of the lower jaw (sciurognath or hystricognath) as the primary character. This is the most commonly used approach for dividing the order into suborders. Many older references emphasize the zygomasseteric system (suborders Protrogomorpha, Sciuromorpha, Hystricomorpha, and Myomorpha).
Several molecular phylogenetic studies have used gene sequences to determine the relationships among rodents, but these studies are yet to produce a single consistent and well-supported taxonomy. Some clades have been consistently produced such as:
- Ctenohystrica contains:
Ctenodactylidae (gundis)
Hystricognathi containing:
Hystricidae
An unnamed clade containing:
Phiomorpha
Caviomorpha
- Ctenodactylidae (gundis)
- Hystricognathi containing:
Hystricidae
An unnamed clade containing:
Phiomorpha
Caviomorpha
- Hystricidae
- An unnamed clade containing:
Phiomorpha
Caviomorpha
- Phiomorpha
- Caviomorpha
- An unnamed clade contains:
Gliridae
Sciuroidea containing:
Aplodontiidae
Sciuridae
- Gliridae
- Sciuroidea containing:
Aplodontiidae
Sciuridae
- Aplodontiidae
- Sciuridae
- Myodonta includes:
Dipodoidea
Muroidea
- Dipodoidea
- Muroidea
The positions of the Castoridae, Geomyoidea, Anomaluridae, and Pedetidae are still being debated.
## Monophyly or polyphyly?
In 1991, a paper submitted to Nature proposed that caviomorphs should be reclassified as a separate order (similar to Lagomorpha), based on an analysis of the amino acid sequences of guinea pigs. This hypothesis was refined in a 1992 paper, which asserted the possibility that caviomorphs may have diverged from myomorphs prior to later divergences of Myomorpha; this would mean caviomorphs, or possibly hystricomorphs, would be moved out of the rodent classification into a separate order. A minority scientific opinion briefly emerged arguing that guinea pigs, degus, and other caviomorphs are not rodents, while several papers were put forward in support of rodent monophyly. Subsequent studies published since 2002, using wider taxon and gene samples, have restored consensus among mammalian biologists that the order Rodentia is monophyletic.
# Notes
- Adkins, R. M. E. L. Gelke, D. Rowe, and R. L. Honeycutt. 2001. Molecular phylogeny and divergence time estimates for major rodent groups: Evidence from multiple genes. Molecular Biology and Evolution, 18:777-791.
- Carleton, M. D. and G. G. Musser. 2005. Order Rodentia. Pp 745-752 in Mammal Species of the World A Taxonomic and Geographic Reference. Johns Hopkins University Press, Baltimore.
- David Lambert and the Diagram Group. The Field Guide to Prehistoric Life. New York: Facts on File Publications, 1985. ISBN 0-8160-1125-7
- Jahn, G. C. 1998. “When Birds Sing at Midnight” War Against Rats Newsletter 6:10-11.
- Leung LKP, Peter G. Cox, Gary C. Jahn and Robert Nugent. 2002. Evaluating rodent management with Cambodian rice farmers. Cambodian Journal of Agriculture Vol. 5, pp. 21-26.
- McKenna, Malcolm C., and Bell, Susan K. 1997. Classification of Mammals Above the Species Level. Columbia University Press, New York, 631 pp. ISBN 0-231-11013-8
- Nowak, R. M. 1999. Walker's Mammals of the World, Vol. 2. Johns Hopkins University Press, London.
- Steppan, S. J., R. A. Adkins, and J. Anderson. 2004. Phylogeny and divergence date estimates of rapid radiations in muroid rodents based on multiple nuclear genes. Systematic Biology, 53:533-553.
- University of California Museum of Paleontology (UCMP). 2007 "Rodentia".
- Wilson, D. E. and D. M. Reeder, eds. 2005. Mammal Species of the World A Taxonomic and Geographic Reference. Johns Hopkins University Press, Baltimore.
# Links
- Website on African rodentia :
- Rodent Photos | Rodent
Rodentia is an order of mammals also known as rodents, characterised by two continuously-growing incisors in the upper and lower jaws which must be kept short by gnawing.[1][2]
Forty percent of mammal species are rodents, and they are found in vast numbers on all continents other than Antarctica. Common rodents include mice, rats, squirrels, chipmunks, gophers, porcupines, beavers, hamsters, gerbils, guinea pigs, chinchillas and degus.[1] Rodents have sharp incisors that they use to gnaw wood, break into food, and bite predators. Most eat seeds or plants, though some have more varied diets. Some species have historically been pests, eating human seed stores and spreading disease.
# Size and range of order
In terms of number of species — although not necessarily in terms of number of organisms (population) or biomass — rodents make up the largest order of mammals. There are about 2,277 species of rodents (Wilson and Reeder, 2005), with over 40 percent of mammalian species belonging to the order.[3] Their success is probably due to their small size, short breeding cycle, and ability to gnaw and eat a wide variety of foods. (Lambert, 2000)
Rodents are found in vast numbers on all continents except Antarctica, most islands, and in all habitats except oceans. They are the only placental order, other than bats (Chiroptera) and Pinnipeds, to reach Australia without human introduction.
# Characteristics
Many rodents are small; the tiny African pygmy mouse is only 6 cm in length and 7 grams in weight. On the other hand, the capybara can weigh up to 65 (Expression error: Missing operand for *. ), and the largest known rodent, the extinct Josephoartigasia monesi, is estimated to weigh about 1,000 (Expression error: Missing operand for *. ), and possibly up to 1,534 (Expression error: Missing operand for *. )[4] or 2,586 (Expression error: Missing operand for *. )[5].
Rodents have two incisors in the upper as well as in the lower jaw which grow continuously and must be kept worn down by gnawing; this is the origin of the name, from the Latin rodere, to gnaw, and dens, dentis, tooth. These teeth are used for cutting wood, biting through the skin of fruit, or for defense. The teeth have enamel on the outside and exposed dentine on the inside, so they self-sharpen during gnawing. Rodents lack canines, and have a space between their incisors and premolars. Nearly all rodents feed on plants, seeds in particular, but there are a few exceptions which eat insects or fish. Some squirrels are known to eat passerine birds like cardinals and blue jays.
Rodents are important in many ecosystems because they reproduce rapidly, and can function as food sources for predators, mechanisms for seed dispersal, and as disease vectors. Humans use rodents as a source of fur, as pets, as model organisms in animal testing, for food, and even in detecting landmines.[6]
Members of non-rodent orders such as Chiroptera (bats), Scandentia (treeshrews), Insectivora (moles, shrews and hedgehogs), Lagomorpha (hares, rabbits and pikas) and mustelid carnivores such as weasels and mink are sometimes confused with rodents.
# Evolution
The fossil record of rodent-like mammals begins shortly after the extinction of the non-avian dinosaurs 65 million years ago, as early as the Paleocene. Some molecular clock data, however, suggests that modern rodents (members of the order Rodentia) already appeared in the late Cretaceous, although other molecular divergence estimations are in agreement with the fossil record.[7][8] By the end of the Eocene epoch, relatives of beavers, dormouse, squirrels, and other groups appeared in the fossil record. They originated in Laurasia, the formerly joined continents of North America, Europe, and Asia. Some species colonized Africa, giving rise to the earliest hystricognaths. There is, however, a minority belief in the scientific community that evidence from mitochondrial DNA indicates that the Hystricognathi may belong to a different evolutionary offshoot and therefore a different order. From there hystricognaths rafted to South America, an isolated continent during the Oligocene and Miocene epochs. By the Miocene, Africa collided with Asia, allowing rodents such as the porcupine to spread into Eurasia. During the Pliocene, rodent fossils appeared in Australia. Even though marsupials are the prominent mammals in Australia, rodents make up almost 25% of the mammals on the continent. Meanwhile, the Americas became joined and some rodents expanded into new territory; mice headed south and porcupines headed north.
# Classification
## Standard classification
The rodents are part of the clades: Glires (along with lagomorphs), Euarchontoglires (along with lagomorphs, primates, treeshrews, and colugos), and Boreoeutheria (along with most other placental mammals). The order Rodentia may be divided into suborders, infraorders, superfamilies and families.
Classification scheme:
ORDER RODENTIA (from Latin, rodere, to gnaw)
- Suborder Anomaluromorpha
Family Anomaluridae: scaly-tailed squirrels
Family Pedetidae: springhares
- Family Anomaluridae: scaly-tailed squirrels
- Family Pedetidae: springhares
- Suborder Castorimorpha
Superfamily Castoroidea
Family Castoridae: beavers
Superfamily Geomyoidea
Family Geomyidae: pocket gophers (true gophers)
Family Heteromyidae: kangaroo rats and kangaroo mice
- Superfamily Castoroidea
Family Castoridae: beavers
- Family Castoridae: beavers
- Superfamily Geomyoidea
Family Geomyidae: pocket gophers (true gophers)
Family Heteromyidae: kangaroo rats and kangaroo mice
- Family Geomyidae: pocket gophers (true gophers)
- Family Heteromyidae: kangaroo rats and kangaroo mice
- Suborder Hystricomorpha
Family incertae sedis Diatomyidae: Laotian rock rat
Infraorder Ctenodactylomorphi
Family Ctenodactylidae: gundis
Infraorder Hystricognathi
Family Bathyergidae: African mole rats
Family Hystricidae: Old World porcupines
Family Petromuridae: dassie rat
Family Thryonomyidae: cane rats
Parvorder Caviomorpha
Family †Heptaxodontidae: giant hutias
Family Abrocomidae: chinchilla rats
Family Capromyidae: hutias
Family Caviidae: cavies, including guinea pigs and the capybara
Family Chinchillidae: chinchillas and viscachas
Family Ctenomyidae: tuco-tucos
Family Dasyproctidae: agoutis
Family Dinomyidae: pacaranas
Family Echimyidae: spiny rats
Family Erethizontidae: New World porcupines
Family Myocastoridae: nutria
Family Octodontidae: octodonts
- Family incertae sedis Diatomyidae: Laotian rock rat
- Infraorder Ctenodactylomorphi
Family Ctenodactylidae: gundis
- Family Ctenodactylidae: gundis
- Infraorder Hystricognathi
Family Bathyergidae: African mole rats
Family Hystricidae: Old World porcupines
Family Petromuridae: dassie rat
Family Thryonomyidae: cane rats
Parvorder Caviomorpha
Family †Heptaxodontidae: giant hutias
Family Abrocomidae: chinchilla rats
Family Capromyidae: hutias
Family Caviidae: cavies, including guinea pigs and the capybara
Family Chinchillidae: chinchillas and viscachas
Family Ctenomyidae: tuco-tucos
Family Dasyproctidae: agoutis
Family Dinomyidae: pacaranas
Family Echimyidae: spiny rats
Family Erethizontidae: New World porcupines
Family Myocastoridae: nutria
Family Octodontidae: octodonts
- Family Bathyergidae: African mole rats
- Family Hystricidae: Old World porcupines
- Family Petromuridae: dassie rat
- Family Thryonomyidae: cane rats
- Parvorder Caviomorpha
Family †Heptaxodontidae: giant hutias
Family Abrocomidae: chinchilla rats
Family Capromyidae: hutias
Family Caviidae: cavies, including guinea pigs and the capybara
Family Chinchillidae: chinchillas and viscachas
Family Ctenomyidae: tuco-tucos
Family Dasyproctidae: agoutis
Family Dinomyidae: pacaranas
Family Echimyidae: spiny rats
Family Erethizontidae: New World porcupines
Family Myocastoridae: nutria
Family Octodontidae: octodonts
- Family †Heptaxodontidae: giant hutias
- Family Abrocomidae: chinchilla rats
- Family Capromyidae: hutias
- Family Caviidae: cavies, including guinea pigs and the capybara
- Family Chinchillidae: chinchillas and viscachas
- Family Ctenomyidae: tuco-tucos
- Family Dasyproctidae: agoutis
- Family Dinomyidae: pacaranas
- Family Echimyidae: spiny rats
- Family Erethizontidae: New World porcupines
- Family Myocastoridae: nutria
- Family Octodontidae: octodonts
- Suborder Myomorpha
Superfamily Dipodoidea
Family Dipodidae: jerboas and jumping mice
Superfamily Muroidea
Family Calomyscidae: mouse-like hamsters
Family Cricetidae: hamsters, New World rats and mice, voles
Family Muridae: true mice and rats, gerbils, spiny mice, crested rat
Family Nesomyidae: climbing mice, rock mice, white-tailed rat, Malagasy rats and mice
Family Platacanthomyidae: spiny dormice
Family Spalacidae: mole rats, bamboo rats, and zokors
- Superfamily Dipodoidea
Family Dipodidae: jerboas and jumping mice
- Family Dipodidae: jerboas and jumping mice
- Superfamily Muroidea
Family Calomyscidae: mouse-like hamsters
Family Cricetidae: hamsters, New World rats and mice, voles
Family Muridae: true mice and rats, gerbils, spiny mice, crested rat
Family Nesomyidae: climbing mice, rock mice, white-tailed rat, Malagasy rats and mice
Family Platacanthomyidae: spiny dormice
Family Spalacidae: mole rats, bamboo rats, and zokors
- Family Calomyscidae: mouse-like hamsters
- Family Cricetidae: hamsters, New World rats and mice, voles
- Family Muridae: true mice and rats, gerbils, spiny mice, crested rat
- Family Nesomyidae: climbing mice, rock mice, white-tailed rat, Malagasy rats and mice
- Family Platacanthomyidae: spiny dormice
- Family Spalacidae: mole rats, bamboo rats, and zokors
- Suborder Sciuromorpha
Family Aplodontiidae: mountain beaver
Family Gliridae (also Myoxidae, Muscardinidae): dormice
Family Sciuridae: squirrels, including chipmunks, prairie dogs, & marmots
- Family Aplodontiidae: mountain beaver
- Family Gliridae (also Myoxidae, Muscardinidae): dormice
- Family Sciuridae: squirrels, including chipmunks, prairie dogs, & marmots
## Alternate classifications
The above taxonomy uses the shape of the lower jaw (sciurognath or hystricognath) as the primary character. This is the most commonly used approach for dividing the order into suborders. Many older references emphasize the zygomasseteric system (suborders Protrogomorpha, Sciuromorpha, Hystricomorpha, and Myomorpha).
Several molecular phylogenetic studies have used gene sequences to determine the relationships among rodents, but these studies are yet to produce a single consistent and well-supported taxonomy. Some clades have been consistently produced such as:
- Ctenohystrica contains:
Ctenodactylidae (gundis)
Hystricognathi containing:
Hystricidae
An unnamed clade containing:
Phiomorpha
Caviomorpha
- Ctenodactylidae (gundis)
- Hystricognathi containing:
Hystricidae
An unnamed clade containing:
Phiomorpha
Caviomorpha
- Hystricidae
- An unnamed clade containing:
Phiomorpha
Caviomorpha
- Phiomorpha
- Caviomorpha
- An unnamed clade contains:
Gliridae
Sciuroidea containing:
Aplodontiidae
Sciuridae
- Gliridae
- Sciuroidea containing:
Aplodontiidae
Sciuridae
- Aplodontiidae
- Sciuridae
- Myodonta includes:
Dipodoidea
Muroidea
- Dipodoidea
- Muroidea
The positions of the Castoridae, Geomyoidea, Anomaluridae, and Pedetidae are still being debated.
## Monophyly or polyphyly?
In 1991, a paper submitted to Nature proposed that caviomorphs should be reclassified as a separate order (similar to Lagomorpha), based on an analysis of the amino acid sequences of guinea pigs.[9] This hypothesis was refined in a 1992 paper, which asserted the possibility that caviomorphs may have diverged from myomorphs prior to later divergences of Myomorpha; this would mean caviomorphs, or possibly hystricomorphs, would be moved out of the rodent classification into a separate order.[10] A minority scientific opinion briefly emerged arguing that guinea pigs, degus, and other caviomorphs are not rodents,[11][12] while several papers were put forward in support of rodent monophyly.[13][14][15] Subsequent studies published since 2002, using wider taxon and gene samples, have restored consensus among mammalian biologists that the order Rodentia is monophyletic.[16][17]
# Notes
- Adkins, R. M. E. L. Gelke, D. Rowe, and R. L. Honeycutt. 2001. Molecular phylogeny and divergence time estimates for major rodent groups: Evidence from multiple genes. Molecular Biology and Evolution, 18:777-791.
- Carleton, M. D. and G. G. Musser. 2005. Order Rodentia. Pp 745-752 in Mammal Species of the World A Taxonomic and Geographic Reference. Johns Hopkins University Press, Baltimore.
- David Lambert and the Diagram Group. The Field Guide to Prehistoric Life. New York: Facts on File Publications, 1985. ISBN 0-8160-1125-7
- Jahn, G. C. 1998. “When Birds Sing at Midnight” War Against Rats Newsletter 6:10-11. [1]
- Leung LKP, Peter G. Cox, Gary C. Jahn and Robert Nugent. 2002. Evaluating rodent management with Cambodian rice farmers. Cambodian Journal of Agriculture Vol. 5, pp. 21-26.
- McKenna, Malcolm C., and Bell, Susan K. 1997. Classification of Mammals Above the Species Level. Columbia University Press, New York, 631 pp. ISBN 0-231-11013-8
- Nowak, R. M. 1999. Walker's Mammals of the World, Vol. 2. Johns Hopkins University Press, London.
- Steppan, S. J., R. A. Adkins, and J. Anderson. 2004. Phylogeny and divergence date estimates of rapid radiations in muroid rodents based on multiple nuclear genes. Systematic Biology, 53:533-553.
- University of California Museum of Paleontology (UCMP). 2007 "Rodentia". [2]
- Wilson, D. E. and D. M. Reeder, eds. 2005. Mammal Species of the World A Taxonomic and Geographic Reference. Johns Hopkins University Press, Baltimore.
# Links
- Website on African rodentia : http://projects.biodiversity.be/africanrodentia
- Rodent Photos | https://www.wikidoc.org/index.php/Rodent | |
981fb6d67eaa8f70c25396234194dd226e2f06d8 | wikidoc | S100A1 | S100A1
S100A1, also known as S100 calcium-binding protein A1 is a protein which in humans is encoded by the S100A1 gene. S100A1 is highly expressed in cardiac and skeletal muscle, and localizes to Z-discs and sarcoplasmic reticulum. S100A1 has shown promise as an effective candidate for gene therapy to treat post-myocardially infarcted cardiac tissue.
# Structure
S100A1 is a member of the S100 family of proteins expressed in cardiac muscle, skeletal muscle and brain, with highest density at Z-lines and sarcoplasmic reticulum. S100A1 contains 4 EF-hand calcium-binding motifs in its dimerized form, and can exist as either a hetero or homodimer. The S100A1 homodimer is high affinity (nanomolar range or tighter), and is formed through hydrophobic packing of an X-type 4-helix bundle created between helices 1, 1', 4, and 4'. Protein nuclear magnetic resonance spectroscopy structural information on the homodimeric form of this protein shows that each monomer is helical and contains two EF-hand calcium-binding loops; one in the N-terminus and a canonical EF hand in the C-terminus having higher calcium affinity (dissociation constant of roughly 20 micromolar). The two EF hand domains neighbor each other in three dimensional space, and are connected to each other through a short beta sheet region (residues 27–29 and 68–70).
Upon binding calcium, helix 3 of S100A1 re-orients from being relatively antiparallel to helix 4 to being roughly perpendicular. This conformational change is different from most EF hands, in that the entering helix, and not the exiting helix, moves. This conformational change exposes a large hydrophobic pocket between helix 3, 4, and the hinge region of S100A1 that is involved in virtually all calcium-dependent target protein interactions. These biophysical properties seem to be well conserved across the S100 family of proteins. Helix 3, 4, and the hinge region are the most divergent areas between individual S100 proteins, and so it is likely that the sequence of these regions is pivotal in fine-tuning calcium-dependent target binding by S100 proteins. S-Nitrosylation of S100A1 at Cys85 reorganizes the conformation of S100A1 at the C-terminal helix and the linker connecting the two EF hand domains.
The most accurate high-resolution solution structure of human apo-S100A1 protein (PDB accession code: 2L0P) has been determined by means of NMR spectroscopy in 2011.
S100 genes include at least 19 members which are located as a cluster on chromosome 1q21.
# Function
S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. This protein may function in stimulation of Ca2+-induced Ca2+ release, inhibition of microtubule assembly, and inhibition of protein kinase C-mediated phosphorylation.
S100A1 is expressed during development in the primitive heart at embryonic day 8 in levels that are similar between atria and ventricles. As development progresses up to embryonic day 17.5, S100A1 expression shifts to a lower levels in atria and higher levels in ventricular myocardium.
S100A1 has shown to be a regulator of myocardial contractility. S100A1 overexpression via adenoviral gene transfer in adult rabbit cardiomyocytes or a cardiac-restricted S100A1 murine transgenic enhanced cardiac contractile performance by increasing sarcoplasmic reticular calcium transients and uptake, altering the calcium sensitivity and cooperativity of myofibrils, enhancing SERCA2A activity and enhancing calcium-induced calcium release. Specifically, S100A1 increases the gain of excitation-contraction coupling and decreases calcium spark frequency in cardiomyocytes. Enhancement of L-type calcium channel transsarcolemmal calcium influx by S100A has been shown to be dependent on protein kinase A. Effects of S100A1 on myofilament proteins may be via Titin; S100A1 has been shown to interact with the PEVK region of Titin in a calcium-dependent manner, and it's binding reduces the force in an in vitro motility assay, suggesting that S100A may modulate Titin-based passive tension prior to systole. In mice with ablation of the S100A1 gene (S100A1-/-), cardiac reserve upon beta adrenergic stimulation was impaired, showing reduced contraction rate and relaxation rate, as well as reduced calcium sensitivity. However, S100A1-/- did not show the eventual cardiac hypertrophy or chamber dilation in aged mice.
In animal models of disease, S100A1 protein levels has been shown to be altered in right ventricular hypertrophied tissue in a model of pulmonary hypertension; several tissue types (brain, skeletal muscle and cardiac muscle) in a model of type I diabetes mellitus; S100A1 has been demonstrated as a regulator of the genetic program underlying cardiac hypertrophy, in that S100A1 inhibits alpha1 adrenergic stimulation of hypertrophic genes, including MYH7, ACTA1 and S100B. In a rat model of myocardial infarction, intracoronary S100A1 adenoviral gene transfer restored sarcoplasmic reticular calcium transients and load, normalized intracellular sodium concentrations, reversed the pathologic expression of the fetal gene program, restored energy supply, normalized contractile function, preserved inotropic reserve, and reduced cardiac hypertrophy 1 week post-myocardial infarction. In support of the adenoviral experiments, S100A1 transgenic overexpressing mice subjected to myocardial infarction showed preserved contractile function, abrogated apoptosis, preserved sarcoplasmic reticulum calcium cycling and beta adrenergic signaling, prevention from cardiac hypertrophy and heart failure, as well as prolonged survival relative to non-transgenic controls.
S100A1 has also been identified as a novel regulator of endothelial cell post-ischemic angiogenesis, as patients with limb ischemia exhibited downregulation of S100A1 expression in hypoxic tissue.
In melanocytic cells, S100A1 gene expression may be regulated by MITF.
# Clinical Significance
S100A1 has shown efficacy in feasibility in treating heart failure symptoms in large, preclinical models and human cardiomyocytes, and thus shows great promise for clinical trials.
Reduced expression of this protein has been implicated in cardiomyopathies, and left ventricular assist device-based therapy does not restore S100A1 levels in patients. S100A1 has shown promise as an early diagnostic biomarker for acute myocardial ischemia, presenting with a distinct timecourse in human plasma following an ischemic event relative to traditional markers creatine kinase, CKMB and troponin I. This injury-released, extracellular pool of S100A1 was investigated in neonatal murine cardiomyocytes and was shown to prevent apoptosis via an ERK1/2-dependent pathway, suggesting that the release of S100A1 from injured cells is an intrinsic survival mechanism for viable myocardium. S100 has also shown promise as a biomarker for uncontrolled hyperoxic reoxygenation during cardiopulmonary bypass in infants with cyanotic heart disease and in adults. S100A1 gene transfer to engineered heart tissue was shown to augment contractile performance of the tissue implants, suggesting that S100A1 may be effective in facilitating cardiac tissue replacement therapy in heart failure patients. However, the clinical efficacy of this strategy remains to be determined.
In addition, multiple drugs, including Pentamidine, Amlexanox, Olopatadine, Cromolyn, and Propanolol, are known to bind to S100A1, although their affinities are often in the mid-micromolar range.
# Interactions
S100 interacts with
- PGM1
- S100B
- S100A4
- TRPM3
- Titin
- RYR2
- SERCA2A
- PLB
- RYR1 | S100A1
S100A1, also known as S100 calcium-binding protein A1 is a protein which in humans is encoded by the S100A1 gene.[1][2] S100A1 is highly expressed in cardiac and skeletal muscle, and localizes to Z-discs and sarcoplasmic reticulum. S100A1 has shown promise as an effective candidate for gene therapy to treat post-myocardially infarcted cardiac tissue.
# Structure
S100A1 is a member of the S100 family of proteins expressed in cardiac muscle, skeletal muscle and brain,[3] with highest density at Z-lines and sarcoplasmic reticulum.[4] S100A1 contains 4 EF-hand calcium-binding motifs in its dimerized form,[5] and can exist as either a hetero or homodimer. The S100A1 homodimer is high affinity (nanomolar range or tighter), and is formed through hydrophobic packing of an X-type 4-helix bundle created between helices 1, 1', 4, and 4'. Protein nuclear magnetic resonance spectroscopy structural information on the homodimeric form of this protein shows that each monomer is helical and contains two EF-hand calcium-binding loops; one in the N-terminus and a canonical EF hand in the C-terminus having higher calcium affinity (dissociation constant of roughly 20 micromolar). The two EF hand domains neighbor each other in three dimensional space, and are connected to each other through a short beta sheet region (residues 27–29 and 68–70).
Upon binding calcium, helix 3 of S100A1 re-orients from being relatively antiparallel to helix 4 to being roughly perpendicular. This conformational change is different from most EF hands, in that the entering helix, and not the exiting helix, moves. This conformational change exposes a large hydrophobic pocket between helix 3, 4, and the hinge region of S100A1 that is involved in virtually all calcium-dependent target protein interactions. These biophysical properties seem to be well conserved across the S100 family of proteins. Helix 3, 4, and the hinge region are the most divergent areas between individual S100 proteins, and so it is likely that the sequence of these regions is pivotal in fine-tuning calcium-dependent target binding by S100 proteins.[6] S-Nitrosylation of S100A1 at Cys85 reorganizes the conformation of S100A1 at the C-terminal helix and the linker connecting the two EF hand domains.[7]
The most accurate high-resolution solution structure of human apo-S100A1 protein (PDB accession code: 2L0P) has been determined by means of NMR spectroscopy in 2011.[8]
S100 genes include at least 19 members which are located as a cluster on chromosome 1q21.[9][10]
# Function
S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. This protein may function in stimulation of Ca2+-induced Ca2+ release, inhibition of microtubule assembly, and inhibition of protein kinase C-mediated phosphorylation.
S100A1 is expressed during development in the primitive heart at embryonic day 8 in levels that are similar between atria and ventricles. As development progresses up to embryonic day 17.5, S100A1 expression shifts to a lower levels in atria and higher levels in ventricular myocardium.[11]
S100A1 has shown to be a regulator of myocardial contractility. S100A1 overexpression via adenoviral gene transfer in adult rabbit cardiomyocytes or a cardiac-restricted S100A1 murine transgenic enhanced cardiac contractile performance by increasing sarcoplasmic reticular calcium transients and uptake, altering the calcium sensitivity and cooperativity of myofibrils, enhancing SERCA2A activity and enhancing calcium-induced calcium release.[12][13][14] Specifically, S100A1 increases the gain of excitation-contraction coupling[15] and decreases calcium spark frequency[16] in cardiomyocytes. Enhancement of L-type calcium channel transsarcolemmal calcium influx by S100A has been shown to be dependent on protein kinase A.[17] Effects of S100A1 on myofilament proteins may be via Titin; S100A1 has been shown to interact with the PEVK region of Titin in a calcium-dependent manner, and it's binding reduces the force in an in vitro motility assay, suggesting that S100A may modulate Titin-based passive tension prior to systole.[18][19] In mice with ablation of the S100A1 gene (S100A1-/-), cardiac reserve upon beta adrenergic stimulation was impaired, showing reduced contraction rate and relaxation rate, as well as reduced calcium sensitivity. However, S100A1-/- did not show the eventual cardiac hypertrophy or chamber dilation in aged mice.[20]
In animal models of disease, S100A1 protein levels has been shown to be altered in right ventricular hypertrophied tissue in a model of pulmonary hypertension;[21] several tissue types (brain, skeletal muscle and cardiac muscle) in a model of type I diabetes mellitus;[22] S100A1 has been demonstrated as a regulator of the genetic program underlying cardiac hypertrophy, in that S100A1 inhibits alpha1 adrenergic stimulation of hypertrophic genes, including MYH7, ACTA1 and S100B.[23] In a rat model of myocardial infarction, intracoronary S100A1 adenoviral gene transfer restored sarcoplasmic reticular calcium transients and load, normalized intracellular sodium concentrations, reversed the pathologic expression of the fetal gene program, restored energy supply, normalized contractile function, preserved inotropic reserve, and reduced cardiac hypertrophy 1 week post-myocardial infarction.[24][25] In support of the adenoviral experiments, S100A1 transgenic overexpressing mice subjected to myocardial infarction showed preserved contractile function, abrogated apoptosis, preserved sarcoplasmic reticulum calcium cycling and beta adrenergic signaling, prevention from cardiac hypertrophy and heart failure, as well as prolonged survival relative to non-transgenic controls.[26][27]
S100A1 has also been identified as a novel regulator of endothelial cell post-ischemic angiogenesis, as patients with limb ischemia exhibited downregulation of S100A1 expression in hypoxic tissue.[28][29]
In melanocytic cells, S100A1 gene expression may be regulated by MITF.[30]
# Clinical Significance
S100A1 has shown efficacy in feasibility in treating heart failure symptoms in large, preclinical models and human cardiomyocytes,[31][32] and thus shows great promise for clinical trials.[33][34][35][36][37][38][39]
Reduced expression of this protein has been implicated in cardiomyopathies,[40] and left ventricular assist device-based therapy does not restore S100A1 levels in patients.[41] S100A1 has shown promise as an early diagnostic biomarker for acute myocardial ischemia, presenting with a distinct timecourse in human plasma following an ischemic event relative to traditional markers creatine kinase, CKMB and troponin I.[42][43] This injury-released, extracellular pool of S100A1 was investigated in neonatal murine cardiomyocytes and was shown to prevent apoptosis via an ERK1/2-dependent pathway, suggesting that the release of S100A1 from injured cells is an intrinsic survival mechanism for viable myocardium.[44] S100 has also shown promise as a biomarker for uncontrolled hyperoxic reoxygenation during cardiopulmonary bypass in infants with cyanotic heart disease[45] and in adults.[46] S100A1 gene transfer to engineered heart tissue was shown to augment contractile performance of the tissue implants, suggesting that S100A1 may be effective in facilitating cardiac tissue replacement therapy in heart failure patients.[47] However, the clinical efficacy of this strategy remains to be determined.
In addition, multiple drugs, including Pentamidine,[6] Amlexanox, Olopatadine, Cromolyn, and Propanolol,[6] are known to bind to S100A1, although their affinities are often in the mid-micromolar range.
# Interactions
S100 interacts with
- PGM1[48]
- S100B[49][50][51]
- S100A4[49][52]
- TRPM3[53]
- Titin[18]
- RYR2[12][54][55]
- SERCA2A[56][57]
- PLB[58]
- RYR1[59] | https://www.wikidoc.org/index.php/S100A1 | |
6a311cf7aaecbbf209b3012937a6f4d0958c30a6 | wikidoc | S100A4 | S100A4
S100 calcium-binding protein A4 (S100A4) is a protein that in humans is encoded by the S100A4 gene.
# Function
The protein encoded by this gene is a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21. This protein may function in motility, invasion, and tubulin polymerization. Chromosomal rearrangements and altered expression of this gene have been implicated in tumor metastasis. Multiple alternatively spliced variants, encoding the same protein, have been identified.
# Interactions
S100A4 has been shown to interact with S100 calcium binding protein A1.
# Therapeutic targeting for cancer
S100A4, a member of the S100 calcium-binding protein family secreted by tumor and stromal cells, supports tumorigenesis by stimulating angiogenesis. Research demonstrated that S100A4 synergizes with vascular endothelial growth factor (VEGF), via the RAGE receptor, in promoting endothelial cell migration by increasing KDR expression and MMP-9 activity. In vivo overexpression of S100A4 led to a significant increase in tumor growth and vascularization in a human melanoma xenograft M21 model. Conversely, when silencing S100A4 by shRNA technology, a dramatic decrease in tumor development of the pancreatic MIA PaCa-2 cell line was observed. Based on these results 5C3 was developed, a neutralizing monoclonal antibody against S100A4. This antibody abolished endothelial cell migration, tumor growth and angiogenesis in immunodeficient mouse xenograft models of MiaPACA-2 and M21-S100A4 cells. It is concluded that extracellular S100A4 inhibition is an attractive approach for the treatment of human cancer. | S100A4
S100 calcium-binding protein A4 (S100A4) is a protein that in humans is encoded by the S100A4 gene.[1]
# Function
The protein encoded by this gene is a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21. This protein may function in motility, invasion, and tubulin polymerization. Chromosomal rearrangements and altered expression of this gene have been implicated in tumor metastasis. Multiple alternatively spliced variants, encoding the same protein, have been identified.[2]
# Interactions
S100A4 has been shown to interact with S100 calcium binding protein A1.[3][4]
# Therapeutic targeting for cancer
S100A4, a member of the S100 calcium-binding protein family secreted by tumor and stromal cells, supports tumorigenesis by stimulating angiogenesis. Research demonstrated that S100A4 synergizes with vascular endothelial growth factor (VEGF), via the RAGE receptor, in promoting endothelial cell migration by increasing KDR expression and MMP-9 activity. In vivo overexpression of S100A4 led to a significant increase in tumor growth and vascularization in a human melanoma xenograft M21 model. Conversely, when silencing S100A4 by shRNA technology, a dramatic decrease in tumor development of the pancreatic MIA PaCa-2 cell line was observed. Based on these results 5C3 was developed, a neutralizing monoclonal antibody against S100A4. This antibody abolished endothelial cell migration, tumor growth and angiogenesis in immunodeficient mouse xenograft models of MiaPACA-2 and M21-S100A4 cells. It is concluded that extracellular S100A4 inhibition is an attractive approach for the treatment of human cancer.[5] | https://www.wikidoc.org/index.php/S100A4 | |
d78b9155120386265e68990b3d41158a21bdbd92 | wikidoc | S100A6 | S100A6
S100 calcium-binding protein A6 (S100A6) is a protein that in humans is encoded by the S100A6 gene.
# Function
The protein encoded by this gene is a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21. This protein may function in stimulation of Ca2+-dependent insulin release, stimulation of prolactin secretion, and exocytosis. Chromosomal rearrangements and altered expression of this gene have been implicated in melanoma.
# Interactions
S100A6 has been shown to interact with S100B and SUGT1.
# Pathology
S100A6 to be reported as possible diagnostic marker of papillary thyroid carcinoma. | S100A6
S100 calcium-binding protein A6 (S100A6) is a protein that in humans is encoded by the S100A6 gene.[1]
# Function
The protein encoded by this gene is a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21. This protein may function in stimulation of Ca2+-dependent insulin release, stimulation of prolactin secretion, and exocytosis. Chromosomal rearrangements and altered expression of this gene have been implicated in melanoma.[1]
# Interactions
S100A6 has been shown to interact with S100B[2][3] and SUGT1.[4]
# Pathology
S100A6 to be reported as possible diagnostic marker of papillary thyroid carcinoma.[5] | https://www.wikidoc.org/index.php/S100A6 | |
6332702359dc1c23c0027f3553cbda03be6f794b | wikidoc | S100A7 | S100A7
S100 calcium-binding protein A7 (S100A7), also known as psoriasin, is a protein that in humans is encoded by the S100A7 gene.
# Function
S100A7 is a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21. This protein differs from the other S100 proteins of known structure in its lack of calcium binding ability in one EF-hand at the N-terminus. The protein functions as a prominent antimicrobial peptide mainly against E. coli.
S100A7 also displays antimicrobial properties. It is secreted by epithelial cells of the skin and is a key antimicrobial protein against Escherichia coli by disrupting their cell membranes. This is the reason that in countries with poor sanitation, human skin is exposed to E. coli strains from faecal matter but it does not usually result in an infection.
S100A7 is highly homologous to S100A15 (koebnerisin) but distinct in expression, tissue distribution and function.
# Clinical significance
This protein is markedly over-expressed in the skin lesions of psoriatic patients, but is excluded as a candidate gene for familial psoriasis susceptibility. The expression of psoriasin is induced in skin wounds through activation of the epidermal growth factor receptor.
# Interactions
S100A7 has been shown to interact with COP9 constitutive photomorphogenic homolog subunit 5, FABP5 and RANBP9.
S100A7 interacts with RAGE (receptor of advanced glycated end products). | S100A7
S100 calcium-binding protein A7 (S100A7), also known as psoriasin, is a protein that in humans is encoded by the S100A7 gene.[1]
# Function
S100A7 is a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21. This protein differs from the other S100 proteins of known structure in its lack of calcium binding ability in one EF-hand at the N-terminus. The protein functions as a prominent antimicrobial peptide mainly against E. coli.[2]
S100A7 also displays antimicrobial properties. It is secreted by epithelial cells of the skin and is a key antimicrobial protein against Escherichia coli by disrupting their cell membranes. This is the reason that in countries with poor sanitation, human skin is exposed to E. coli strains from faecal matter but it does not usually result in an infection.[3]
S100A7 is highly homologous to S100A15 (koebnerisin) but distinct in expression, tissue distribution and function.[4][5][6][7]
# Clinical significance
This protein is markedly over-expressed in the skin lesions of psoriatic patients, but is excluded as a candidate gene for familial psoriasis susceptibility.[2] The expression of psoriasin is induced in skin wounds[8] through activation of the epidermal growth factor receptor.
# Interactions
S100A7 has been shown to interact with COP9 constitutive photomorphogenic homolog subunit 5,[9] FABP5[10][11] and RANBP9.[12]
S100A7 interacts with RAGE (receptor of advanced glycated end products).[4][13] | https://www.wikidoc.org/index.php/S100A7 | |
496bc57519c184953f9073d78a6f9234c8507fb1 | wikidoc | S100A9 | S100A9
S100 calcium-binding protein A9 (S100A9) also known as migration inhibitory factor-related protein 14 (MRP14) or calgranulin B is a protein that in humans is encoded by the S100A9 gene.
The proteins S100A8 and S100A9 form a heterodimer called calprotectin.
# Function
S100-A9 is a member of the S100 family of proteins containing 2 EF hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21. This protein may function in the inhibition of casein kinase.
MRP14 complexes with MRP-8 (S100A8), another member of the S100 family of calcium-modulated proteins; together, MRP8 and MRP14 regulate myeloid cell function by binding to Toll-like receptor 4 (TLR4) and the receptor for advanced glycation end products.
# Clinical significance
Altered expression of the S100A9 protein is associated with the disease cystic fibrosis.
MRP-8/14 broadly regulates vascular inflammation and contributes to the biological response to vascular injury by promoting leukocyte recruitment.
MRP-8/14 also regulates vascular insults by controlling neutrophil and macrophage accumulation, macrophage cytokine production, and SMC proliferation. The above study has shown therefore the deficiency of MRP-8 and MRP-14 reduces neutrophil- and monocyte-dependent vascular inflammation and attenuates the severity of diverse vascular injury responses in vivo. MRP-8/14 may be a useful biomarker of platelet and inflammatory disease activity in atherothrombosis and may serve as a novel target for therapeutic intervention. Also, the platelet transcriptome reveals quantitative differences between acute and stable coronary artery disease. MRP-14 expression increases before ST-segment-elevation myocardial infarction, (STEMI), and increasing plasma concentrations of MRP-8/14 among healthy individuals predict the risk of future cardiovascular events.
S100A9 (myeloid-related protein 14, MRP 14 or calgranulin B) has been implicated in the abnormal differentiation of myeloid cells in the stroma of cancer, and to leukemia progression. This contributes to creating an overall immunosuppressive microenvironment that may contribute to the inability of a protective or therapeutic cellular immune response to be generated by the tumor-bearing host. Outside of malignancy, S100A9 in association with its dimerization partner, S100A8 (MRP8 or calgranulin A) signals for lymphocyte recruitment in sites of inflammation. S100A9/A8 (synonyma: Calgranulin A/B; Calprotectin) are also regarded as marker proteins for a number of inflammatory diseases in humans, especially in rheumatoid arthritis.
Myeloid-related protein (MRP)-8 is an inflammatory protein found in several mucosal secretions. In cervico-vaginal secretions MRP-8 can stimulate HIV production; and thus might be involved in sexual transmission of HIV, as well as other sexually transmitted diseases (STD). In Vitro studies have shown that HIV-inducing of recombinant MRP-8 can increase HIV expression by up to 40-fold.
# Animal studies
A S100A9 knockout mouse has (a mouse mutant, that is deficient of S100A9) been constructed. This mouse is fertile, viable and healthy. However, expression of S100A8 protein, the dimerization partner of S100A9, is also absent in these mice in differentiated myeloid cells. This mouse line has been used to study the role of S100A9 and S100A8 in a number of experimental inflammatory conditions. | S100A9
S100 calcium-binding protein A9 (S100A9) also known as migration inhibitory factor-related protein 14 (MRP14) or calgranulin B is a protein that in humans is encoded by the S100A9 gene.[1]
The proteins S100A8 and S100A9 form a heterodimer called calprotectin.
# Function
S100-A9 is a member of the S100 family of proteins containing 2 EF hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21. This protein may function in the inhibition of casein kinase.[1]
MRP14 complexes with MRP-8 (S100A8), another member of the S100 family of calcium-modulated proteins; together, MRP8 and MRP14 regulate myeloid cell function by binding to Toll-like receptor 4 (TLR4)[2][3] and the receptor for advanced glycation end products.[4][4]
# Clinical significance
Altered expression of the S100A9 protein is associated with the disease cystic fibrosis.[1]
MRP-8/14 broadly regulates vascular inflammation and contributes to the biological response to vascular injury by promoting leukocyte recruitment.[5]
MRP-8/14 also regulates vascular insults by controlling neutrophil and macrophage accumulation, macrophage cytokine production, and SMC proliferation. The above study has shown therefore the deficiency of MRP-8 and MRP-14 reduces neutrophil- and monocyte-dependent vascular inflammation and attenuates the severity of diverse vascular injury responses in vivo. MRP-8/14 may be a useful biomarker of platelet and inflammatory disease activity in atherothrombosis and may serve as a novel target for therapeutic intervention.[6] Also, the platelet transcriptome reveals quantitative differences between acute and stable coronary artery disease. MRP-14 expression increases before ST-segment-elevation myocardial infarction, (STEMI), and increasing plasma concentrations of MRP-8/14 among healthy individuals predict the risk of future cardiovascular events.[7]
S100A9 (myeloid-related protein 14, MRP 14 or calgranulin B) has been implicated in the abnormal differentiation of myeloid cells in the stroma of cancer, and to leukemia progression.[8][9] This contributes to creating an overall immunosuppressive microenvironment that may contribute to the inability of a protective or therapeutic cellular immune response to be generated by the tumor-bearing host. Outside of malignancy, S100A9 in association with its dimerization partner, S100A8 (MRP8 or calgranulin A) signals for lymphocyte recruitment in sites of inflammation.[10] S100A9/A8 (synonyma: Calgranulin A/B; Calprotectin) are also regarded as marker proteins for a number of inflammatory diseases in humans, especially in rheumatoid arthritis.
Myeloid-related protein (MRP)-8 is an inflammatory protein found in several mucosal secretions. In cervico-vaginal secretions MRP-8 can stimulate HIV production;[11] and thus might be involved in sexual transmission of HIV, as well as other sexually transmitted diseases (STD). In Vitro studies have shown that HIV-inducing of recombinant MRP-8 can increase HIV expression by up to 40-fold.[11]
# Animal studies
A S100A9 knockout mouse has (a mouse mutant, that is deficient of S100A9) been constructed. This mouse is fertile, viable and healthy. However, expression of S100A8 protein, the dimerization partner of S100A9, is also absent in these mice in differentiated myeloid cells.[12] This mouse line has been used to study the role of S100A9 and S100A8 in a number of experimental inflammatory conditions. | https://www.wikidoc.org/index.php/S100A9 | |
54b7a2f7bf11c07a3f7300f3eaa3cceae85605c4 | wikidoc | SADDAN | SADDAN
# Overview
SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) is a rare inherited disorder of bone growth characterized by skeletal, brain, and skin abnormalities.
All people with this condition are extremely short with particularly short arms and legs. Other signs and symptoms include unusual bowing of the leg bones; a small chest with short ribs and curved collar bones; short, broad fingers; and folds of extra skin on the arms and legs. Structural abnormalities of the brain lead to seizures, profound developmental delay, and mental retardation. Acanthosis nigricans, a progressive skin disorder characterized by thick, dark, velvety skin, develops in infancy or early childhood. People with SADDAN often live into childhood and adulthood.
Many of the features of SADDAN are similar to those seen in other skeletal disorders, specifically achondroplasia and thanatophoric dysplasia.
# Epidemiology
This disorder is very rare; it has been described in only a small number of individuals worldwide.
# Genetics
Mutations in the FGFR3 gene cause SADDAN. The protein made by the FGFR3 gene is a receptor that plays a role in the development and maintenance of bone and brain tissue. A mutation in the gene may overactivate the receptor, which leads to disturbances in bone growth. Researchers have not determined how the mutation disrupts brain development or causes acanthosis nigricans.
SADDAN is considered an autosomal dominant disorder because one mutated copy of the FGFR3 gene in each cell is sufficient to cause the condition. The few described cases of SADDAN have been caused by new mutations in the FGFR3 gene. No individuals with this disorder are known to have had children; therefore, the disorder has not been passed to the next generation. | SADDAN
# Overview
SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) is a rare inherited disorder of bone growth characterized by skeletal, brain, and skin abnormalities.
All people with this condition are extremely short with particularly short arms and legs. Other signs and symptoms include unusual bowing of the leg bones; a small chest with short ribs and curved collar bones; short, broad fingers; and folds of extra skin on the arms and legs. Structural abnormalities of the brain lead to seizures, profound developmental delay, and mental retardation. Acanthosis nigricans, a progressive skin disorder characterized by thick, dark, velvety skin, develops in infancy or early childhood. People with SADDAN often live into childhood and adulthood.
Many of the features of SADDAN are similar to those seen in other skeletal disorders, specifically achondroplasia and thanatophoric dysplasia.
# Epidemiology
This disorder is very rare; it has been described in only a small number of individuals worldwide.
# Genetics
Mutations in the FGFR3 gene cause SADDAN. The protein made by the FGFR3 gene is a receptor that plays a role in the development and maintenance of bone and brain tissue. A mutation in the gene may overactivate the receptor, which leads to disturbances in bone growth. Researchers have not determined how the mutation disrupts brain development or causes acanthosis nigricans.
SADDAN is considered an autosomal dominant disorder because one mutated copy of the FGFR3 gene in each cell is sufficient to cause the condition. The few described cases of SADDAN have been caused by new mutations in the FGFR3 gene. No individuals with this disorder are known to have had children; therefore, the disorder has not been passed to the next generation. | https://www.wikidoc.org/index.php/SADDAN | |
bd2c408be09b401bebe085fdddc91aa895c779f4 | wikidoc | SAMHD1 | SAMHD1
SAM domain and HD domain-containing protein 1 is a protein that in humans is encoded by the SAMHD1 gene. SAMHD1 is a cellular enzyme, responsible for blocking replication of HIV in dendritic cells, macrophages and monocytes. It is an enzyme that exhibits phosphohydrolase activity, converting deoxynucleoside triphosphates (dNTPs) to inorganic phosphate (iPPP) and a 2'-deoxynucleoside (i.e. deoxynucleosides without a phosphate group). In doing so, SAMHD1 depletes the pool of dNTPs available to a reverse transcriptase for viral cDNA synthesis and thus prevents viral replication. SAMHD1 has also shown nuclease activity. Although a ribonuclease activity was described to be required for HIV-1 restriction, recent data confirmed that SAMHD1-mediated HIV-1 restriction in cells does not involve ribonuclease activity.
# Nomenclature
The SAMHD1 protein is also known as:
- AGS5: Aicardi- Goutières syndrome type 5
- DCIP: Dendritic cell-derived IFNG-induced protein2
- Mg11: Interferon-gamma-inducible protein
- HDDC1: HD domain containing 1
- MOP-5: Monocyte protein 5
- SAMH1_HUMAN
- SBBI88
- CHBL2
# Gene
The gene encoding human SAMHD1 was originally identified in a human dendritic cell cDNA library as an orthologue of a mouse gene IFN-γ-induced gene Mg11. The SAMHD1 gene is located on chromosome 20. SAMHD1 spans 59,532 bp of genomic sequence (chromosome 20:34,954,059–35,013,590) in 16 exons and encodes a 626 amino-acid (aa) protein with a molecular weight of 72.2 kDa. SAMHD1 expressed in both cycling and noncycling cells, but the antiviral activity of SAMHD1 is limited to noncycling cells.
# Structure
The SAMHD1 is 626 amino acids (aa) long and has 2 domains:
a. Sterile Alpha Motif (SAM) domain: residues 45 – 110 aa. In general, SAM domains are known to function as protein–protein and protein–nucleic acid interactions in organisms from yeast to humans, docking sites for kinases, signal transduction and regulation of transcription.
b. Histidine- Aspartic (HD) domain-containing protein 1: residues 164 – 319 aa. HD domains proteins are characterized by a doublet of histidine and aspartic acid catalytic residues, and have been shown to possess putative nuclease, dGTP triphosphatase, phosphatase or phosphodiesterase activities.
A crystal structure of a SAMHD1 fragment comprising catalytic core reveals that the protein is dimeric. Also studies have shown that SAMHD1 oligomerizes and forms tetramers. SAMHD1 is phosphorylated on residue T592 in cycling cells but that this phosphorylation is lost when cells are in a noncycling state.
# Function
Mutations in SAMHD1 are found in Aicardi–Goutières syndrome (AGS), “a hereditary autoimmune encephalopathy that is characterized by aberrant production of type I interferon (IFN) and symptoms mimicking congenital viral infection”. Monocytes isolated from individuals with AGS are highly susceptible to HIV-1.
SAMHD1 was identified as a host protein that is bound and blocked by lentiviral protein, Vpx. Vpx promotes macrophage and DC infection by targeting SAMHD1.
The human SAMHD1 protein has dNTP triphosphatase activity, specifically dGTP-stimulated dNTP triphosphohydrolase activity, and nuclease activity against single-stranded DNA and RNA which is associated with its HD domain. Other studies demonstrated that silencing SAMHD1 enhanced HIV-1 and SIV Δvpx infection of myeloid cells, also enhances HIV-1 infection of resting CD4+ T cells.
# Role in disease
## Aicardi-Goutieres syndrome
16 mutations in the SAMHD1 gene have been identified in patients with Aicardi-Goutieres syndrome. Mutations result in a SAMHD1 less functional protein. However, it is not known how this protein dysfunction leads to immune system abnormalities, inflammatory damage to the brain and skin, and other characteristics of this syndrome.
## Restriction of viral infection
SAMHD1 was identified as the cellular protein responsible of the reverse transcription block to HIV-1 infection observed in myeloid cells as well as in quiescent CD4+ T cells. SAMHD1 inhibits HIV-1 infection in myeloid cells by limiting the intracellular pool of dNTPs. The dNTP triphosphohydrolase activity of SAMHD1 has been proposed to reduce the intracellular dNTP level, restricting HIV-1 replication and preventing activation of the immune system, a nuclease activity against single-stranded (ss)DNAs and RNAs, as well as against RNA in DNA/RNA hybrids. Retroviral restriction ability of SAMHD1 is regulated by phosphorylation, for this purpose SAMHD1 associates with the cyclin A2/CDK1 complex that mediates its phosphorylation at threonine 592. Phosphorylated SAMHD1 has been observed to have minimal to no activity in cycling cells. Conversely, unphosphorylated SAMHD1 in non-cycling cells have potent restriction activity.
## Expression modulation and antimetabolite degradation in cancer cells
SAMHD1 protein expression can be influenced at four levels in cancer cells. First, mutations in the SAMHD1 gene can prevent SAMHD1 mRNA generation or a functional protein after translations. Second, promoter methylation can prevent SAMHD1 mRNA transcription. Third, miRNA-155 and miRNA-181a can prevent the translation, thus preventing protein production. Finally, SAMHD1 degradation occurs during the S phase of the cell cycle. Non-adherent tumor cell lines – B cells, T cells and myeloid cells can be rapidly dividing cells, have low to no detectable levels of SAMHD1 protein, as compared to adherent cells.
Regulation of dNTP concentration by SAMHD1 in cancer cells might be an important mechanism with therapeutic implications. Antimetabolites are anticancer nucleosides, nucleotides, and base analogs used as anticancer agents to promote cell death by several different mechanisms of action. For some of these antimetabolites, the intracellular triphosphate form of the analog is the active compound. SAMHD1 has been shown to be able to hydrolyze arabinose 5’-triphosphates. SAMHD1 has been shown to be a biomarker and influence arabinose C (ara-C; cytarabine) responsiveness. Viral protein x (Vpx) has been proposed to be potential therapy to improve cytarabine therapy for hematological malignancies. | SAMHD1
SAM domain and HD domain-containing protein 1 is a protein that in humans is encoded by the SAMHD1 gene. SAMHD1 is a cellular enzyme, responsible for blocking replication of HIV in dendritic cells,[1] macrophages[2] and monocytes.[3] It is an enzyme that exhibits phosphohydrolase activity,[4][5] converting deoxynucleoside triphosphates (dNTPs) to inorganic phosphate (iPPP) and a 2'-deoxynucleoside (i.e. deoxynucleosides without a phosphate group). In doing so, SAMHD1 depletes the pool of dNTPs available to a reverse transcriptase for viral cDNA synthesis and thus prevents viral replication.[6] SAMHD1 has also shown nuclease activity.[7] Although a ribonuclease activity was described to be required for HIV-1 restriction,[8] recent data confirmed that SAMHD1-mediated HIV-1 restriction in cells does not involve ribonuclease activity.[9]
# Nomenclature
The SAMHD1 protein is also known as:
- AGS5: Aicardi- Goutières syndrome type 5[10]
- DCIP: Dendritic cell-derived IFNG-induced protein2[11]
- Mg11: Interferon-gamma-inducible protein[11]
- HDDC1: HD domain containing 1
- MOP-5: Monocyte protein 5
- SAMH1_HUMAN
- SBBI88
- CHBL2
# Gene
The gene encoding human SAMHD1 was originally identified in a human dendritic cell cDNA library as an orthologue of a mouse gene IFN-γ-induced gene Mg11.[11] The SAMHD1 gene is located on chromosome 20. SAMHD1 spans 59,532 bp of genomic sequence (chromosome 20:34,954,059–35,013,590) in 16 exons and encodes a 626 amino-acid (aa) protein with a molecular weight of 72.2 kDa.[12][13] SAMHD1 expressed in both cycling and noncycling cells, but the antiviral activity of SAMHD1 is limited to noncycling cells.[14]
# Structure
The SAMHD1 is 626 amino acids (aa) long and has 2 domains:
a. Sterile Alpha Motif (SAM) domain: residues 45 – 110 aa.[15][16] In general, SAM domains are known to function as protein–protein and protein–nucleic acid interactions in organisms from yeast to humans, docking sites for kinases, signal transduction and regulation of transcription.[17][18]
b. Histidine- Aspartic (HD) domain-containing protein 1: residues 164 – 319 aa.[15][16] HD domains proteins are characterized by a doublet of histidine and aspartic acid catalytic residues, and have been shown to possess putative nuclease, dGTP triphosphatase, phosphatase or phosphodiesterase activities.[17][19]
A crystal structure of a SAMHD1 fragment comprising catalytic core reveals that the protein is dimeric.[5] Also studies have shown that SAMHD1 oligomerizes and forms tetramers.[20] SAMHD1 is phosphorylated on residue T592 in cycling cells but that this phosphorylation is lost when cells are in a noncycling state.[21]
# Function
Mutations in SAMHD1 are found in Aicardi–Goutières syndrome (AGS), “a hereditary autoimmune encephalopathy that is characterized by aberrant production of type I interferon (IFN) and symptoms mimicking congenital viral infection”.[16] Monocytes isolated from individuals with AGS are highly susceptible to HIV-1.[3]
SAMHD1 was identified as a host protein that is bound and blocked by lentiviral protein, Vpx. Vpx promotes macrophage and DC infection by targeting SAMHD1.[22]
The human SAMHD1 protein has dNTP triphosphatase activity, specifically dGTP-stimulated dNTP triphosphohydrolase activity, and nuclease activity against single-stranded DNA and RNA which is associated with its HD domain.[7][23] Other studies demonstrated that silencing SAMHD1 enhanced HIV-1 and SIV Δvpx infection of myeloid cells, also enhances HIV-1 infection of resting CD4+ T cells.[14][23]
# Role in disease
## Aicardi-Goutieres syndrome
16 mutations in the SAMHD1 gene have been identified in patients with Aicardi-Goutieres syndrome. Mutations result in a SAMHD1 less functional protein. However, it is not known how this protein dysfunction leads to immune system abnormalities, inflammatory damage to the brain and skin, and other characteristics of this syndrome.[3][16]
## Restriction of viral infection
SAMHD1 was identified as the cellular protein responsible of the reverse transcription block to HIV-1 infection observed in myeloid cells as well as in quiescent CD4+ T cells. SAMHD1 inhibits HIV-1 infection in myeloid cells by limiting the intracellular pool of dNTPs.[22] The dNTP triphosphohydrolase activity of SAMHD1 has been proposed to reduce the intracellular dNTP level, restricting HIV-1 replication and preventing activation of the immune system, a nuclease activity against single-stranded (ss)DNAs and RNAs, as well as against RNA in DNA/RNA hybrids.[17][22] Retroviral restriction ability of SAMHD1 is regulated by phosphorylation, for this purpose SAMHD1 associates with the cyclin A2/CDK1 complex that mediates its phosphorylation at threonine 592. Phosphorylated SAMHD1 has been observed to have minimal to no activity in cycling cells. Conversely, unphosphorylated SAMHD1 in non-cycling cells have potent restriction activity.[21]
## Expression modulation and antimetabolite degradation in cancer cells
SAMHD1 protein expression can be influenced at four levels in cancer cells. First, mutations in the SAMHD1 gene can prevent SAMHD1 mRNA generation or a functional protein after translations.[24] Second, promoter methylation can prevent SAMHD1 mRNA transcription.[25][26] Third, miRNA-155 and miRNA-181a can prevent the translation, thus preventing protein production.[27][28] Finally, SAMHD1 degradation occurs during the S phase of the cell cycle.[29] Non-adherent tumor cell lines – B cells, T cells and myeloid cells can be rapidly dividing cells, have low to no detectable levels of SAMHD1 protein, as compared to adherent cells.
Regulation of dNTP concentration by SAMHD1 in cancer cells might be an important mechanism with therapeutic implications.[30] Antimetabolites are anticancer nucleosides, nucleotides, and base analogs used as anticancer agents to promote cell death by several different mechanisms of action.[31] For some of these antimetabolites, the intracellular triphosphate form of the analog is the active compound.[31] SAMHD1 has been shown to be able to hydrolyze arabinose 5’-triphosphates.[32] SAMHD1 has been shown to be a biomarker and influence arabinose C (ara-C; cytarabine) responsiveness.[33] Viral protein x (Vpx) has been proposed to be potential therapy to improve cytarabine therapy for hematological malignancies.[34] | https://www.wikidoc.org/index.php/SAMHD1 | |
0c3fb9b86833e944b3b3eebead404fb192261911 | wikidoc | SAP130 | SAP130
Histone deacetylase complex subunit SAP130 is an enzyme that in humans is encoded by the SAP130 gene.
# Function
SAP130 is a subunit of the histone deacetylase (see HDAC1; MIM 601241)-dependent SIN3A (MIM 607776) corepressor complex (Fleischer et al., 2003).
# Interactions
SAP130 has been shown to interact with:
- CSN1S1,
- CUL2,
- Myc,
- SIN3A, and
- Von Hippel-Lindau tumor suppressor and
# Model organisms
Model organisms have been used in the study of SAP130 function. A conditional knockout mouse line called Sap130tm1a(KOMP)Mbp was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping | SAP130
Histone deacetylase complex subunit SAP130 is an enzyme that in humans is encoded by the SAP130 gene.[1][2][3]
# Function
SAP130 is a subunit of the histone deacetylase (see HDAC1; MIM 601241)-dependent SIN3A (MIM 607776) corepressor complex (Fleischer et al., 2003).[supplied by OMIM][3]
# Interactions
SAP130 has been shown to interact with:
- CSN1S1,[4]
- CUL2,[4]
- Myc,[5]
- SIN3A,[2] and
- Von Hippel-Lindau tumor suppressor[4] and
# Model organisms
Model organisms have been used in the study of SAP130 function. A conditional knockout mouse line called Sap130tm1a(KOMP)Mbp was generated at the Wellcome Trust Sanger Institute.[6] Male and female animals underwent a standardized phenotypic screen[7] to determine the effects of deletion.[8][9][10][11] Additional screens performed: - In-depth immunological phenotyping[12] | https://www.wikidoc.org/index.php/SAP130 | |
4dbf6e712fd400452cf84e18e8e47909dbfbd390 | wikidoc | SCARB1 | SCARB1
Scavenger receptor class B type 1 (SRB1) also known as SR-BI is a protein that in humans is encoded by the SCARB1 gene. SR-BI functions as a receptor for high-density lipoprotein.
# Function
Scavenger receptor class B, type I (SR-BI) is an integral membrane protein found in numerous cell types/tissues, including the liver and adrenal. It is best known for its role in facilitating the uptake of cholesteryl esters from high-density lipoproteins in the liver. This process drives the movement of cholesterol from peripheral tissues towards the liver, where cholesterol can either be secreted via the bile duct or be used to synthesise steroid hormones. This movement of cholesterol is known as reverse cholesterol transport and is a protective mechanism against the development of atherosclerosis, which is the principal cause of heart disease and stroke.
SR-BI is crucial in lipid soluble vitamin uptake.
In melanocytic cells SCARB1 gene expression may be regulated by the MITF.
# Species distribution
SR-BI has also been identified in the livers of non-mammalian species (turtle, goldfish, shark, chicken, frog, and skate), suggesting it emerged early in vertebrate evolutionary history. The turtle also seems to upregulate SB-RI during egg development, indicating that cholesterol efflux may be at peak levels during developmental stages.
# Clinical significance
SCARB1 along with CD81 is the receptor for the entry of the Hepatitis C virus into liver cells.
# Preclinical research
Although malignant tumors are known to display extreme heterogeneity, overexpression of SR-B1 is a relatively consistent marker in cancerous tissues. While SR-B1 normally mediates the transfer of cholesterol between high-density lipoproteins (HDL) and healthy cells, it also facilitates the selective uptake of cholesterol by malignant cells. In this way, upregulation of the SR-B1 receptor becomes an enabling factor for self-sufficient proliferation in cancerous tissue.
SR-B1 mediated delivery has also been used in the transfection of cancer cells with siRNA, or small interfering RNAs. This therapy causes RNA interference, in which short segments of double stranded RNA acts to silence targeted oncogenes post-transcription. SR-B1 mediation reduces siRNA degradation and off-target accumulation while enhancing delivery to targeted tissues. In "metastatic and taxane-resistant models of ovarian cancer, rHDL-mediated siren delivery improved responses.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | SCARB1
Scavenger receptor class B type 1 (SRB1) also known as SR-BI is a protein that in humans is encoded by the SCARB1 gene.[1] SR-BI functions as a receptor for high-density lipoprotein.[2]
# Function
Scavenger receptor class B, type I (SR-BI) is an integral membrane protein found in numerous cell types/tissues, including the liver and adrenal. It is best known for its role in facilitating the uptake of cholesteryl esters from high-density lipoproteins in the liver. This process drives the movement of cholesterol from peripheral tissues towards the liver, where cholesterol can either be secreted via the bile duct or be used to synthesise steroid hormones.[3] This movement of cholesterol is known as reverse cholesterol transport and is a protective mechanism against the development of atherosclerosis, which is the principal cause of heart disease and stroke.
SR-BI is crucial in lipid soluble vitamin uptake.[4]
In melanocytic cells SCARB1 gene expression may be regulated by the MITF.[5]
# Species distribution
SR-BI has also been identified in the livers of non-mammalian species (turtle, goldfish, shark, chicken, frog, and skate), suggesting it emerged early in vertebrate evolutionary history. The turtle also seems to upregulate SB-RI during egg development, indicating that cholesterol efflux may be at peak levels during developmental stages.[6]
# Clinical significance
SCARB1 along with CD81 is the receptor for the entry of the Hepatitis C virus into liver cells.[7]
# Preclinical research
Although malignant tumors are known to display extreme heterogeneity, overexpression of SR-B1 is a relatively consistent marker in cancerous tissues. While SR-B1 normally mediates the transfer of cholesterol between high-density lipoproteins (HDL) and healthy cells, it also facilitates the selective uptake of cholesterol by malignant cells. In this way, upregulation of the SR-B1 receptor becomes an enabling factor for self-sufficient proliferation in cancerous tissue.[8][9]
SR-B1 mediated delivery has also been used in the transfection of cancer cells with siRNA, or small interfering RNAs. This therapy causes RNA interference, in which short segments of double stranded RNA acts to silence targeted oncogenes post-transcription. SR-B1 mediation reduces siRNA degradation and off-target accumulation while enhancing delivery to targeted tissues. In "metastatic and taxane-resistant models of ovarian cancer, rHDL-mediated siren delivery improved responses.[10]
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | https://www.wikidoc.org/index.php/SCARB1 | |
3de200a178ab1cbe780e881b0d335152ec2770e2 | wikidoc | SCARB2 | SCARB2
Lysosome membrane protein 2 (LIMP-2) is a protein that in humans is encoded by the SCARB2 gene. LIMP-2 is expressed in brain, heart, liver, lung and kidney, mainly in the membrane of lysosome organelles; however, in cardiac muscle, LIMP-2 is also expressed at intercalated discs. LIMP-2 in a membrane protein in lysosomes that functions to regulate lysosomal/endosomal transport. Mutations in LIMP-2 have been shown to cause Gaucher disease, myoclonic epilepsy, and action myoclonus renal failure syndrome. Abnormal levels of LIMP-2 have also been found in patients with hypertrophic cardiomyopathy.
# Structure
Human LIMP-2 has a theoretical molecular weight of 54.3 kDa and is 478 amino acids in length.
Though LIMP-2 was initially discovered in 1985 by Lewis et al. from rat liver lysosomes, LIMP-2 was cloned in 1992 by two groups, one isolated LIMP-2 from human metastatic pancreatic islet tumor cells, and one from rat liver lysosomal membranes. LIMP-2 was isolated as a protein of approximate molecular weight 85 kDa, synthesized from a precursor oform of approximately 77 kDa. The weight discrepancy between its theoretical (54.3 kDa) and observed (85 kDa) is due to the presence of 10 high mannose-type N-linked oligosaccharide chains in the human form of this protein, compared to 11 in mouse and rat. LIMP-2 has two hydrophobic regions, one near the N-terminus and one near the C-terminus, as well as a short isoleucine/leucine-rich cytoplasmic tail consisting of 20 amino acids that serves as the lysosomal targeting sequence. LIMP-2 has been shown to be expressed in brain, heart, liver, lung and kidney.
# Function
The protein encoded by this gene is a type III glycoprotein that is located primarily in limiting membranes of lysosomes and endosomes. Studies of the similar protein in mice and rat suggested that this protein may participate in membrane transportation and the reorganization of endosomal/lysosomal compartment. In rat hepatic cells, LIMP-2 exhibited a half-life for internalization and lysosomal transport of 32 min and 2.0 h, respectively, which resembled that of well-known lysosomal proteins, lamp-1 and lamp-2, albeit different amino acid sequences in their cytoplasmic tails.
LIMP2 has recently been identified as a novel component of intercalated discs in cardiac muscle. Intercalated discs are composed of gap junctions, adherens junctions and desmosomes, and are critical for the mechanical and electrical coupling of adjacent cardiomyocytes. The discovery of LIMP-2 as a component of this complex came about from a genetic screen of a homozygous, hypertensive transgenic rat model of renin overexpression, in which a population of these rats rapidly develop heart failure and another remains compensated. Out of 143 differentially-regulated genes, LIMP-2 was identified to be significantly upregulated in heart failure-prone rat cardiac muscle biopsies, which also proved true in human heart failure. Further analysis employing a LIMP-2 knockout mouse demonstrated that animals lacking LIMP-2 failed to flight a normal hypertrophic response following Angiotensin II treatment, however they developed interstitial fibrosis and dilated cardiomyopathy coordinate with disrupted intercalated disc structure. Biochemical and immunohistochemical analyses discovered that LIMP-2 interacts with N-cadherin at intercalated discs, a function outside of lysosomal membranes. Knockdown of LIMP-2 with RNA interference decreased the binding of N-cadherin to the phosphorylated form of beta-catenin, and LIMP-2 overexpression had the reverse effect.
LIMP-2 plays other roles in other organs. Characteristic tubular proteinuria observed in LIMP-2 knockout mice has been shown to be due to a failure of in lysosomal/endosomal fusion, thus proteins reabsorbed in the proximal tubule of the kidney are not properly proteolyzed, causing the proteinuria. Deficiency of LIMP-2 in mice was also reported to impair cell membrane transport processes and cause pelvic junction obstruction, deafness, and peripheral neuropathy.
# Clinical significance
In patients with hypertrophic cardiomyopathy due to aortic stenosis, SCARB2 mRNA is significantly upregulated, suggesting that LIMP-2 may act as a hypertrophic marker.
Mutations in SCARB2 have been shown to cause action myoclonus renal failure syndrome, a rare syndrome characterized by progressive neurological disease and associated with proteinuria, kidney failure, and Focal segmental glomerulosclerosis.
Mutations in SCARB2 have also been shown to cause Gaucher disease and myoclonic epilepsy, as LIMP-2 is critical for the proper sorting and targeting of glucocerebrosidase enzyme (the enzyme deficient in Gaucher disease) to lysosomes.
SCARB2 is a receptor for two viruses that cause hand, foot, and mouth disease in children, Enterovirus 71 and Coxsackievirus A16.
# Interactions
LIMP-2 has been shown to interact with:
- N-cadherin. | SCARB2
Lysosome membrane protein 2 (LIMP-2) is a protein that in humans is encoded by the SCARB2 gene.[1] LIMP-2 is expressed in brain, heart, liver, lung and kidney, mainly in the membrane of lysosome organelles; however, in cardiac muscle, LIMP-2 is also expressed at intercalated discs. LIMP-2 in a membrane protein in lysosomes that functions to regulate lysosomal/endosomal transport. Mutations in LIMP-2 have been shown to cause Gaucher disease, myoclonic epilepsy, and action myoclonus renal failure syndrome. Abnormal levels of LIMP-2 have also been found in patients with hypertrophic cardiomyopathy.
# Structure
Human LIMP-2 has a theoretical molecular weight of 54.3 kDa and is 478 amino acids in length.[2]
Though LIMP-2 was initially discovered in 1985 by Lewis et al. from rat liver lysosomes,[3] LIMP-2 was cloned in 1992 by two groups, one isolated LIMP-2 from human metastatic pancreatic islet tumor cells, and one from rat liver lysosomal membranes.[4][5] LIMP-2 was isolated as a protein of approximate molecular weight 85 kDa, synthesized from a precursor oform of approximately 77 kDa. The weight discrepancy between its theoretical (54.3 kDa) and observed (85 kDa) is due to the presence of 10 high mannose-type N-linked oligosaccharide chains in the human form of this protein, compared to 11 in mouse and rat.[6] LIMP-2 has two hydrophobic regions, one near the N-terminus and one near the C-terminus, as well as a short isoleucine/leucine-rich cytoplasmic tail consisting of 20 amino acids that serves as the lysosomal targeting sequence.[7][8] LIMP-2 has been shown to be expressed in brain, heart, liver, lung and kidney.[6]
# Function
The protein encoded by this gene is a type III glycoprotein that is located primarily in limiting membranes of lysosomes and endosomes. Studies of the similar protein in mice and rat suggested that this protein may participate in membrane transportation and the reorganization of endosomal/lysosomal compartment.[9] In rat hepatic cells, LIMP-2 exhibited a half-life for internalization and lysosomal transport of 32 min and 2.0 h, respectively, which resembled that of well-known lysosomal proteins, lamp-1 and lamp-2, albeit different amino acid sequences in their cytoplasmic tails.[10]
LIMP2 has recently been identified as a novel component of intercalated discs in cardiac muscle. Intercalated discs are composed of gap junctions, adherens junctions and desmosomes, and are critical for the mechanical and electrical coupling of adjacent cardiomyocytes. The discovery of LIMP-2 as a component of this complex came about from a genetic screen of a homozygous, hypertensive transgenic rat model of renin overexpression, in which a population of these rats rapidly develop heart failure and another remains compensated.[11] Out of 143 differentially-regulated genes, LIMP-2 was identified to be significantly upregulated in heart failure-prone rat cardiac muscle biopsies, which also proved true in human heart failure. Further analysis employing a LIMP-2 knockout mouse demonstrated that animals lacking LIMP-2 failed to flight a normal hypertrophic response following Angiotensin II treatment, however they developed interstitial fibrosis and dilated cardiomyopathy coordinate with disrupted intercalated disc structure. Biochemical and immunohistochemical analyses discovered that LIMP-2 interacts with N-cadherin at intercalated discs, a function outside of lysosomal membranes. Knockdown of LIMP-2 with RNA interference decreased the binding of N-cadherin to the phosphorylated form of beta-catenin, and LIMP-2 overexpression had the reverse effect.[12]
LIMP-2 plays other roles in other organs. Characteristic tubular proteinuria observed in LIMP-2 knockout mice has been shown to be due to a failure of in lysosomal/endosomal fusion, thus proteins reabsorbed in the proximal tubule of the kidney are not properly proteolyzed, causing the proteinuria.[13] Deficiency of LIMP-2 in mice was also reported to impair cell membrane transport processes and cause pelvic junction obstruction, deafness, and peripheral neuropathy.[14]
# Clinical significance
In patients with hypertrophic cardiomyopathy due to aortic stenosis, SCARB2 mRNA is significantly upregulated, suggesting that LIMP-2 may act as a hypertrophic marker.[12]
Mutations in SCARB2 have been shown to cause action myoclonus renal failure syndrome, a rare syndrome characterized by progressive neurological disease and associated with proteinuria, kidney failure, and Focal segmental glomerulosclerosis.[15][16][17]
Mutations in SCARB2 have also been shown to cause Gaucher disease and myoclonic epilepsy,[18] as LIMP-2 is critical for the proper sorting and targeting of glucocerebrosidase enzyme (the enzyme deficient in Gaucher disease) to lysosomes.
SCARB2 is a receptor for two viruses that cause hand, foot, and mouth disease in children, Enterovirus 71 and Coxsackievirus A16.[19]
# Interactions
LIMP-2 has been shown to interact with:
- N-cadherin.[12] | https://www.wikidoc.org/index.php/SCARB2 | |
3293a7b67907b3f81a325f7b30c0053b0a51fd58 | wikidoc | SCENAR | SCENAR
The Scenar device, is the latest incarnation of an electronic instrument developed by scientists working in the Russian aerospace industry, in the town of Taganrog, Russia. The name is an acronym derived from "Self Controlled Energo-Neuro-adaptive Regulation". It has, in earlier incarnations been known as the "Inter-X -5002". Prof. Dr. Alexander M. Revenko (neurology) is the founder of the company.
# Description
The device is sold for the treatment of acute and chronic pain, and is represented as being useful in solo therapy as well as in combination with other therapeutic modalities, as it "has very few
contraindications" .
Scenar is represented as being capable of interaction with the nervous, immune and endocrine systems through a biofeedback mechanism. It is believed that it "ensures regulation of various mediators and neuropeptides". And, it main goal is the maintenance of homeostasis through interactions with the body's immune and hormonal systems.
# History
In the beginning, there the SCENAR-035, or 'troika', as it is pronounced in Russian. The Grandmother of SCENARs. It was a good, reliable, stable, and effective model. Not very pretty on the outside, in a black rectangular case, yet nevertheless very functional. SCENAR-035 is known mostly just inside Russia, and some doctors work with it even now. In fact, those almost unbelievable SCENAR results reported by Dr. Yuri Gorfinkel and Dr Revenko in 1998 in his famous Summary of individual results (which appears all over the SCENAR literature) were obtained mostly with the SCENAR-035. This model was designed by Dr. Karasev and massively produced by OKB Ritm.
# FDA Approvals
Scenar technology is, as of May, 2010, an FDA approved device, for treatment of pain, under the following class: DEVICE: SCENAR, MODEL 10, RITM OKB ZAO 510(k) NO: K092117(TRADITIONAL). It is cleared for the treatment and management of acute and chronic pain and the management of post-surgical and post-traumatic pain. It may be dispensed only upon the prescription of a licensed health care provider.
# Waveforms
# Scientific Research
Several studies have shown benefits in treatment of various conditions, most of which demonstrate results significantly greater than could be explained by placebo alone. Some studies the company provides were never published, but were performed at their request, however there are some rather interesting and positive results.
## Enuresis
- 1995 - V.A Lebedev (Physiotherapist), reported in the journal Вопросы курортологии, физиотерапии и лечебной физкультуры (Investigations in therapeutic spas, physiotherapy and therapeutic physical culture), that he "recommends a self-control energoneuroadaptive regulator (SCENAR) as effective in the treatment of neurogenic dysfunction of the bladder in children with nocturnal enuresis. This regulator operates according to the principles of Chinese medicine and may be used in sanatoria and at home by the children's parents specially trained by physiotherapist" .
## Pain
- 2004 - Lopatina, A.B, reported in a Dissertation for her Doctorate in Education, that the Scenar had shown benefits in "speeding the recovery period in athletes" .
- 2005 - A study of 60 patients post trochanteric joint surgery, with the early model Scenar (InterX) device, run in Moscow, Russia and published in the Journal of Bone and Joint Surgery, Gorodetskiy et al, conclude that the scenar treated patients had significantly reduced pain as compared to the sham (placebo) or for the "non-invasive neuro-stimulation" groups. .
- 2006 - Presenting at the XVth International Congress on Sports rehabilitation and Traumatology, P. Massetti gave a case study of two young men, 6 months post contusion; one 24 years old, with tears of the femoris and medial vastus lateralis, after 7 treatments showed significant reduction in pain, and increased range-of-motion, and after one week of treatment, the symptoms "were completely resolved" ; and the other 38 years old, with strain of the tibialis medius, interfering with his ability to participate in sports. His pain extended into the insertion of the Achilles tendon. His treatment was 2x week, together with CO2 laser and ultrasound. Following 10 applications of alternating laser+ultrasound and Scenar therapy the patient had a complete remission of symptoms .
- 2006 - At the same Congress in which he gave his case report, Massetti published a paper in which he indicates having treated 20 patients, including both professional and amateur athletes with varying painful conditions. According to his report, all of the patients, after 2 treatments, 2x/week demonstrated "significant reduction in symptoms" unexplainable as resulting from any other possible cause. Massetti concludes that the Scenar "is an instrument capable of drastically reducing the time of recuperation in significant traumatic events" ,
- 2008 - Writing about his experiences at the European Speed Skating championships (Germany) and the subsequent World's in Spain, Rosario Bella, (a Physiotherapist) for the FIHP (Roller Hockey), in a report published at the medical site FCE news, of Scenar use together with kinesiotaping, states, that the "results were appreciable in noting the time of recuperation and eduction of symptoms to a tolerable level in a good percentage of the cases treated, even during the competition". And, that the SCENAR taken together with the taping provided a synergistic effect, then when taken alone.
- 2010 - With results similar to their 2005 study, Gorodetskiy, et al, publishing in The Journal of Foot and Ankle Surgery in 2010, found results comparable to their earlier study, in patients post malleolar (ankle joint) fracture surgery .
## Post-herpetic neuralgia
- 2007 - M.R. Ing, publishing in the Hawaii Medical Journal, treated three consecutive patients with post-herpetic neuralgia and found that ALL resolved their pain in no more than 5 sessions over a three week period .
## Duodenal ulcer
- 2006 - In a study published in Клиническая Медицина (Clinical medicine), Tsimmerman, et al, reported that 103 cases of duodenal ulcer were treated with Scenar alone and together with standard therapy for H pylori. They determined that "led to positive changes in most of the parameters under study", and "Addition of SCENAR therapy to the complex conventional pharmacotherapy 'sped up' ulcer healing, increased the effectiveness of Helicobacter pylori eradication, and improved the condition of the gastroduodenal mucosa" . | SCENAR
Template:Infobox Organization
The Scenar device, is the latest incarnation of an electronic instrument developed by scientists working in the Russian aerospace industry, in the town of Taganrog, Russia. The name is an acronym derived from "Self Controlled Energo-Neuro-adaptive Regulation". It has, in earlier incarnations been known as the "Inter-X -5002". Prof. Dr. Alexander M. Revenko (neurology) is the founder of the company. [1]
# Description
The device is sold for the treatment of acute and chronic pain, and is represented as being useful in solo therapy as well as in combination with other therapeutic modalities, as it "has very few
contraindications" [1].
Scenar is represented as being capable of interaction with the nervous, immune and endocrine systems through a biofeedback mechanism. It is believed that it "ensures regulation of various mediators and neuropeptides". And, it main goal is the maintenance of homeostasis through interactions with the body's immune and hormonal systems[1].
# History
In the beginning, there the SCENAR-035, or 'troika', as it is pronounced in Russian. The Grandmother of SCENARs. It was a good, reliable, stable, and effective model. Not very pretty on the outside, in a black rectangular case, yet nevertheless very functional. SCENAR-035 is known mostly just inside Russia, and some doctors work with it even now. In fact, those almost unbelievable SCENAR results reported by Dr. Yuri Gorfinkel and Dr Revenko in 1998 in his famous Summary of individual results (which appears all over the SCENAR literature) were obtained mostly with the SCENAR-035. This model was designed by Dr. Karasev and massively produced by OKB Ritm.
# FDA Approvals
Scenar technology is, as of May, 2010, an FDA approved device, for treatment of pain, under the following class: DEVICE: SCENAR, MODEL 10, RITM OKB ZAO 510(k) NO: K092117(TRADITIONAL). It is cleared for the treatment and management of acute and chronic pain and the management of post-surgical and post-traumatic pain. It may be dispensed only upon the prescription of a licensed health care provider.[2]
# Waveforms
# Scientific Research
Several studies have shown benefits in treatment of various conditions, most of which demonstrate results significantly greater than could be explained by placebo alone. Some studies the company provides were never published, but were performed at their request, however there are some rather interesting and positive results.
## Enuresis
- 1995 - V.A Lebedev (Physiotherapist), reported in the journal Вопросы курортологии, физиотерапии и лечебной физкультуры (Investigations in therapeutic spas, physiotherapy and therapeutic physical culture), that he "recommends a self-control energoneuroadaptive regulator (SCENAR) as effective in the treatment of neurogenic dysfunction of the bladder in children with nocturnal enuresis. This regulator operates according to the principles of Chinese medicine and may be used in sanatoria and at home by the children's parents specially trained by physiotherapist" [3].
## Pain
- 2004 - Lopatina, A.B, reported in a Dissertation for her Doctorate in Education, that the Scenar had shown benefits in "speeding the recovery period in athletes" [4].
- 2005 - A study of 60 patients post trochanteric joint surgery, with the early model Scenar (InterX) device, run in Moscow, Russia and published in the Journal of Bone and Joint Surgery, Gorodetskiy et al, conclude that the scenar treated patients had significantly reduced pain as compared to the sham (placebo) or for the "non-invasive neuro-stimulation" groups. [5].
- 2006 - Presenting at the XVth International Congress on Sports rehabilitation and Traumatology, P. Massetti gave a case study of two young men, 6 months post contusion; one 24 years old, with tears of the femoris and medial vastus lateralis, after 7 treatments showed significant reduction in pain, and increased range-of-motion, and after one week of treatment, the symptoms "were completely resolved" ; and the other 38 years old, with strain of the tibialis medius, interfering with his ability to participate in sports. His pain extended into the insertion of the Achilles tendon. His treatment was 2x week, together with CO2 laser and ultrasound. Following 10 applications of alternating laser+ultrasound and Scenar therapy the patient had a complete remission of symptoms [6].
- 2006 - At the same Congress in which he gave his case report, Massetti published a paper in which he indicates having treated 20 patients, including both professional and amateur athletes with varying painful conditions. According to his report, all of the patients, after 2 treatments, 2x/week demonstrated "significant reduction in symptoms" unexplainable as resulting from any other possible cause. Massetti concludes that the Scenar "is an instrument capable of drastically reducing the time of recuperation in significant traumatic events" , [7]
- 2008 - Writing about his experiences at the European Speed Skating championships (Germany) and the subsequent World's in Spain, Rosario Bella, (a Physiotherapist) for the FIHP (Roller Hockey), in a report published at the medical site FCE news, of Scenar use together with kinesiotaping, states, that the "results were appreciable in noting the time of recuperation and eduction of symptoms to a tolerable level in a good percentage of the cases treated, even during the competition". And, that the SCENAR taken together with the taping provided a synergistic effect, then when taken alone. [8]
- 2010 - With results similar to their 2005 study, Gorodetskiy, et al, publishing in The Journal of Foot and Ankle Surgery in 2010, found results comparable to their earlier study, in patients post malleolar (ankle joint) fracture surgery [9].
## Post-herpetic neuralgia
- 2007 - M.R. Ing, publishing in the Hawaii Medical Journal, treated three consecutive patients with post-herpetic neuralgia and found that ALL resolved their pain in no more than 5 sessions over a three week period [10].
## Duodenal ulcer
- 2006 - In a study published in Клиническая Медицина (Clinical medicine), Tsimmerman, et al, reported that 103 cases of duodenal ulcer were treated with Scenar alone and together with standard therapy for H pylori. They determined that "led to positive changes in most of the parameters under study", and "Addition of SCENAR therapy to the complex conventional pharmacotherapy [sic] 'sped up' ulcer healing, increased the effectiveness of Helicobacter pylori eradication, and improved the condition of the gastroduodenal mucosa" [11]. | https://www.wikidoc.org/index.php/SCENAR | |
56f4fd11ba3f8214e0d65094330ba5850d1c8eb3 | wikidoc | SCNN1A | SCNN1A
The SCNN1A gene encodes for the α subunit of the epithelial sodium channel ENaC in vertebrates. ENaC is assembled as a heterotrimer composed of three homologous subunits α, β, and γ or δ, β, and γ. The other ENAC subunits are encoded by SCNN1B, SCNN1G, and SCNN1D.
ENaC is expressed in epithelial cells and is different from the voltage-gated sodium channel that is involved in the generation of action potentials in neurons. The abbreviation for the genes encoding for voltage-gated sodium channel starts with three letters: SCN. In contrast to these sodium channels, ENaC is constitutively active and is not voltage-dependent. The second N in the abbreviation (SCNN1A) represents that these are NON-voltage-gated channels.
In most vertebrates, sodium ions are the major determinant of the osmolarity of the extracellular fluid. ENaC allows transfer of sodium ions across the epithelial cell membrane in so-called "tight-epithelia" that have low permeability. The flow of sodium ions across epithelia affects osmolarity of the extracellular fluid. Thus, ENaC plays a central role in the regulation of body fluid and electrolyte homeostasis and consequently affects blood pressure.
As ENaC is strongly inhibited by amiloride, it is also referred to as an "amiloride-sensitive sodium channel".
# History
The first mRNA encoding the alpha subunit of ENaC was isolated by two independent groups by screening a rat colon cDNA library.
# Gene structure
The human gene SCNN1A is located in the short arm of chromosome 12 (12p3).
Human SCNN1A includes 13 exons spanning about 29,000 bp. The protein coding region is located in exons 2-13. The positions of introns are conserved in all four human ENaC genes. The positions of the introns are also highly conserved across vertebrates See: Ensembl GeneTree.
Analysis of α subunit mRNA from human lung and kidney showed that during transcription of SCNN1A gene different mRNAs are produced as a result of alternative translation initiation and splicing sites. The isoforms translated from these differ in their activities.
# Tissue-specific expression
SCNN1A, SCNN1B, and SCNN1G are commonly expressed in tight epithelia that have low water permeability. The major organs where ENaC is expressed include parts of the kidney tubular epithelia, the respiratory airway, the female reproductive tract, testis, including, spermatogonia in the seminiferous tubules, Sertoli cells, and spermatoozoa, colon and salivary glands. In the skin, SCNN1A is expressed in the keratinocytes in the epidermal layer, in the sebaceous sweat glands, and the smooth muscle cells mostly within the cytoplasm. In contrast, in the eccrine sweat glands ENaC is mostly located on the luminal surface of eccrine duct epithelia.
ENaC is also expressed in the tongue, where it has been shown to be essential for the perception of salt taste.
The expression of ENaC subunit genes is regulated mainly by the mineralocorticoid hormone aldosterone that is activated by the renin-angiotensin system.
# Protein structure
The primary structures of all four ENaC subunits show strong similarity. Thus, these four proteins represent a family of proteins that share a common ancestor. In global alignment (meaning alignments of sequences along their entire length and not just a partial segment), the human α subunit shares 34% identity with the δ subunit and 26-27% identity with the β and γ subunits.
All four ENaC subunit sequences have two hydrophobic stretches that form two transmembrane segments named as TM1 and TM2.
In the membrane-bound form, the TM segments are embedded in the membrane bilayer, the amino- and carboxy-terminal regions are located inside the cell, and the segment between the two TMs remains outside of the cell as the extracellular region of ENaC. This extracellular region includes about 70% of the residues of each subunit. Thus, in the membrane-bound form, the bulk of each subunit is located outside of the cell.
The structure of ENaC has not been yet determined. Yet, the structure of a homologous protein ASIC1 has been resolved. The chicken ASIC1 structure revealed that ASIC1 is assembled as a homotrimer of three identical subunits. The authors of the original study suggested that the ASIC1 trimer resembles a hand holding a ball. Hence distinct domains of ASIC1 have been referred to as palm, knuckle, finger, thumb, and β-ball.
Alignment of ENaC subunit sequences with ASIC1 sequence reveals that TM1 and TM2 segments and palm domain are conserved, and the knuckle, finger and thumb domains have insertions in ENaC. Site-directed mutagenesis studies on ENaC subunits provide evidence that many basic features of the ASIC1 structural model apply to ENaC as well.
# Associated diseases
The disease most commonly associated with mutations in SCNN1A is the multi-system form of type I pseudohypoaldosteronism (PHA1B) that was first characterized by A. Hanukoglu as an autosomal recessive disease. This is a syndrome of unresponsiveness to aldosterone in patients that have high serum levels of aldosterone but suffer from symptoms of aldosterone deficiency with a high risk of mortality due to severe salt loss. Initially, this disease was thought to be a result of a mutation in the mineralocorticoid receptor (NR3C2) that binds aldosterone. But homozygosity mapping in 11 affected families revealed that the disease is associated with two loci on chromosome 12p13.1-pter and chromosome 16p12.2-13 that include the genes for SCNN1A and SCNN1B and SCNN1G respectively. Sequencing of the ENaC genes identified mutation in affected patients, and functional expression of the mutated cDNAs further confirmed that identified mutations lead to the loss of activity of ENaC.
In the majority of the patients with multi-system PHA1B a homozygous mutation or two compound heterozygous mutations have been detected.
# Interactions
SCNN1A has been shown to interact with:
- NEDD4L,
- NEDD4, and
- Ubiquitin C | SCNN1A
The SCNN1A gene encodes for the α subunit of the epithelial sodium channel ENaC in vertebrates. ENaC is assembled as a heterotrimer composed of three homologous subunits α, β, and γ or δ, β, and γ.[1] The other ENAC subunits are encoded by SCNN1B, SCNN1G, and SCNN1D.
ENaC is expressed in epithelial cells[1] and is different from the voltage-gated sodium channel that is involved in the generation of action potentials in neurons. The abbreviation for the genes encoding for voltage-gated sodium channel starts with three letters: SCN. In contrast to these sodium channels, ENaC is constitutively active and is not voltage-dependent. The second N in the abbreviation (SCNN1A) represents that these are NON-voltage-gated channels.
In most vertebrates, sodium ions are the major determinant of the osmolarity of the extracellular fluid.[2] ENaC allows transfer of sodium ions across the epithelial cell membrane in so-called "tight-epithelia" that have low permeability. The flow of sodium ions across epithelia affects osmolarity of the extracellular fluid. Thus, ENaC plays a central role in the regulation of body fluid and electrolyte homeostasis and consequently affects blood pressure.[3]
As ENaC is strongly inhibited by amiloride, it is also referred to as an "amiloride-sensitive sodium channel".
# History
The first mRNA encoding the alpha subunit of ENaC was isolated by two independent groups by screening a rat colon cDNA library.[4][5]
# Gene structure
The human gene SCNN1A is located in the short arm of chromosome 12 (12p3).[6]
[7] Human SCNN1A includes 13 exons spanning about 29,000 bp. The protein coding region is located in exons 2-13.[7] The positions of introns are conserved in all four human ENaC genes.[8] The positions of the introns are also highly conserved across vertebrates See: Ensembl GeneTree.
Analysis of α subunit mRNA from human lung and kidney showed that during transcription of SCNN1A gene different mRNAs are produced as a result of alternative translation initiation and splicing sites. The isoforms translated from these differ in their activities.[9][10][11][12]
# Tissue-specific expression
SCNN1A, SCNN1B, and SCNN1G are commonly expressed in tight epithelia that have low water permeability. The major organs where ENaC is expressed include parts of the kidney tubular epithelia,[1][3][13] the respiratory airway,[14] the female reproductive tract,[14] testis, including, spermatogonia in the seminiferous tubules, Sertoli cells, and spermatoozoa,[15] colon and salivary glands.[13] In the skin, SCNN1A is expressed in the keratinocytes in the epidermal layer, in the sebaceous sweat glands, and the smooth muscle cells mostly within the cytoplasm.[16] In contrast, in the eccrine sweat glands ENaC is mostly located on the luminal surface of eccrine duct epithelia.[16]
ENaC is also expressed in the tongue, where it has been shown to be essential for the perception of salt taste.[13]
The expression of ENaC subunit genes is regulated mainly by the mineralocorticoid hormone aldosterone that is activated by the renin-angiotensin system.[17][18]
[19]
# Protein structure
The primary structures of all four ENaC subunits show strong similarity.[1] Thus, these four proteins represent a family of proteins that share a common ancestor. In global alignment (meaning alignments of sequences along their entire length and not just a partial segment), the human α subunit shares 34% identity with the δ subunit and 26-27% identity with the β and γ subunits.
All four ENaC subunit sequences have two hydrophobic stretches that form two transmembrane segments named as TM1 and TM2.[20]
In the membrane-bound form, the TM segments are embedded in the membrane bilayer, the amino- and carboxy-terminal regions are located inside the cell, and the segment between the two TMs remains outside of the cell as the extracellular region of ENaC. This extracellular region includes about 70% of the residues of each subunit. Thus, in the membrane-bound form, the bulk of each subunit is located outside of the cell.
The structure of ENaC has not been yet determined. Yet, the structure of a homologous protein ASIC1 has been resolved.[21][22] The chicken ASIC1 structure revealed that ASIC1 is assembled as a homotrimer of three identical subunits. The authors of the original study suggested that the ASIC1 trimer resembles a hand holding a ball.[21] Hence distinct domains of ASIC1 have been referred to as palm, knuckle, finger, thumb, and β-ball.[21]
Alignment of ENaC subunit sequences with ASIC1 sequence reveals that TM1 and TM2 segments and palm domain are conserved, and the knuckle, finger and thumb domains have insertions in ENaC. Site-directed mutagenesis studies on ENaC subunits provide evidence that many basic features of the ASIC1 structural model apply to ENaC as well.[23][24][25]
# Associated diseases
The disease most commonly associated with mutations in SCNN1A is the multi-system form of type I pseudohypoaldosteronism (PHA1B) that was first characterized by A. Hanukoglu as an autosomal recessive disease.[26] This is a syndrome of unresponsiveness to aldosterone in patients that have high serum levels of aldosterone but suffer from symptoms of aldosterone deficiency with a high risk of mortality due to severe salt loss.[1] Initially, this disease was thought to be a result of a mutation in the mineralocorticoid receptor (NR3C2) that binds aldosterone. But homozygosity mapping in 11 affected families revealed that the disease is associated with two loci on chromosome 12p13.1-pter and chromosome 16p12.2-13 that include the genes for SCNN1A and SCNN1B and SCNN1G respectively.[27] Sequencing of the ENaC genes identified mutation in affected patients, and functional expression of the mutated cDNAs further confirmed that identified mutations lead to the loss of activity of ENaC.[28]
In the majority of the patients with multi-system PHA1B a homozygous mutation or two compound heterozygous mutations have been detected.[29][30][31]
# Interactions
SCNN1A has been shown to interact with:
- NEDD4L,[32][33]
- NEDD4,[32][34][35] and
- Ubiquitin C[36][37] | https://www.wikidoc.org/index.php/SCNN1A | |
7532b95ba7acd9668c6765574819e58015011bc6 | wikidoc | SCNN1B | SCNN1B
The SCNN1B gene encodes for the β subunit of the epithelial sodium channel ENaC in vertebrates. ENaC is assembled as a heterotrimer composed of three homologous subunits α, β, and γ or δ, β, and γ. The other ENAC subunits are encoded by SCNN1A, SCNN1G, and SCNN1D.
ENaC is expressed in epithelial cells and is different from the voltage-gated sodium channel that is involved in the generation of action potentials in neurons. The abbreviation for the genes encoding for voltage-gated sodium channel starts with three letters: SCN. In contrast to these sodium channels, ENaC is constitutively active and is not voltage-dependent. The second N in the abbreviation (SCNN1A) represents that these are NON-voltage-gated channels.
In most vertebrates, sodium ions are the major determinant of the osmolarity of the extracellular fluid. ENaC allows transfer of sodium ions across the epithelial cell membrane in so-called "tight-epithelia" that have low permeability. The flow of sodium ions across epithelia affects osmolarity of the extracellular fluid. Thus, ENaC plays a central role in the regulation of body fluid and electrolyte homeostasis and consequently affects blood pressure.
As ENaC is strongly inhibited by amiloride, it is also referred to as an "amiloride-sensitive sodium channel".
# History
The first cDNA encoding the beta subunit of ENaC was cloned and sequenced by Canessa et al. from rat mRNA. A year later, two independent groups reported the cDNA sequences of the beta- and gamma-subunits of the human ENaC. The exon-intron organization of the human beta ENaC gene SCNN1B was determined by Saxena et al. by sequencing genomic DNA from three subjects from three different ethnic groups. This study also established that the exon-intron architecture of the three subunits of ENaC have remained highly conserved despite the divergence of their sequences.
# Gene structure
While the human gene SCNN1A is located in chromosome 12p, the human genes encoding SCNN1B and SCNN1G are located in juxtaposition in the short arm of chromosome 16 (16p12-p13). Sequencing of the human genomic DNA indicated that the SCNN1B gene has 13 exons separated by 12 introns. The positions of introns are conserved in all three human ENaC genes, SCNN1A, SCNN1B and SCNN1G. The positions of the introns are also highly conserved across vertebrates. See: Ensembl GeneTree.
Analysis of transcripts of the SCNN1B gene in human kidney and lung showed several alternative transcription and translation initiation sites. However, only one of these transcripts (ENST00000343070) is highly expressed and other transcripts appear at low amounts.
# Tissue-specific expression
The three ENaC subunits encoded by SCNN1A, SCNN1B, and SCNN1G are commonly expressed in tight epithelia that have low water permeability. The major organs where ENaC is expressed include parts of the kidney tubular epithelia, the respiratory airway, the female reproductive tract, colon, salivary and sweat glands.
ENaC is also expressed in the tongue, where it has been shown to be essential for the perception of salt taste.
The expression of ENaC subunit genes is regulated mainly by the mineralocorticoid hormone aldosterone that is activated by the renin-angiotensin system.
# Protein structure
The primary structures of all four ENaC subunits show strong similarity. Thus, these four proteins represent a family of proteins that share a common ancestor. In global alignment (meaning alignments of sequences along their entire length and not just a partial segment), the human β subunit shares 34% identity with the γ subunit and 26 and 23% identity with the α and δ subunits.
All four ENaC subunit sequences have two hydrophobic stretches that form two transmembrane segments named as TM1 and TM2.
In the membrane-bound form, the TM segments are embedded in the membrane bilayer, the amino- and carboxy-terminal regions are located inside the cell, and the segment between the two TMs remains outside of the cell as the extracellular region of ENaC. This extracellular region includes about 70% of the residues of each subunit. Thus, in the membrane-bound form, the bulk of each subunit is located outside of the cell.
The structure of ENaC has not been yet determined. Yet, the structure of a homologous protein ASIC1 has been resolved. The chicken ASIC1 structure revealed that ASIC1 is assembled as a homotrimer of three identical subunits. The authors of the original study suggested that each ASIC1 subunit resembles a hand holding a ball. Hence distinct domains of ASIC1 have been referred to as palm, knuckle, finger, thumb, and β-ball.
Alignment of ENaC subunit sequences with ASIC1 sequence reveals that TM1 and TM2 segments and palm domain are conserved, and the knuckle, finger and thumb domains have insertions in ENaC. Site-directed mutagenesis studies on ENaC subunits provide evidence that many basic features of the ASIC1 structural model apply to ENaC as well. Yet, ENaC is an obligate heterotrimer composed of three subunits as an αβγ or a βγδ trimer.
In the carboxy terminus of three ENaC subunits, (α, β and γ) there is a special conserved consensus sequence PPPXYXXL that is called the PY motif. This sequence is recognized by the so-called WW domains in a special E3 ubiquitin-protein ligase named Nedd4-2. Nedd4-2 ligates ubiquitin to the C-terminus of the ENaC subunit which marks the protein for degradation.
# Associated diseases
At present, three major hereditary disorders are known to be associated with mutations in the SCNN1B gene. These are:
1. Multisystem pseudohypoaldosteronism, 2. Liddle syndrome, and 3. Cystic fibrosis-like disease.
## Multi-system form of type I pseudohypoaldosteronism (PHA1B)
The disease most commonly associated with mutations in SCNN1B is the multi-system form of type I pseudohypoaldosteronism (PHA1B) that was first characterized by A. Hanukoglu as an autosomal recessive disease. This is a syndrome of unresponsiveness to aldosterone in patients that have high serum levels of aldosterone but suffer from symptoms of aldosterone deficiency with a high risk of mortality due to severe salt loss. Initially, this disease was thought to be a result of a mutation in the mineralocorticoid receptor (NR3C2) that binds aldosterone. But homozygosity mapping in 11 affected families revealed that the disease is associated with two loci on chromosome 12p13.1-pter and chromosome 16p12.2-13 that include the genes for SCNN1A and SCNN1B and SCNN1G respectively. Sequencing of the ENaC genes identified mutation in affected patients, and functional expression of the mutated cDNAs further confirmed that identified mutations lead to the loss of activity of ENaC.
In the majority of the patients with multi-system PHA1B a homozygous mutation or two compound heterozygous mutations have been detected.
## Liddle syndrome
Liddle syndrome is generally caused by mutations in the PY motif or truncation of the C-terminus including loss of the PY motif in the β or γ ENaC subunits. Even though there is a PY motif also in the α subunit, so far Liddle disease has not observed in association with a mutation in the α subunit. Liddle syndrome is inherited as an autosomal dominant disease with a phenotype that includes early onset hypertension, metabolic alkalosis and low levels of plasma renin activity and mineralocorticoid hormone aldosterone. In the absence of a recognizable PY motif, ubiquitin-protein ligase Nedd4-2 cannot bind to the ENaC subunit and hence cannot attach a ubiquitin to it. Consequently, proteolysis of ENaC by proteasome is inhibited and ENaC accumulates in the membrane leading to enhanced activity of ENaC that causes hypertension.
# Interactions
SCNN1B has been shown to interact with WWP2 and NEDD4.
# Notes | SCNN1B
The SCNN1B gene encodes for the β subunit of the epithelial sodium channel ENaC in vertebrates. ENaC is assembled as a heterotrimer composed of three homologous subunits α, β, and γ or δ, β, and γ. The other ENAC subunits are encoded by SCNN1A, SCNN1G, and SCNN1D.[1]
ENaC is expressed in epithelial cells[1] and is different from the voltage-gated sodium channel that is involved in the generation of action potentials in neurons. The abbreviation for the genes encoding for voltage-gated sodium channel starts with three letters: SCN. In contrast to these sodium channels, ENaC is constitutively active and is not voltage-dependent. The second N in the abbreviation (SCNN1A) represents that these are NON-voltage-gated channels.
In most vertebrates, sodium ions are the major determinant of the osmolarity of the extracellular fluid.[2] ENaC allows transfer of sodium ions across the epithelial cell membrane in so-called "tight-epithelia" that have low permeability. The flow of sodium ions across epithelia affects osmolarity of the extracellular fluid. Thus, ENaC plays a central role in the regulation of body fluid and electrolyte homeostasis and consequently affects blood pressure.[3]
As ENaC is strongly inhibited by amiloride, it is also referred to as an "amiloride-sensitive sodium channel".
# History
The first cDNA encoding the beta subunit of ENaC was cloned and sequenced by Canessa et al. from rat mRNA.[4] A year later, two independent groups reported the cDNA sequences of the beta- and gamma-subunits of the human ENaC.[5][6] The exon-intron organization of the human beta ENaC gene SCNN1B was determined by Saxena et al. by sequencing genomic DNA from three subjects from three different ethnic groups.[7] This study also established that the exon-intron architecture of the three subunits of ENaC have remained highly conserved despite the divergence of their sequences.[7]
# Gene structure
While the human gene SCNN1A is located in chromosome 12p,[8] the human genes encoding SCNN1B and SCNN1G are located in juxtaposition in the short arm of chromosome 16 (16p12-p13).[6] Sequencing of the human genomic DNA indicated that the SCNN1B gene has 13 exons separated by 12 introns.[7] The positions of introns are conserved in all three human ENaC genes, SCNN1A, SCNN1B and SCNN1G.[7] The positions of the introns are also highly conserved across vertebrates. See: Ensembl GeneTree.
Analysis of transcripts of the SCNN1B gene in human kidney and lung showed several alternative transcription and translation initiation sites.[9] However, only one of these transcripts (ENST00000343070) is highly expressed and other transcripts appear at low amounts.[9]
# Tissue-specific expression
The three ENaC subunits encoded by SCNN1A, SCNN1B, and SCNN1G are commonly expressed in tight epithelia that have low water permeability.[1] The major organs where ENaC is expressed include parts of the kidney tubular epithelia,[3][10] the respiratory airway,[11] the female reproductive tract,[11] colon, salivary and sweat glands.[10]
ENaC is also expressed in the tongue, where it has been shown to be essential for the perception of salt taste.[10]
The expression of ENaC subunit genes is regulated mainly by the mineralocorticoid hormone aldosterone that is activated by the renin-angiotensin system.[12]
[13]
# Protein structure
The primary structures of all four ENaC subunits show strong similarity. Thus, these four proteins represent a family of proteins that share a common ancestor. In global alignment (meaning alignments of sequences along their entire length and not just a partial segment), the human β subunit shares 34% identity with the γ subunit and 26 and 23% identity with the α and δ subunits.[1]
All four ENaC subunit sequences have two hydrophobic stretches that form two transmembrane segments named as TM1 and TM2.[14]
In the membrane-bound form, the TM segments are embedded in the membrane bilayer, the amino- and carboxy-terminal regions are located inside the cell, and the segment between the two TMs remains outside of the cell as the extracellular region of ENaC. This extracellular region includes about 70% of the residues of each subunit. Thus, in the membrane-bound form, the bulk of each subunit is located outside of the cell.
The structure of ENaC has not been yet determined. Yet, the structure of a homologous protein ASIC1 has been resolved.[15][16] The chicken ASIC1 structure revealed that ASIC1 is assembled as a homotrimer of three identical subunits. The authors of the original study suggested that each ASIC1 subunit resembles a hand holding a ball.[15] Hence distinct domains of ASIC1 have been referred to as palm, knuckle, finger, thumb, and β-ball.[15]
Alignment of ENaC subunit sequences with ASIC1 sequence reveals that TM1 and TM2 segments and palm domain are conserved, and the knuckle, finger and thumb domains have insertions in ENaC. Site-directed mutagenesis studies on ENaC subunits provide evidence that many basic features of the ASIC1 structural model apply to ENaC as well. Yet, ENaC is an obligate heterotrimer composed of three subunits as an αβγ or a βγδ trimer.[17]
In the carboxy terminus of three ENaC subunits, (α, β and γ) there is a special conserved consensus sequence PPPXYXXL that is called the PY motif. This sequence is recognized by the so-called WW domains in a special E3 ubiquitin-protein ligase named Nedd4-2.[18] Nedd4-2 ligates ubiquitin to the C-terminus of the ENaC subunit which marks the protein for degradation.[18]
# Associated diseases
At present, three major hereditary disorders are known to be associated with mutations in the SCNN1B gene. These are:
1. Multisystem pseudohypoaldosteronism, 2. Liddle syndrome, and 3. Cystic fibrosis-like disease.[1]
## Multi-system form of type I pseudohypoaldosteronism (PHA1B)
The disease most commonly associated with mutations in SCNN1B is the multi-system form of type I pseudohypoaldosteronism (PHA1B) that was first characterized by A. Hanukoglu as an autosomal recessive disease.[19] This is a syndrome of unresponsiveness to aldosterone in patients that have high serum levels of aldosterone but suffer from symptoms of aldosterone deficiency with a high risk of mortality due to severe salt loss. Initially, this disease was thought to be a result of a mutation in the mineralocorticoid receptor (NR3C2) that binds aldosterone. But homozygosity mapping in 11 affected families revealed that the disease is associated with two loci on chromosome 12p13.1-pter and chromosome 16p12.2-13 that include the genes for SCNN1A and SCNN1B and SCNN1G respectively.[20] Sequencing of the ENaC genes identified mutation in affected patients, and functional expression of the mutated cDNAs further confirmed that identified mutations lead to the loss of activity of ENaC.[21]
In the majority of the patients with multi-system PHA1B a homozygous mutation or two compound heterozygous mutations have been detected.[22][23][24]
## Liddle syndrome
Liddle syndrome is generally caused by mutations in the PY motif or truncation of the C-terminus including loss of the PY motif in the β or γ ENaC subunits.[25][26][27][28][29][30] Even though there is a PY motif also in the α subunit, so far Liddle disease has not observed in association with a mutation in the α subunit. Liddle syndrome is inherited as an autosomal dominant disease with a phenotype that includes early onset hypertension, metabolic alkalosis and low levels of plasma renin activity and mineralocorticoid hormone aldosterone. In the absence of a recognizable PY motif, ubiquitin-protein ligase Nedd4-2 cannot bind to the ENaC subunit and hence cannot attach a ubiquitin to it. Consequently, proteolysis of ENaC by proteasome is inhibited and ENaC accumulates in the membrane leading to enhanced activity of ENaC that causes hypertension.[31][32][33][34]
# Interactions
SCNN1B has been shown to interact with WWP2[35][36] and NEDD4.[35][36][37]
# Notes | https://www.wikidoc.org/index.php/SCNN1B | |
6b7ad969bf0d5faf43c062ba71fe43de0783b339 | wikidoc | SCNN1D | SCNN1D
The SCNN1D gene encodes for the δ (delta) subunit of the epithelial sodium channel ENaC in vertebrates. ENaC is assembled as a heterotrimer composed of three homologous subunits α, β, and γ or δ, β, and γ. The other ENAC subunits are encoded by SCNN1A, SCNN1B, and SCNN1G.
ENaC is expressed in epithelial cells and is different from the voltage-gated sodium channel that is involved in the generation of action potentials in neurons. The abbreviation for the genes encoding for voltage-gated sodium channel starts with three letters: SCN. In contrast to these sodium channels, ENaC is constitutively active and is not voltage-dependent. The second N in the abbreviation (SCNN1D) represents that these are NON-voltage-gated channels.
In most vertebrates, sodium ions are the major determinant of the osmolarity of the extracellular fluid. ENaC allows transfer of sodium ions across the epithelial cell membrane in so-called "tight-epithelia" that have low permeability. The flow of sodium ions across epithelia affects osmolarity of the extracellular fluid. Thus, ENaC plays a central role in the regulation of body fluid and electrolyte homeostasis and consequently affects blood pressure.
As ENaC is strongly inhibited by amiloride, it is also referred to as an "amiloride-sensitive sodium channel".
# History
The first cDNA encoding the delta subunit of ENaC was cloned and sequenced by Waldmann et al. from human kidney mRNA.
# Gene structure
The sequence of the SCNN1D gene was first revealed by the human genome project. SCNN1D is located in the short arm of chromosome 1 (Ensembl database code: ENSG00000162572) and starts at nucleotide 1,280,436 on the forward strand. Its length is about 11,583 bp. The gene encodes several alternative transcripts with different transcription and translation initiation sites (see Fig. 1 below). In mRNA samples from human brain, alternative splicing products have been detected, cloned and characterized.
The SCNN1D gene is found in most vertebrates. But the gene has been lost in the mouse and rat genomes.
# Tissue-specific expression
The tissue specific expression of the δ-subunit is very different from that of the other three subunits encoded by SCNN1A, SCNN1B, and SCNN1G. While the α, β, and γ subunits are expressed mainly in the kidney tubular epithelia, the respiratory airway, the female reproductive tract, colon, salivary and sweat glands, the δ-subunit is expressed mainly in the brain, pancreas, testis and ovary.
# Protein structure
The primary structures of all four ENaC subunits show strong similarity. Thus, these four proteins represent a family of proteins that share a common ancestor. In global alignment (meaning alignments of sequences along their entire length and not just a partial segment), the human δ subunit shares 34% identity with the α subunit and 23% identity with the β and γ subunits.
All four ENaC subunit sequences have two hydrophobic stretches that form two transmembrane segments named as TM1 and TM2.
In the membrane-bound form, the TM segments are embedded in the membrane bilayer, the amino- and carboxy-terminal regions are located inside the cell, and the segment between the two TMs remains outside of the cell as the extracellular region of ENaC. This extracellular region includes about 70% of the residues of each subunit. Thus, in the membrane-bound form, the bulk of each subunit is located outside of the cell.
The structure of ENaC has not been yet determined. Yet, the structure of a homologous protein ASIC1 has been resolved. The chicken ASIC1 structure revealed that ASIC1 is assembled as a homotrimer of three identical subunits. The authors of the original study suggested that the ASIC1 trimer resembles a hand holding a ball. Hence distinct domains of ASIC1 have been referred to as palm, knuckle, finger, thumb, and β-ball.
Alignment of ENaC subunit sequences with ASIC1 sequence reveals that TM1 and TM2 segments and palm domain are conserved, and the knuckle, finger and thumb domains have insertions in ENaC. Site-directed mutagenesis studies on ENaC subunits provide evidence that many basic features of the ASIC1 structural model apply to ENaC as well. Yet, ENaC is an obligate heterotrimer composed of three subunits as an αβγ or a βγδ trimer.
# Associated diseases
So far mutations in the delta subunit have not been associated with a specific disease.
# Notes | SCNN1D
The SCNN1D gene encodes for the δ (delta) subunit of the epithelial sodium channel ENaC in vertebrates. ENaC is assembled as a heterotrimer composed of three homologous subunits α, β, and γ or δ, β, and γ.[1] The other ENAC subunits are encoded by SCNN1A, SCNN1B, and SCNN1G.
ENaC is expressed in epithelial cells and is different from the voltage-gated sodium channel that is involved in the generation of action potentials in neurons. The abbreviation for the genes encoding for voltage-gated sodium channel starts with three letters: SCN. In contrast to these sodium channels, ENaC is constitutively active and is not voltage-dependent. The second N in the abbreviation (SCNN1D) represents that these are NON-voltage-gated channels.
In most vertebrates, sodium ions are the major determinant of the osmolarity of the extracellular fluid.[2] ENaC allows transfer of sodium ions across the epithelial cell membrane in so-called "tight-epithelia" that have low permeability. The flow of sodium ions across epithelia affects osmolarity of the extracellular fluid. Thus, ENaC plays a central role in the regulation of body fluid and electrolyte homeostasis and consequently affects blood pressure.[3]
As ENaC is strongly inhibited by amiloride, it is also referred to as an "amiloride-sensitive sodium channel".
# History
The first cDNA encoding the delta subunit of ENaC was cloned and sequenced by Waldmann et al. from human kidney mRNA.[4]
# Gene structure
The sequence of the SCNN1D gene was first revealed by the human genome project. SCNN1D is located in the short arm of chromosome 1 (Ensembl database code: ENSG00000162572) and starts at nucleotide 1,280,436 on the forward strand. Its length is about 11,583 bp. The gene encodes several alternative transcripts with different transcription and translation initiation sites (see Fig. 1 below). In mRNA samples from human brain, alternative splicing products have been detected, cloned and characterized.[5][6]
The SCNN1D gene is found in most vertebrates.[1] But the gene has been lost in the mouse and rat genomes.
[7]
[8]
# Tissue-specific expression
The tissue specific expression of the δ-subunit is very different from that of the other three subunits encoded by SCNN1A, SCNN1B, and SCNN1G. While the α, β, and γ subunits are expressed mainly in the kidney tubular epithelia, the respiratory airway,[9] the female reproductive tract,[9] colon, salivary and sweat glands,[10] the δ-subunit is expressed mainly in the brain, pancreas, testis and ovary.[8]
# Protein structure
The primary structures of all four ENaC subunits show strong similarity. Thus, these four proteins represent a family of proteins that share a common ancestor. In global alignment (meaning alignments of sequences along their entire length and not just a partial segment), the human δ subunit shares 34% identity with the α subunit and 23% identity with the β and γ subunits.[1]
All four ENaC subunit sequences have two hydrophobic stretches that form two transmembrane segments named as TM1 and TM2.[11]
In the membrane-bound form, the TM segments are embedded in the membrane bilayer, the amino- and carboxy-terminal regions are located inside the cell, and the segment between the two TMs remains outside of the cell as the extracellular region of ENaC. This extracellular region includes about 70% of the residues of each subunit. Thus, in the membrane-bound form, the bulk of each subunit is located outside of the cell.
The structure of ENaC has not been yet determined. Yet, the structure of a homologous protein ASIC1 has been resolved.[12][13] The chicken ASIC1 structure revealed that ASIC1 is assembled as a homotrimer of three identical subunits. The authors of the original study suggested that the ASIC1 trimer resembles a hand holding a ball.[12] Hence distinct domains of ASIC1 have been referred to as palm, knuckle, finger, thumb, and β-ball.[12]
Alignment of ENaC subunit sequences with ASIC1 sequence reveals that TM1 and TM2 segments and palm domain are conserved, and the knuckle, finger and thumb domains have insertions in ENaC. Site-directed mutagenesis studies on ENaC subunits provide evidence that many basic features of the ASIC1 structural model apply to ENaC as well.[1] Yet, ENaC is an obligate heterotrimer composed of three subunits as an αβγ or a βγδ trimer.[14]
# Associated diseases
So far mutations in the delta subunit have not been associated with a specific disease.
# Notes | https://www.wikidoc.org/index.php/SCNN1D | |
70519078d586722a446106ae2a0815886fa2d90a | wikidoc | SCNN1G | SCNN1G
The SCNN1G gene encodes for the γ subunit of the epithelial sodium channel ENaC in vertebrates. ENaC is assembled as a heterotrimer composed of three homologous subunits α, β, and γ or δ, β, and γ. The other ENAC subunits are encoded by SCNN1A, SCNN1B, and SCNN1D.
ENaC is expressed in epithelial cells and is different from the voltage-gated sodium channel that is involved in the generation of action potentials in neurons. The abbreviation for the genes encoding for voltage-gated sodium channel starts with three letters: SCN. In contrast to these sodium channels, ENaC is constitutively active and is not voltage-dependent. The second N in the abbreviation (SCNN1) represents that these are NON-voltage-gated channels.
In most vertebrates, sodium ions are the major determinant of the osmolarity of the extracellular fluid. ENaC allows transfer of sodium ions across the epithelial cell membrane in so-called "tight-epithelia" that have low permeability. The flow of sodium ions across epithelia affects osmolarity of the extracellular fluid. Thus, ENaC plays a central role in the regulation of body fluid and electrolyte homeostasis and consequently affects blood pressure.
As ENaC is strongly inhibited by amiloride, it is also referred to as an "amiloride-sensitive sodium channel".
# History
The first cDNA encoding the gamma subunit of ENaC was cloned and sequenced by Canessa et al. from rat mRNA. A year later, two independent groups reported the cDNA sequences of the beta- and gamma-subunits of the human ENaC.
The complete coding sequence human γ subunit was reported by Saxena et al.
# Gene structure
While the human gene SCNN1A is located in chromosome 12p, the human genes encoding SCNN1B and SCNN1G are located in juxtoposition in the short arm of chromosome 16 (16p12-p13). The structures of the human and rat SCNN1G genes were first reported by Thomas et al. Later studies by Saxena et al. reported the complete coding sequence of the human SCNN1G gene establishing that it has 13 exons The positions of introns are conserved in all three human ENaC genes, SCNN1A, SCNN1B and SCNN1G. The positions of the introns are also highly conserved across vertebrates See: Ensembl GeneTree.
# Tissue-specific expression
The three ENaC subunits encoded by SCNN1A, SCNN1B, and SCNN1G are commonly expressed in tight epithelia that have low water permeability. The major organs where ENaC is expressed include parts of the kidney tubular epithelia, the respiratory airway, the female reproductive tract, colon, salivary and sweat glands.
ENaC is also expressed in the tongue, where it has been shown to be essential for the perception of salt taste.
The expression of ENaC subunit genes is regulated mainly by the mineralocorticoid hormone aldosterone that is activated by the renin-angiotensin system.
# Protein structure
The primary structures of all four ENaC subunits show strong similarity. Thus, these four proteins represent a family of proteins that share a common ancestor. In global alignment (meaning alignments of sequences along their entire length and not just a partial segment), the human γ subunit shares 34% identity with the β subunit and 27 and 23% identity with the α and δ subunits.
All four ENaC subunit sequences have two hydrophobic stretches that form two transmembrane segments named as TM1 and TM2.
In the membrane-bound form, the TM segments are embedded in the membrane bilayer, the amino- and carboxy-terminal regions are located inside the cell, and the segment between the two TMs remains outside of the cell as the extracellular region of ENaC. This extracellular region includes about 70% of the residues of each subunit. Thus, in the membrane-bound form, the bulk of each subunit is located outside of the cell.
The structure of ENaC has not been yet determined. Yet, the structure of a homologous protein ASIC1 has been resolved. The chicken ASIC1 structure revealed that ASIC1 is assembled as a homotrimer of three identical subunits. The authors of the original study suggested that the ASIC1 trimer resembles a hand holding a ball. Hence distinct domains of ASIC1 have been referred to as palm, knuckle, finger, thumb, and β-ball.
Site-directed mutagenesis of the human γ subunit suggests that ENaC subunits have a structure similar to that of ASIC1. The ion selectivity filter of ENaC has been modeled based on the ASIC1 structure.
Alignment of ENaC subunit sequences with ASIC1 sequence reveals that TM1 and TM2 segments and palm domain are conserved, and the knuckle, finger and thumb domains have insertions in ENaC. Site-directed mutagenesis studies on ENaC subunits provide evidence that many basic features of the ASIC1 structural model apply to ENaC as well.
In the carboxy terminus of three ENaC subunits, (α, β and γ) there is a special conserved consensus sequence PPPXYXXL that is called the PY motif. This sequence is recognized by the so-called WW domains in a special E3 ubiquitin-protein ligase named Nedd4-2. Nedd4-2 ligates ubiquitin to the C-terminus of the ENaC subunit which marks the protein for degradation.
# Associated diseases
At present, three major hereditary disorders are known to be associated with mutations in the SCNN1G gene. These are:
1. Multisystem pseudohypoaldosteronism, 2. Liddle syndrome, and 3. Cystic fibrosis-like disease.
## Multi-system form of type I pseudohypoaldosteronism (PHA1B)
The disease most commonly associated with mutations in SCNN1B is the multi-system form of type I pseudohypoaldosteronism (PHA1B) that was first characterized by A. Hanukoglu as an autosomal recessive disease. This is a syndrome of unresponsiveness to aldosterone in patients that have high serum levels of aldosterone but suffer from symptoms of aldosterone deficiency with a high risk of mortality due to severe salt loss. Initially, this disease was thought to be a result of a mutation in the mineralocorticoid receptor (NR3C2) that binds aldosterone. But homozygosity mapping in 11 affected families revealed that the disease is associated with two loci on chromosome 12p13.1-pter and chromosome 16p12.2-13 that include the genes for SCNN1A and SCNN1B and SCNN1G respectively. Sequencing of the ENaC genes identified mutation in affected patients, and functional expression of the mutated cDNAs further confirmed that identified mutations lead to the loss of activity of ENaC.
In the majority of the patients with multi-system PHA1B a homozygous mutation or two compound heterozygous mutations have been detected.
## Liddle syndrome
Liddle syndrome is generally caused by mutations in the PY motif or truncation of the C-terminus including loss of the PY motif in the β or γ ENaC subunits. Even though there is a PY motif also in the α subunit, so far Liddle disease has not observed in association with a mutation in the α subunit. Liddle syndrome is inherited as an autosomal dominant disease with a phenotype that includes early onset hypertension, metabolic alkalosis and low levels of plasma renin activity and mineralocorticoid hormone aldosterone. In the absence of a recognizable PY motif, ubiquitin-protein ligase Nedd4-2 cannot bind to the ENaC subunit and hence cannot attach a ubiquitin to it. Consequently, proteolysis of ENaC by proteasome is inhibited and ENaC accumulates in the membrane leading to enhanced activity of ENaC that causes hypertension.
# Interactions
SCNN1G has been shown to interact with:
- NEDD4,
- STX1A, and
- Ubiquitin C | SCNN1G
The SCNN1G gene encodes for the γ subunit of the epithelial sodium channel ENaC in vertebrates. ENaC is assembled as a heterotrimer composed of three homologous subunits α, β, and γ or δ, β, and γ. The other ENAC subunits are encoded by SCNN1A, SCNN1B, and SCNN1D.[1]
ENaC is expressed in epithelial cells and is different from the voltage-gated sodium channel that is involved in the generation of action potentials in neurons. The abbreviation for the genes encoding for voltage-gated sodium channel starts with three letters: SCN. In contrast to these sodium channels, ENaC is constitutively active and is not voltage-dependent. The second N in the abbreviation (SCNN1) represents that these are NON-voltage-gated channels.
In most vertebrates, sodium ions are the major determinant of the osmolarity of the extracellular fluid.[2] ENaC allows transfer of sodium ions across the epithelial cell membrane in so-called "tight-epithelia" that have low permeability. The flow of sodium ions across epithelia affects osmolarity of the extracellular fluid. Thus, ENaC plays a central role in the regulation of body fluid and electrolyte homeostasis and consequently affects blood pressure.[3]
As ENaC is strongly inhibited by amiloride, it is also referred to as an "amiloride-sensitive sodium channel".
# History
The first cDNA encoding the gamma subunit of ENaC was cloned and sequenced by Canessa et al. from rat mRNA.[4] A year later, two independent groups reported the cDNA sequences of the beta- and gamma-subunits of the human ENaC.[5][6]
The complete coding sequence human γ subunit was reported by Saxena et al.[7]
# Gene structure
While the human gene SCNN1A is located in chromosome 12p,[8] the human genes encoding SCNN1B and SCNN1G are located in juxtoposition in the short arm of chromosome 16 (16p12-p13).[6] The structures of the human and rat SCNN1G genes were first reported by Thomas et al.[9][10] Later studies by Saxena et al. reported the complete coding sequence of the human SCNN1G gene establishing that it has 13 exons [7] The positions of introns are conserved in all three human ENaC genes, SCNN1A, SCNN1B and SCNN1G.[11] The positions of the introns are also highly conserved across vertebrates See: Ensembl GeneTree.
# Tissue-specific expression
The three ENaC subunits encoded by SCNN1A, SCNN1B, and SCNN1G are commonly expressed in tight epithelia that have low water permeability. The major organs where ENaC is expressed include parts of the kidney tubular epithelia,[1][3][12] the respiratory airway,[13] the female reproductive tract,[13] colon, salivary and sweat glands.[12]
ENaC is also expressed in the tongue, where it has been shown to be essential for the perception of salt taste.[12]
The expression of ENaC subunit genes is regulated mainly by the mineralocorticoid hormone aldosterone that is activated by the renin-angiotensin system.[14][15]
# Protein structure
The primary structures of all four ENaC subunits show strong similarity. Thus, these four proteins represent a family of proteins that share a common ancestor. In global alignment (meaning alignments of sequences along their entire length and not just a partial segment), the human γ subunit shares 34% identity with the β subunit and 27 and 23% identity with the α and δ subunits.
All four ENaC subunit sequences have two hydrophobic stretches that form two transmembrane segments named as TM1 and TM2.[1][16]
In the membrane-bound form, the TM segments are embedded in the membrane bilayer, the amino- and carboxy-terminal regions are located inside the cell, and the segment between the two TMs remains outside of the cell as the extracellular region of ENaC. This extracellular region includes about 70% of the residues of each subunit. Thus, in the membrane-bound form, the bulk of each subunit is located outside of the cell.[1]
The structure of ENaC has not been yet determined. Yet, the structure of a homologous protein ASIC1 has been resolved.[17][18] The chicken ASIC1 structure revealed that ASIC1 is assembled as a homotrimer of three identical subunits. The authors of the original study suggested that the ASIC1 trimer resembles a hand holding a ball.[17] Hence distinct domains of ASIC1 have been referred to as palm, knuckle, finger, thumb, and β-ball.[17]
Site-directed mutagenesis of the human γ subunit suggests that ENaC subunits have a structure similar to that of ASIC1.[19] The ion selectivity filter of ENaC has been modeled based on the ASIC1 structure.[20]
Alignment of ENaC subunit sequences with ASIC1 sequence reveals that TM1 and TM2 segments and palm domain are conserved, and the knuckle, finger and thumb domains have insertions in ENaC. Site-directed mutagenesis studies on ENaC subunits provide evidence that many basic features of the ASIC1 structural model apply to ENaC as well.[1]
In the carboxy terminus of three ENaC subunits, (α, β and γ) there is a special conserved consensus sequence PPPXYXXL that is called the PY motif. This sequence is recognized by the so-called WW domains in a special E3 ubiquitin-protein ligase named Nedd4-2.[21] Nedd4-2 ligates ubiquitin to the C-terminus of the ENaC subunit which marks the protein for degradation.[21]
# Associated diseases
At present, three major hereditary disorders are known to be associated with mutations in the SCNN1G gene. These are:
1. Multisystem pseudohypoaldosteronism, 2. Liddle syndrome, and 3. Cystic fibrosis-like disease.[1]
## Multi-system form of type I pseudohypoaldosteronism (PHA1B)
The disease most commonly associated with mutations in SCNN1B is the multi-system form of type I pseudohypoaldosteronism (PHA1B) that was first characterized by A. Hanukoglu as an autosomal recessive disease.[22] This is a syndrome of unresponsiveness to aldosterone in patients that have high serum levels of aldosterone but suffer from symptoms of aldosterone deficiency with a high risk of mortality due to severe salt loss. Initially, this disease was thought to be a result of a mutation in the mineralocorticoid receptor (NR3C2) that binds aldosterone. But homozygosity mapping in 11 affected families revealed that the disease is associated with two loci on chromosome 12p13.1-pter and chromosome 16p12.2-13 that include the genes for SCNN1A and SCNN1B and SCNN1G respectively.[23] Sequencing of the ENaC genes identified mutation in affected patients, and functional expression of the mutated cDNAs further confirmed that identified mutations lead to the loss of activity of ENaC.[24]
In the majority of the patients with multi-system PHA1B a homozygous mutation or two compound heterozygous mutations have been detected.[25][26][27]
## Liddle syndrome
Liddle syndrome is generally caused by mutations in the PY motif or truncation of the C-terminus including loss of the PY motif in the β or γ ENaC subunits.[28][29][30][31][32][33] Even though there is a PY motif also in the α subunit, so far Liddle disease has not observed in association with a mutation in the α subunit. Liddle syndrome is inherited as an autosomal dominant disease with a phenotype that includes early onset hypertension, metabolic alkalosis and low levels of plasma renin activity and mineralocorticoid hormone aldosterone. In the absence of a recognizable PY motif, ubiquitin-protein ligase Nedd4-2 cannot bind to the ENaC subunit and hence cannot attach a ubiquitin to it. Consequently, proteolysis of ENaC by proteasome is inhibited and ENaC accumulates in the membrane leading to enhanced activity of ENaC that causes hypertension.[34][35][36][37]
# Interactions
SCNN1G has been shown to interact with:
- NEDD4,[38][39][40]
- STX1A,[41] and
- Ubiquitin C[42][43] | https://www.wikidoc.org/index.php/SCNN1G | |
33490d351af0819220a073334b4f5950d5ef0288 | wikidoc | SDHAF1 | SDHAF1
Succinate dehydrogenase complex assembly factor 1 (SDHAF1), also known as LYR motif-containing protein 8 (LYRM8), is a protein that in humans is encoded by the SDHAF1, or LYRM8, gene. SDHAF1 is a chaperone protein involved in the assembly of the succinate dehydrogenase (SDH) complex (complex II). Mutations in this gene are associated with SDH-defective infantile leukoencephalopathy and mitochondrial complex II deficiency.
# Structure
SDHAF1 is located on the q arm of chromosome 19 in position 13.12 and has 1 exon. The SDHAF1 gene produces a 12.8 kDa protein composed of 115 amino acids. SDHAF1 is ubiquitously expressed and belongs to the complex I LYR family and SDHAF1 subfamily. As such, SDHAF1 is one of at least eight proteins that has a LYR tripeptide motif, thought to be important for Fe-S metabolism. SDHAF1 also contains an N-terminal mitochondrial targeting sequence that does not get cleaved following import into the mitochondria. The encoded protein is fairly hydrophilic and does not contain a transmembrane domain.
# Function
SDHAF1 is essential for the assembly of the succinate dehydrogenase (SDH) complex (complex II), an enzyme complex that is a component of both the tricarboxylic acid (TCA) cycle and the mitochondrial electron transport chain, and which couples the oxidation of succinate to fumarate with the reduction of ubiquinone (coenzyme Q) to ubiquinol. The succinate dehydrogenase (SDH) complex of the mitochondrial respiratory chain is composed of 4 individual subunits. The protein encoded by the SDHAF1 gene resides in the mitochondria, and is essential for SDH assembly, but does not physically associate with the complex in vivo. Specifically, SDHAF1 mediates and promotes the maturation of the SDHB subunit of the SDH catalytic dimer. The iron-sulfur (Fe-S) protein subunit SDHB is required for functional succinate dehydrogenase. By protecting SDHB from damaging oxidants, SDHAF1 plays a vital role in the assembly and stability of succinate dehydrogenase (SDH). Alternatively, SDHAF1 may facilitate Fe-S cluster acquisition by SDHB by directly binding to the co-chaperone HSC20, which is an essential component of the Fe-S biogenesis machinery that facilitates transfer of the Fe-S prosthetic group from the main scaffold protein ISCU to recipient apo-proteins (i.e. SDHB),
# Clinical Significance
Variants of SDHAF1 have been associated with mitochondrial complex II deficiency and infantile leukoencephalopathy. Mitochondrial complex II deficiency is a disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations. Clinical features include psychomotor regression in infants, poor growth with lack of speech development, severe spastic quadriplegia, dystonia, progressive leukoencephalopathy, muscle weakness, exercise intolerance, and cardiomyopathy. Some patients manifest Leigh syndrome or Kearns-Sayre syndrome. Missense mutations c.164 G > C, p.Arg55Pro and c.170 G > A, p.Gly57Glu, homozygous transversion 169G-C, p. Gly57-Arg, homozygous non sense mutation c.103G>T (p.Glu35X), and homozygous nonsense mutation c.22C > T, p.Gln8X have been associated with mitochondrial complex II deficiency due to SDHAF1 disfunction.
# Interactions
SDHAF1 has 27 protein-protein interactions with 15 of them being co-complex interactions. HSCB, SDHB, ccdc136, KRT27, CIDEB, HSPA9, and ISCU have all been found to interact with SDHAF1. | SDHAF1
Succinate dehydrogenase complex assembly factor 1 (SDHAF1), also known as LYR motif-containing protein 8 (LYRM8), is a protein that in humans is encoded by the SDHAF1, or LYRM8, gene. SDHAF1 is a chaperone protein involved in the assembly of the succinate dehydrogenase (SDH) complex (complex II). Mutations in this gene are associated with SDH-defective infantile leukoencephalopathy and mitochondrial complex II deficiency.[1][2][3]
# Structure
SDHAF1 is located on the q arm of chromosome 19 in position 13.12 and has 1 exon.[1] The SDHAF1 gene produces a 12.8 kDa protein composed of 115 amino acids.[4][5] SDHAF1 is ubiquitously expressed and belongs to the complex I LYR family and SDHAF1 subfamily.[2] As such, SDHAF1 is one of at least eight proteins that has a LYR tripeptide motif, thought to be important for Fe-S metabolism.[6] SDHAF1 also contains an N-terminal mitochondrial targeting sequence that does not get cleaved following import into the mitochondria. The encoded protein is fairly hydrophilic and does not contain a transmembrane domain.[7]
# Function
SDHAF1 is essential for the assembly of the succinate dehydrogenase (SDH) complex (complex II), an enzyme complex that is a component of both the tricarboxylic acid (TCA) cycle and the mitochondrial electron transport chain, and which couples the oxidation of succinate to fumarate with the reduction of ubiquinone (coenzyme Q) to ubiquinol.[2] The succinate dehydrogenase (SDH) complex of the mitochondrial respiratory chain is composed of 4 individual subunits. The protein encoded by the SDHAF1 gene resides in the mitochondria, and is essential for SDH assembly, but does not physically associate with the complex in vivo.[1] Specifically, SDHAF1 mediates and promotes the maturation of the SDHB subunit of the SDH catalytic dimer. The iron-sulfur (Fe-S) protein subunit SDHB is required for functional succinate dehydrogenase. By protecting SDHB from damaging oxidants, SDHAF1 plays a vital role in the assembly and stability of succinate dehydrogenase (SDH).[8][7][2] Alternatively, SDHAF1 may facilitate Fe-S cluster acquisition by SDHB by directly binding to the co-chaperone HSC20, which is an essential component of the Fe-S biogenesis machinery that facilitates transfer of the Fe-S prosthetic group from the main scaffold protein ISCU to recipient apo-proteins (i.e. SDHB),[6]
# Clinical Significance
Variants of SDHAF1 have been associated with mitochondrial complex II deficiency and infantile leukoencephalopathy. Mitochondrial complex II deficiency is a disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations. Clinical features include psychomotor regression in infants, poor growth with lack of speech development, severe spastic quadriplegia, dystonia, progressive leukoencephalopathy, muscle weakness, exercise intolerance, and cardiomyopathy. Some patients manifest Leigh syndrome or Kearns-Sayre syndrome. Missense mutations c.164 G > C, p.Arg55Pro and c.170 G > A, p.Gly57Glu, homozygous transversion 169G-C, p. Gly57-Arg, homozygous non sense mutation c.103G>T (p.Glu35X), and homozygous nonsense mutation c.22C > T, p.Gln8X have been associated with mitochondrial complex II deficiency due to SDHAF1 disfunction.[2][7][9][6]
# Interactions
SDHAF1 has 27 protein-protein interactions with 15 of them being co-complex interactions. HSCB, SDHB, ccdc136, KRT27, CIDEB, HSPA9, and ISCU have all been found to interact with SDHAF1.[10][6] | https://www.wikidoc.org/index.php/SDHAF1 | |
6a31c34532b2e3c12753ee6287499425be84ee62 | wikidoc | SDHAF2 | SDHAF2
Succinate dehydrogenase complex assembly factor 2, formerly known as SDH5 and also known as SDH assembly factor 2 or SDHAF2 is a protein that in humans is encoded by the SDHAF2 gene. This gene encodes a mitochondrial protein needed for the flavination of a succinate dehydrogenase complex subunit required for activity of the complex. Mutations in this gene are associated with paraganglioma.
# Structure
SDHAF2 is located on the q arm of Chromosome 11 in position 12.2 and spans 16,642 base pairs. The SDHAF2 gene produces a 6.7 kDa protein composed of 65 amino acids. This highly conserved protein is a cofactor of flavin adenine dinucleotide (FAD). The structure represents a five-helix bundle with a region of well-defined conserved surface residues. This conserved region includes a negatively charged periphery and a positively charged surface, and a patch that is hydrophobic. The region is located in α-helices I, II, and the connecting band.
# Function
The SDHAF2 gene encodes a mitochondrial protein associated with the succinate dehydrogenase (SDH) complex (mitochondrial complex II) in the mitochondrial respiratory chain, which plays essential roles in both the electron transport chain and the Krebs(tricarboxylic acid) cycle. SDHAF2 is integral in the proper function of the SDH complex, mainly in SDH-dependent respiration, and interacts with the catalytic subunit of the complex. SDHAF2 participates in the flavination of SDH1(SDHA), another subunit of the SDH complex. It does so by incorporating the flavin adenine dinucleotide (FAD) cofactor into SDHA. Such flavination is required for a fully functional SDH complex. Knockdown of SDHAF2 leads to the loss-of-function of the SDH complex, a decrease in the enzyme complex stability, and a substantial reduction in all subunits. SDHAF2 was also found to function as a tumor suppressor.
# Clinical significance
SDHAF2 is a tumor suppressor gene. Constitutional mutations in this gene cause hereditary paraganglioma, a neuroendocrine tumor formerly known to be linked to SDH subunit mutations. paraganglioma is a neural crest tumor usually derived from the chemoreceptor tissue of a paraganglion, and may develop at various body sites, including the head, neck, thorax and abdomen. Most commonly, they are located in the head and neck region, specifically at the carotid bifurcation, the jugular foramen, the vagus nerve, and in the middle ear. Phenotypes include excessive catecholamine induced hypertension, dysfunction of major blood vessels and cranial nerves, significant morbidity, sweating, and palpitations. In cases of extra-adrenal localization, the tumor may turn metastatic and aggressive. Loss of SDH complex function has been known to be responsible for paraganglioma. Mutations in this gene are found in the DNA of only a small fraction of patients with the disease.
# Interactions
SDHAF2 interacts with SDHA within the SDH catalytic dimer. In addition to SDHA, SDHAF2 has 17 protein-protein interactions, including interactions with proteins such as IMMT, SUCLG2, UBINEDDSUMO1, SSX2IP, and others. | SDHAF2
Succinate dehydrogenase complex assembly factor 2, formerly known as SDH5 and also known as SDH assembly factor 2 or SDHAF2 is a protein that in humans is encoded by the SDHAF2 gene. This gene encodes a mitochondrial protein needed for the flavination of a succinate dehydrogenase complex subunit required for activity of the complex. Mutations in this gene are associated with paraganglioma.[1]
# Structure
SDHAF2 is located on the q arm of Chromosome 11 in position 12.2 and spans 16,642 base pairs.[1] The SDHAF2 gene produces a 6.7 kDa protein composed of 65 amino acids.[2][3] This highly conserved protein is a cofactor of flavin adenine dinucleotide (FAD).[4] The structure represents a five-helix bundle with a region of well-defined conserved surface residues. This conserved region includes a negatively charged periphery and a positively charged surface, and a patch that is hydrophobic. The region is located in α-helices I, II, and the connecting band.[5]
# Function
The SDHAF2 gene encodes a mitochondrial protein associated with the succinate dehydrogenase (SDH) complex (mitochondrial complex II) in the mitochondrial respiratory chain, which plays essential roles in both the electron transport chain and the Krebs(tricarboxylic acid) cycle. SDHAF2 is integral in the proper function of the SDH complex, mainly in SDH-dependent respiration, and interacts with the catalytic subunit of the complex. SDHAF2 participates in the flavination of SDH1(SDHA), another subunit of the SDH complex. It does so by incorporating the flavin adenine dinucleotide (FAD) cofactor into SDHA. Such flavination is required for a fully functional SDH complex. Knockdown of SDHAF2 leads to the loss-of-function of the SDH complex, a decrease in the enzyme complex stability, and a substantial reduction in all subunits. SDHAF2 was also found to function as a tumor suppressor.[6][7][8][9]
# Clinical significance
SDHAF2 is a tumor suppressor gene. Constitutional mutations in this gene cause hereditary paraganglioma, a neuroendocrine tumor formerly known to be linked to SDH subunit mutations. paraganglioma is a neural crest tumor usually derived from the chemoreceptor tissue of a paraganglion, and may develop at various body sites, including the head, neck, thorax and abdomen. Most commonly, they are located in the head and neck region, specifically at the carotid bifurcation, the jugular foramen, the vagus nerve, and in the middle ear.[10] Phenotypes include excessive catecholamine induced hypertension, dysfunction of major blood vessels and cranial nerves, significant morbidity, sweating, and palpitations. In cases of extra-adrenal localization, the tumor may turn metastatic and aggressive. Loss of SDH complex function has been known to be responsible for paraganglioma.[8][7][6] Mutations in this gene are found in the DNA of only a small fraction of patients with the disease.[7]
# Interactions
SDHAF2 interacts with SDHA within the SDH catalytic dimer. In addition to SDHA, SDHAF2 has 17 protein-protein interactions, including interactions with proteins such as IMMT, SUCLG2, UBINEDDSUMO1, SSX2IP, and others.[11] | https://www.wikidoc.org/index.php/SDHAF2 | |
1880e67de59b513a6129c05b621946cedddd9da3 | wikidoc | SEC16B | SEC16B
Protein transport protein Sec16B also known as regucalcin gene promoter region-related protein p117 (RGPR-p117) and leucine zipper transcription regulator 2 (LZTR2) is a protein that in humans is encoded by the SEC16B gene.
# Discovery
RGPR-p117/SEC16B, which was named as a regucalcin gene promoter region-related protein, was originally discovered as a novel transcription factor that specifically binds to a nuclear factor I (NFI) consensus motif TTGGC(N)6CC that is located on the 5’-flanking region of the regucalcin gene (rgn) in 2001. This gene is a highly conserved a leucine zipper motif, and it was also named as the leucine zipper transcription regulator 2 (LZTR2). In 2007, RGPR-p117 was also renamed as Sec16 homologue B (SEC16B), an endoplasmic reticulum export factor.
# Gene
The gene consists of 26 exons spanning approximately 4.1 kbp and is localized on human chromosome 1q25.2. This gene expression is stimulated through various signaling factors in cells. RGPR-p117 is present in the plasma membranes, cytoplasm, mitochondria, microsomes and nucleus of the cells. Cytoplasm RGPR-p117 is translocated to nucleus. Phosphorylated RGPR-p117 specifically binds to the TTGGC motif in the promoter region of various genes to enhance the gene expression of various proteins, and plays a crucial role as a transcription factor in the cells.
# Function
In the role in the regulation of cell regulation, RGPR-p117 possesses protective effects on apoptotic cell death induced by various signaling factors. Overexpression of RGPR-p117 did not cause an alteration of cell proliferation and led to significant decreases in protein and DNA contents in cloned normal rat kidney proximal tubular epithelial NRK52E cells. It also plays a role as an endoplasmic reticulum export factor to deliver to newly synthesized proteins and lipids to the Golgi. RGPR-p117/SEC16B may be involved in human obesity to possess an association between single nucleotide polymorphisms and different measures of obesity.
# Model organisms
Model organisms have been used in the study of SEC16B function. A conditional knockout mouse line, called Sec16btm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty one tests were carried out on mutant mice and one significant abnormality was observed: homozygote mutants had decreased circulating cholesterol levels. | SEC16B
Protein transport protein Sec16B also known as regucalcin gene promoter region-related protein p117 (RGPR-p117) and leucine zipper transcription regulator 2 (LZTR2) is a protein that in humans is encoded by the SEC16B gene.[1][2][3]
# Discovery
RGPR-p117/SEC16B, which was named as a regucalcin gene promoter region-related protein, was originally discovered as a novel transcription factor that specifically binds to a nuclear factor I (NFI) consensus motif TTGGC(N)6CC that is located on the 5’-flanking region of the regucalcin gene (rgn) in 2001.[2][4] This gene is a highly conserved a leucine zipper motif, and it was also named as the leucine zipper transcription regulator 2 (LZTR2). In 2007, RGPR-p117 was also renamed as Sec16 homologue B (SEC16B), an endoplasmic reticulum export factor.[5]
# Gene
The gene consists of 26 exons spanning approximately 4.1 kbp and is localized on human chromosome 1q25.2.[2] This gene expression is stimulated through various signaling factors in cells.[6][7] RGPR-p117 is present in the plasma membranes, cytoplasm, mitochondria, microsomes and nucleus of the cells.[7] Cytoplasm RGPR-p117 is translocated to nucleus.[6] Phosphorylated RGPR-p117 specifically binds to the TTGGC motif in the promoter region of various genes to enhance the gene expression of various proteins, and plays a crucial role as a transcription factor in the cells.[7][8][9]
# Function
In the role in the regulation of cell regulation, RGPR-p117 possesses protective effects on apoptotic cell death induced by various signaling factors.[8] Overexpression of RGPR-p117 did not cause an alteration of cell proliferation and led to significant decreases in protein and DNA contents in cloned normal rat kidney proximal tubular epithelial NRK52E cells.[10] It also plays a role as an endoplasmic reticulum export factor to deliver to newly synthesized proteins and lipids to the Golgi.[5][11][12] RGPR-p117/SEC16B may be involved in human obesity to possess an association between single nucleotide polymorphisms and different measures of obesity.[13][14][15]
# Model organisms
Model organisms have been used in the study of SEC16B function. A conditional knockout mouse line, called Sec16btm1a(KOMP)Wtsi[21][22] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[23][24][25]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[19][26] Twenty one tests were carried out on mutant mice and one significant abnormality was observed: homozygote mutants had decreased circulating cholesterol levels.[19] | https://www.wikidoc.org/index.php/SEC16B | |
d1c6ed54554f5d9ac0568ebf704759556ccb21bc | wikidoc | SEC23A | SEC23A
Sec23 homolog A (S. cerevisiae), also known as SEC23A, is a protein which in humans is encoded by the SEC23A gene.
# Function
The protein encoded by this gene is a member of the SEC23 subfamily of the SEC23/SEC24 family. It contains a gelsolin domain. It is part of a protein complex and found in the ribosome-free transitional face of the endoplasmic reticulum (ER) and associated vesicles. This protein has similarity to yeast Sec23p component of COPII. COPII is the coat protein complex responsible for vesicle budding from the ER. The encoded protein is suggested to play a role in the ER-Golgi protein trafficking.
SEC23 interacts with both SEC16A and SEC16B.
# Interactions
SEC23A has been shown to interact with SEC24C, Sec16A/p250 and iPLA1β/p125.
Sec23 has also been shown to interact with TRAPPⅠ, Grh1p also known as GRASP65 and Dynactin. Because they are involved in anterograde vesicle transport from ER to Golgi, Sec23 is involved in vesicle transport. | SEC23A
Sec23 homolog A (S. cerevisiae), also known as SEC23A, is a protein which in humans is encoded by the SEC23A gene.[1]
# Function
The protein encoded by this gene is a member of the SEC23 subfamily of the SEC23/SEC24 family. It contains a gelsolin domain.[2] It is part of a protein complex and found in the ribosome-free transitional face of the endoplasmic reticulum (ER) and associated vesicles. This protein has similarity to yeast Sec23p component of COPII. COPII is the coat protein complex responsible for vesicle budding from the ER. The encoded protein is suggested to play a role in the ER-Golgi protein trafficking.[1]
SEC23 interacts with both SEC16A and SEC16B.[citation needed]
# Interactions
SEC23A has been shown to interact with SEC24C,[3] Sec16A/p250 and iPLA1β/p125.[4]
Sec23 has also been shown to interact with TRAPPⅠ, Grh1p also known as GRASP65 and Dynactin. Because they are involved in anterograde vesicle transport from ER to Golgi, Sec23 is involved in vesicle transport.[5] | https://www.wikidoc.org/index.php/SEC23A | |
9c5e38ede0c189b933ebbbe734f5b9c88e3b5681 | wikidoc | SEC23B | SEC23B
Protein transport protein Sec23B is a protein that in humans is encoded by the SEC23B gene.
The protein encoded by this gene is a member of the SEC23 subfamily of the SEC23/SEC24 family, which is involved in vesicle trafficking. The encoded protein has similarity to yeast Sec23p component of COPII. COPII is the coat protein complex responsible for vesicle budding from the ER. The function of this gene product has been implicated in cargo selection and concentration.
Multiple alternatively spliced transcript variants encoding the same protein have been found for this gene. Mutations in SEC23B cause an autosomal recessive disorder called congenital dyserythropoietic anemia type II (CDAII). | SEC23B
Protein transport protein Sec23B is a protein that in humans is encoded by the SEC23B gene.[1][2][3]
The protein encoded by this gene is a member of the SEC23 subfamily of the SEC23/SEC24 family, which is involved in vesicle trafficking. The encoded protein has similarity to yeast Sec23p component of COPII. COPII is the coat protein complex responsible for vesicle budding from the ER. The function of this gene product has been implicated in cargo selection and concentration.
Multiple alternatively spliced transcript variants encoding the same protein have been found for this gene.[3] Mutations in SEC23B cause an autosomal recessive disorder called congenital dyserythropoietic anemia type II (CDAII). | https://www.wikidoc.org/index.php/SEC23B | |
271e39344ddc702aaded6dff528f75eaeac0bfc7 | wikidoc | SEC24A | SEC24A
SEC24 family, member A (S. cerevisiae) is a protein that in humans is encoded by the SEC24A gene. The protein belongs to a protein family that are homologous to yeast Sec24. It is a component of coat protein II (COPII)-coated vesicles that mediate protein transport from the endoplasmic reticulum.
# Model organisms
Model organisms have been used in the study of SEC24A function. A conditional knockout mouse line, called Sec24atm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on mutant mice and one significant abnormality was observed. Male homozygotes had decreased circulating cholesterol and LDL cholesterol levels. | SEC24A
SEC24 family, member A (S. cerevisiae) is a protein that in humans is encoded by the SEC24A gene.[1] The protein belongs to a protein family that are homologous to yeast Sec24.[2] It is a component of coat protein II (COPII)-coated vesicles that mediate protein transport from the endoplasmic reticulum.[1]
# Model organisms
Model organisms have been used in the study of SEC24A function. A conditional knockout mouse line, called Sec24atm1a(KOMP)Wtsi[8][9] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[10][11][12]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[6][13] Twenty five tests were carried out on mutant mice and one significant abnormality was observed.[6] Male homozygotes had decreased circulating cholesterol and LDL cholesterol levels.[6] | https://www.wikidoc.org/index.php/SEC24A | |
511c27da588b1259898ab08d615b7aeff5f235a1 | wikidoc | SEMA3A | SEMA3A
Semaphorin-3A is a protein that in humans is encoded by the SEMA3A gene.
# Function
The SEMA3A gene is a member of the semaphorin family and encodes a protein with an Ig-like C2-type (immunoglobulin-like) domain, a PSI domain and a Sema domain. This secreted Sema3A protein can function as either a chemorepulsive agent, inhibiting axonal outgrowth, or as a chemoattractive agent, stimulating the growth of apical dendrites. In both cases, the protein is vital for normal neuronal pattern development.
Semaphorin-3A is secreted by neurons and surrounding tissue to guide migrating cells and axons in the developing nervous system. Axon pathfinding is the process by which neurons follow very precise paths, sends out axons, and react to specific chemical environments to reach the correct endpoint. The guidance is critical for the precise formation of neurons and the surrounding vasculature. Guidance cues, such as Sema3A, induce the collapse and paralysis of neuronal growth cones during development of the nervous system.
This guidance cue for axons of neurons is signaled through receptor complexes containing Neuropilin-1 (NRP1) and a co-receptor. One of the first identified intracellular messenger required for the growth cone-collapse induced by Sema3A is the CRMP protein called CRMP2.
In addition to its role in the nervous system, Sema3A also acts as an inhibitor of angiogenesis, the process by which new blood vessels develop.
# Clinical significance
The protein Sema3A is highly expressed in scar tissue after traumatic central nervous system injuries, such as spinal cord injury. Sema3A, and the other class 3 semaphorins, contributes to the failure of neuronal regeneration after CNS injury by regulating axonal re-growth, re-myelination, re-vascularisation, and the immune response.
Increased expression of Sema3A is associated with schizophrenia and is seen in a variety of human tumor cell lines. Also, aberrant release of this protein is associated with the progression of Alzheimer's disease.
Additionally, the terminal Schwann cells of ALS mice (SOD1 mutant) express Sema3A at fast-fatigable fiber neuromuscular junctions greater than wild-type mice. This expression is greatest pre-symptomatically corresponding to ALS progression in which fast-fatigable fiber denervation precedes clinical symptoms. Because Sema3A is involved in growth cone collapse and axon pruning and repulsion, it potentially holds a causal relationship to synaptic weakening and denervation that precedes motor neuron apoptosis in ALS. | SEMA3A
Semaphorin-3A is a protein that in humans is encoded by the SEMA3A gene.[1][2][3]
# Function
The SEMA3A gene is a member of the semaphorin family and encodes a protein with an Ig-like C2-type (immunoglobulin-like) domain, a PSI domain and a Sema domain. This secreted Sema3A protein can function as either a chemorepulsive agent, inhibiting axonal outgrowth, or as a chemoattractive agent, stimulating the growth of apical dendrites. In both cases, the protein is vital for normal neuronal pattern development.[3]
Semaphorin-3A is secreted by neurons and surrounding tissue to guide migrating cells and axons in the developing nervous system. Axon pathfinding is the process by which neurons follow very precise paths, sends out axons, and react to specific chemical environments to reach the correct endpoint. The guidance is critical for the precise formation of neurons and the surrounding vasculature. Guidance cues, such as Sema3A, induce the collapse and paralysis of neuronal growth cones during development of the nervous system.
This guidance cue for axons of neurons is signaled through receptor complexes containing Neuropilin-1 (NRP1) and a co-receptor.[4][5][6] One of the first identified intracellular messenger required for the growth cone-collapse induced by Sema3A is the CRMP protein called CRMP2.
In addition to its role in the nervous system, Sema3A also acts as an inhibitor of angiogenesis, the process by which new blood vessels develop.[7]
# Clinical significance
The protein Sema3A is highly expressed in scar tissue after traumatic central nervous system injuries, such as spinal cord injury. Sema3A, and the other class 3 semaphorins, contributes to the failure of neuronal regeneration after CNS injury by regulating axonal re-growth, re-myelination, re-vascularisation, and the immune response.[8]
Increased expression of Sema3A is associated with schizophrenia and is seen in a variety of human tumor cell lines. Also, aberrant release of this protein is associated with the progression of Alzheimer's disease.[3][9]
Additionally, the terminal Schwann cells of ALS mice (SOD1 mutant) express Sema3A at fast-fatigable fiber neuromuscular junctions greater than wild-type mice.[10] This expression is greatest pre-symptomatically corresponding to ALS progression in which fast-fatigable fiber denervation precedes clinical symptoms.[11] Because Sema3A is involved in growth cone collapse and axon pruning and repulsion, it potentially holds a causal relationship to synaptic weakening and denervation that precedes motor neuron apoptosis in ALS.[10] | https://www.wikidoc.org/index.php/SEMA3A | |
d85d18b1c8c02a0c93443dbc2d2a8fc543a3bcbd | wikidoc | SEMA4A | SEMA4A
Semaphorin-4A is a protein that in humans is encoded by the SEMA4A gene.
# Function
SEMA4A is a member of the semaphorin family of soluble and transmembrane proteins. Semaphorins are involved in guidance of axonal migration during neuronal development and in immune responses.
# Clinical significance
A germline variant in SEMA4A (V78M) has been demonstrated to confer risk for colorectal cancer type X. | SEMA4A
Semaphorin-4A is a protein that in humans is encoded by the SEMA4A gene.[1][2]
# Function
SEMA4A is a member of the semaphorin family of soluble and transmembrane proteins. Semaphorins are involved in guidance of axonal migration during neuronal development and in immune responses.[supplied by OMIM][2]
# Clinical significance
A germline variant in SEMA4A (V78M) has been demonstrated to confer risk for colorectal cancer type X.[3] | https://www.wikidoc.org/index.php/SEMA4A | |
801e2795f3e137080cea357778a12ca7422bc2db | wikidoc | SEMA4D | SEMA4D
Semaphorin-4D (SEMA4D) also known as Cluster of Differentiation 100 (CD100), is a protein of the semaphorin family that in humans is encoded by the SEMA4D gene.
# Function
Semaphorin 4D (Sema 4D) is an axon guidance molecule which is secreted by oligodendrocytes and induces growth cone collapse in the central nervous system. By binding plexin B1 receptor it functions as an R-Ras GTPase-activating protein (GAP) and repels axon growth cones in both the mature central nervous system.
In the immune system, CD100 binds CD72 to activate B cells and dendritic cells, though much about this interaction is still under investigation.
During skin damage repairs, SEMA4D interacts with Plexin B2 on gamma delta t cells to play a role in the healing process. | SEMA4D
Semaphorin-4D (SEMA4D) also known as Cluster of Differentiation 100 (CD100), is a protein of the semaphorin family that in humans is encoded by the SEMA4D gene.[1]
# Function
Semaphorin 4D (Sema 4D) is an axon guidance molecule which is secreted by oligodendrocytes and induces growth cone collapse in the central nervous system. By binding plexin B1 receptor it functions as an R-Ras GTPase-activating protein (GAP) and repels axon growth cones in both the mature central nervous system.[2]
In the immune system, CD100 binds CD72 to activate B cells and dendritic cells, though much about this interaction is still under investigation.[3][4]
During skin damage repairs, SEMA4D interacts with Plexin B2 on gamma delta t cells to play a role in the healing process.[5] | https://www.wikidoc.org/index.php/SEMA4D | |
b66f9a62320aa4f9cd8dbbd94d0a5c4d3bb3365d | wikidoc | SEMA5A | SEMA5A
Semaphorin-5A is a protein that in humans is encoded by the SEMA5A gene.
Members of the semaphorin protein family, such as SEMA5A, are involved in axonal guidance during neural development (Adams et al., 1996).
Semaphorine 5A also plays a role in autism, reducing the ability of neurons to form connections with other neurons in certain brain regions (Mosca-Boidron et al 2016). | SEMA5A
Semaphorin-5A is a protein that in humans is encoded by the SEMA5A gene.[1][2][3]
Members of the semaphorin protein family, such as SEMA5A, are involved in axonal guidance during neural development (Adams et al., 1996).[supplied by OMIM][3]
Semaphorine 5A also plays a role in autism, reducing the ability of neurons to form connections with other neurons in certain brain regions (Mosca-Boidron et al 2016). | https://www.wikidoc.org/index.php/SEMA5A | |
e016e74e06fef8536804274d794761bf9e311323 | wikidoc | SERAC1 | SERAC1
Serine active site-containing protein 1, or Protein SERAC1 is a protein in humans that is encoded by the SERAC1 gene. The protein encoded by this gene is a phosphatidylglycerol remodeling protein found at the interface of mitochondria and endoplasmic reticula, where it mediates phospholipid exchange. The encoded protein plays a major role in mitochondrial function and intracellular cholesterol trafficking. Defects in this gene are a cause of 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL). Two transcript variants, one protein-coding and the other non-protein coding, have been found for this gene.
# Structure
The SERAC1 gene is located on the q arm of chromosome 6 at position 25.3 and it spans 58,776 base pairs. The SERAC1 gene produces an 18.7 kDa protein composed of 162 amino acids. The structure of the encoded protein contains a C-terminal serine-lipase/esterase domain containing the consensus lipase motif GxSxG, and an N-terminal signal sequence.
# Function
The SERAC1 gene encodes for a protein necessary for phosphatidylglycerol remodeling. phosphatidylglycerol remodeling is a process of altering or remodeling a particular phospholipid called phosphatidylglycerol. Phosphatidylglycerol helps make cardiolipin, an important ingredient that surrounds the Inner mitochondrial membrane. Cardiolipin is responsible for converting energy acquired from food to a cell-usable form and required for proper mitochondrial function. Because of cardiolipin, the remodeling process of phosphatidylglycerol is essential for mitochondrial function and intracellular cholesterol trafficking.
Additionally, SERAC1 is involved in the movement of cholesterol, which are fatty, waxy substances within cells. Cholesterol is a component of cell structure, and produces hormones and digestive acids. The protein may also be involved in the transacylation-acylation reaction to produce phosphatidylglycerol-36:1 and bis(monoacylglycerol)phosphate biosynthetic pathway.
# Clinical Significance
Mutations in the SERAC1 gene have been associated to impairment of both mitochondrial function and intracellular cholesterol trafficking. Such mutations have been majorly associated withand Leigh syndrome and 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, known as MEGDEL syndrome.
## MEGDEL syndrome
SERAC1 mutations have been heavily associated with MGDEL syndrome. MGDEL syndrome (3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome) is an autosomal recessive disorder characterized by childhood onset of delayed psychomotor development or psychomotor regression, sensorineural deafness, spasticity or dystonia and increased excretion of 3-methylglutaconic acid. Brain imaging shows cerebral and cerebellar atrophy as well as lesions in the basal ganglia reminiscent of Leigh syndrome. Laboratory studies show increased serum lactate and alanine, mitochondrial oxidative phosphorylation defects, abnormal mitochondria, abnormal phosphatidylglycerol and cardiolipin profiles in fibroblasts, and abnormal accumulation of unesterified cholesterol within cells.
The SERAC1 gene mutations that cause this condition reduce the amount of SERAC1 protein that is produced or lead to production of a protein with little or no function. As a result, phosphatidylglycerol remodeling is impaired, which likely alters the composition of cardiolipin. Researchers speculate that the abnormal cardiolipin affects mitochondrial function, reducing cellular energy production and leading to the neurological and hearing problems characteristic of MEGDEL syndrome. It is unclear how SERAC1 gene mutations lead to abnormal release of 3-methylglutaconic acid in the urine.
A c.202C>T mutation in this gene has been found in a patient suffering from 3-methylglutaconic aciduria, and related symptoms. Two patients with Homozygous G>C transversions in the SERAC1 gene have been found to show symptoms of MEGDEL syndrome with deafness, encephalopathy, and Leigh-like syndrome. Another patient with a homozygous 4 base pair deletion (1167delTCAG) showed symptoms of recurrent infections, failure to thrive, mental retardation, spasticity and extrapyramidal symptoms.
## Leigh syndrome
Leigh syndrome is an early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, muscle weakness, vision loss, eye movement abnormalities, seizures, and dysphagia.
# Interactions
SERAC1 has been shown to have Protein-protein interactions with the following.
- SDF4
- EFGR
- APP
- SLC18A1
- LPAR4
- CBWD1 | SERAC1
Serine active site-containing protein 1, or Protein SERAC1 is a protein in humans that is encoded by the SERAC1 gene.[1][2][3] The protein encoded by this gene is a phosphatidylglycerol remodeling protein found at the interface of mitochondria and endoplasmic reticula, where it mediates phospholipid exchange. The encoded protein plays a major role in mitochondrial function and intracellular cholesterol trafficking. Defects in this gene are a cause of 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL). Two transcript variants, one protein-coding and the other non-protein coding, have been found for this gene.[1]
# Structure
The SERAC1 gene is located on the q arm of chromosome 6 at position 25.3 and it spans 58,776 base pairs.[1] The SERAC1 gene produces an 18.7 kDa protein composed of 162 amino acids.[4][5] The structure of the encoded protein contains a C-terminal serine-lipase/esterase domain containing the consensus lipase motif GxSxG, and an N-terminal signal sequence.[6]
# Function
The SERAC1 gene encodes for a protein necessary for phosphatidylglycerol remodeling. phosphatidylglycerol remodeling is a process of altering or remodeling a particular phospholipid called phosphatidylglycerol. Phosphatidylglycerol helps make cardiolipin, an important ingredient that surrounds the Inner mitochondrial membrane. Cardiolipin is responsible for converting energy acquired from food to a cell-usable form and required for proper mitochondrial function. Because of cardiolipin, the remodeling process of phosphatidylglycerol is essential for mitochondrial function and intracellular cholesterol trafficking.[7][2][3]
Additionally, SERAC1 is involved in the movement of cholesterol, which are fatty, waxy substances within cells. Cholesterol is a component of cell structure, and produces hormones and digestive acids. The protein may also be involved in the transacylation-acylation reaction to produce phosphatidylglycerol-36:1 and bis(monoacylglycerol)phosphate biosynthetic pathway.[7][2][3]
# Clinical Significance
Mutations in the SERAC1 gene have been associated to impairment of both mitochondrial function and intracellular cholesterol trafficking.[6] Such mutations have been majorly associated withand Leigh syndrome and 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, known as MEGDEL syndrome.[8]
## MEGDEL syndrome
SERAC1 mutations have been heavily associated with MGDEL syndrome. MGDEL syndrome (3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome) is an autosomal recessive disorder characterized by childhood onset of delayed psychomotor development or psychomotor regression, sensorineural deafness, spasticity or dystonia and increased excretion of 3-methylglutaconic acid. Brain imaging shows cerebral and cerebellar atrophy as well as lesions in the basal ganglia reminiscent of Leigh syndrome. Laboratory studies show increased serum lactate and alanine, mitochondrial oxidative phosphorylation defects, abnormal mitochondria, abnormal phosphatidylglycerol and cardiolipin profiles in fibroblasts, and abnormal accumulation of unesterified cholesterol within cells.[3][2]
The SERAC1 gene mutations that cause this condition reduce the amount of SERAC1 protein that is produced or lead to production of a protein with little or no function. As a result, phosphatidylglycerol remodeling is impaired, which likely alters the composition of cardiolipin. Researchers speculate that the abnormal cardiolipin affects mitochondrial function, reducing cellular energy production and leading to the neurological and hearing problems characteristic of MEGDEL syndrome. It is unclear how SERAC1 gene mutations lead to abnormal release of 3-methylglutaconic acid in the urine.[7][1]
A c.202C>T mutation in this gene has been found in a patient suffering from 3-methylglutaconic aciduria, and related symptoms.[9] Two patients with Homozygous G>C transversions in the SERAC1 gene have been found to show symptoms of MEGDEL syndrome with deafness, encephalopathy, and Leigh-like syndrome.[6] Another patient with a homozygous 4 base pair deletion (1167delTCAG) showed symptoms of recurrent infections, failure to thrive, mental retardation, spasticity and extrapyramidal symptoms.[10]
## Leigh syndrome
Leigh syndrome is an early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, muscle weakness, vision loss, eye movement abnormalities, seizures, and dysphagia.[11]
# Interactions
SERAC1 has been shown to have Protein-protein interactions with the following.[12][2]
- SDF4
- EFGR
- APP
- SLC18A1
- LPAR4
- CBWD1 | https://www.wikidoc.org/index.php/SERAC1 | |
4d89b6954d66cee2938044be2bd1fd06ab24b3eb | wikidoc | SETBP1 | SETBP1
SET binding protein 1 is a protein that in humans is encoded by the SETBP1 gene.
# Gene
The gene is located on Chromosome 18, specifically on the long (q) arm of the chromosome at position 12.3. This is also written as 18q12.3.
# Function
The SETBP1 gene provides instructions for making a protein known as the SET binding protein 1, which is widely distributed throughout somatic cells. The protein is known to bind to another protein called SET. SETBP1 is a DNA-binding protein that forms part of a group of proteins that act together on histone methylation to make chromatin more accessible and regulate gene expression. There is still more to learn about the overall function of the SETBP1 protein
and the effect of SET binding.
# Clinical significance
Gain-of-function mutations in the SETBP1 gene are associated with Schinzel–Giedion syndrome.
Loss-of-function mutations in the SETBP1 gene are associated with a SETBP1-related developmental delay called SETBP1 disorder which causes a spectrum of symptoms including absent speech/expressive language delays, mild-severe intellectual disability, autistic-traits/autism, developmental delays, ADHD, and seizures.
SETBP1 is a oncogene; specific somatic mutations of this gene were discovered in patients affected by atypical Chronic Myeloid Leukemia (aCML) and related diseases. These mutations, which are identical to the ones present in SGS as germ line mutations, impair the degradation of SETBP1 and therefore cause increased cellular levels of the protein. | SETBP1
SET binding protein 1 is a protein that in humans is encoded by the SETBP1 gene.[1]
# Gene
The gene is located on Chromosome 18, specifically on the long (q) arm of the chromosome at position 12.3. This is also written as 18q12.3.
# Function
The SETBP1 gene provides instructions for making a protein known as the SET binding protein 1, which is widely distributed throughout somatic cells. The protein is known to bind to another protein called SET. SETBP1 is a DNA-binding protein that forms part of a group of proteins that act together on histone methylation to make chromatin more accessible and regulate gene expression.[2] There is still more to learn about the overall function of the SETBP1 protein
and the effect of SET binding.
# Clinical significance
Gain-of-function mutations in the SETBP1 gene are associated with Schinzel–Giedion syndrome.[3]
Loss-of-function mutations in the SETBP1 gene are associated with a SETBP1-related developmental delay called SETBP1 disorder which causes a spectrum of symptoms including absent speech/expressive language delays, mild-severe intellectual disability, autistic-traits/autism, developmental delays, ADHD, and seizures.[4]
[5]
SETBP1 is a oncogene; specific somatic mutations of this gene were discovered in patients affected by atypical Chronic Myeloid Leukemia (aCML) and related diseases. These mutations, which are identical to the ones present in SGS as germ line mutations, impair the degradation of SETBP1 and therefore cause increased cellular levels of the protein.[6] | https://www.wikidoc.org/index.php/SETBP1 | |
644d598b1b18944a0dc7f055e939b8d92bc80962 | wikidoc | SETDB1 | SETDB1
Histone-lysine N-methyltransferase SETDB1 is an enzyme that in humans is encoded by the SETDB1 gene.SETDB1 is also known as KMT1E or H3K9 methyltransferase ESET.
# Function
The SET domain is a highly conserved, approximately 150-amino acid motif implicated in the modulation of chromatin structure. It was originally identified as part of a larger conserved region present in the Drosophila Trithorax protein and was subsequently identified in the Drosophila Su(var)3-9 and 'Enhancer of zeste' proteins, from which the acronym SET is derived. Studies have suggested that the SET domain may be a signature of proteins that modulate transcriptionally active or repressed chromatin states through chromatin remodeling activities.
# Model organisms
Model organisms have been used in the study of SETDB1 function. A conditional knockout mouse line, called Setdb1tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty seven tests were carried out on mutant mice and four significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and two significant abnormalities were observed. Females had abnormal peripheral blood lymphocytes data and both sexes displayed increased bone strength and mineral content.
# Interactions
SETDB1 has been shown to interact with TRIM28.> | SETDB1
Histone-lysine N-methyltransferase SETDB1 is an enzyme that in humans is encoded by the SETDB1 gene.[1][2]SETDB1 is also known as KMT1E or H3K9 methyltransferase ESET.
# Function
The SET domain is a highly conserved, approximately 150-amino acid motif implicated in the modulation of chromatin structure. It was originally identified as part of a larger conserved region present in the Drosophila Trithorax protein and was subsequently identified in the Drosophila Su(var)3-9 and 'Enhancer of zeste' proteins, from which the acronym SET is derived. Studies have suggested that the SET domain may be a signature of proteins that modulate transcriptionally active or repressed chromatin states through chromatin remodeling activities.[2]
# Model organisms
Model organisms have been used in the study of SETDB1 function. A conditional knockout mouse line, called Setdb1tm1a(EUCOMM)Wtsi[8][9] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[10][11][12]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[6][13] Twenty seven tests were carried out on mutant mice and four significant abnormalities were observed.[6] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and two significant abnormalities were observed. Females had abnormal peripheral blood lymphocytes data and both sexes displayed increased bone strength and mineral content.[6]
# Interactions
SETDB1 has been shown to interact with TRIM28.[14]> | https://www.wikidoc.org/index.php/SETDB1 | |
2448e638abf1ca82d95c759b40245bd8b7bbfb4f | wikidoc | SETMAR | SETMAR
Histone-lysine N-methyltransferase SETMAR is an enzyme that in humans is encoded by the SETMAR gene.
# Model organisms
Model organisms have been used in the study of SETMAR function. A conditional knockout mouse line, called Setmartm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on mutant mice and two significant abnormalities were observed. Homozygous mutant animals of both sex had abnormal retinal pigmentation and morphology, while males also had atypical peripheral blood lymphocyte parameters. | SETMAR
Histone-lysine N-methyltransferase SETMAR is an enzyme that in humans is encoded by the SETMAR gene.[1][2]
# Model organisms
Model organisms have been used in the study of SETMAR function. A conditional knockout mouse line, called Setmartm1a(EUCOMM)Wtsi[9][10] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[11][12][13]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[7][14] Twenty five tests were carried out on mutant mice and two significant abnormalities were observed.[7] Homozygous mutant animals of both sex had abnormal retinal pigmentation and morphology, while males also had atypical peripheral blood lymphocyte parameters.[7] | https://www.wikidoc.org/index.php/SETMAR | |
46e3901f7bf5202d8309d2f7e4b970c2622105bb | wikidoc | SH2D3C | SH2D3C
SH2 domain containing 3C, also known as SH2D3C, is a protein that in humans is encoded by the SH2D3C gene.
# Function
Sh2d3c is a gene on human chromosome 9 that encodes an SH2 domain containing protein known as NSP3. The mouse homologue is found on chromosome 2. The NSP (Novel SH2-containing Protein) family of proteins contains three members, NSP1, NSP2, and NSP3 (this protein), all of which have a similar architecture, with an N-terminal SH2 domain, a proline serine rich region, which contains consensus sequences for MAP kinase substrates, and a conserved C-terminus, which binds to the Cas family of adapter proteins, and also shows homology to GEF domains.
NSP3 was originally identified by three independent groups of researchers. The mouse homologue of NSP3 has been shown to have two distinct isoforms, generated by alternative splicing, that are expressed in different tissues. The shorter isoform, known as Chat (Cas/Hef1 associated signal transducer) is expressed in brain, lung, heart, kidney, muscle, liver, and intestine, while the larger isoform, known as Chat-H (the "H" is for Hematopoietic), is expressed in spleen, thymus, and lymph nodes. The two isoforms differ only in their N-terminus, which has been shown by one group to be important for membrane localization.
Through its interaction with Hef1, Chat-H, has been shown to be an important regulator of lymphocyte adhesion, acting upstream of Rap1 in the integrin activation pathway. | SH2D3C
SH2 domain containing 3C, also known as SH2D3C, is a protein that in humans is encoded by the SH2D3C gene.[1]
# Function
Sh2d3c is a gene on human chromosome 9 that encodes an SH2 domain containing protein known as NSP3. The mouse homologue is found on chromosome 2. The NSP (Novel SH2-containing Protein) family of proteins contains three members, NSP1, NSP2, and NSP3 (this protein), all of which have a similar architecture, with an N-terminal SH2 domain, a proline serine rich region, which contains consensus sequences for MAP kinase substrates, and a conserved C-terminus, which binds to the Cas family of adapter proteins, and also shows homology to GEF domains.
NSP3 was originally identified by three independent groups of researchers.[2][3][4] The mouse homologue of NSP3 has been shown to have two distinct isoforms, generated by alternative splicing, that are expressed in different tissues. The shorter isoform, known as Chat (Cas/Hef1 associated signal transducer) is expressed in brain, lung, heart, kidney, muscle, liver, and intestine, while the larger isoform, known as Chat-H (the "H" is for Hematopoietic), is expressed in spleen, thymus, and lymph nodes.[4] The two isoforms differ only in their N-terminus, which has been shown by one group to be important for membrane localization.[5]
Through its interaction with Hef1, Chat-H, has been shown to be an important regulator of lymphocyte adhesion, acting upstream of Rap1 in the integrin activation pathway.[5] | https://www.wikidoc.org/index.php/SH2D3C | |
b22dd03dcb4a9f6b26187eb7b2c288c546f29064 | wikidoc | SH3D21 | SH3D21
SH3D21 is a nuclear protein that is encoded by the SH3D21 gene. In humans, this gene is located on chromosome 1 p34.3. The human mRNA transcript is 2527 base pairs and the final protein product is 756 amino acids. While the exact function of this protein remains unknown, due to the presence of three SH3 domains, it has been implicated in protein-protein interactions.
# Gene
SH3D21 is expressed in low levels in most tissue. Microarray analysis has shown SH3D21 expression to be decreased in TP63 knockout mice. SH3D21 has been shown to be expressed highly in the superior cervical ganglion, the dorsal root ganglia and the trigeminal ganglion. Transcription of SH3D21 is known to be upregulated in the presence of testosterone.
# Protein
SH3D21 contains three SH3 domains. These domains are located near the N-terminus of the protein. In humans, these SH3 domains have a common amino acid sequence Asp-Glu-Leu. This sequence motif is also conserved in other species. SH3D21 has been found to interact with Adenylate Kinase 2, Artemin, and Importin 13. The human protein has two isoforms and no paralogs. The second isoform is 645 amino acids long and is identical to the first isoform, except it is missing the first 111 amino acids. Due to this, the second isoform is missing the first, and half of the second, N-terminal SH3 domain. Secondary structure analysis of SH3D21 indicates a long alpha helical structure near the C-terminus. The purpose of this structure is unknown. SH3D21 is predicted to have many phosphorylation sites and multiple sumolyation sites throughout the entirety of the protein.
# Function
The function of this gene is still unclear. However, research has linked SH3D21 expression changes to male infertility and Ataxia Telangiectasia.
Further studies have implicated the chromosomal region of 1p34.3 in Intracranial Aneurysm and as a negative prognosis sign in colorectal cancer. These studies do not, however, directly mention SH3D21.
# Homology
SH3D21 is well-conserved in mammals. BLAST analysis found distant orthologs in Osteichthyes with a max identity of 28%. Sequence identity was calculated using available sequence data and ALIGN software. | SH3D21
SH3D21 is a nuclear protein that is encoded by the SH3D21 gene. In humans, this gene is located on chromosome 1 p34.3.[1] The human mRNA transcript is 2527 base pairs and the final protein product is 756 amino acids.[2] While the exact function of this protein remains unknown, due to the presence of three SH3 domains, it has been implicated in protein-protein interactions.[3]
# Gene
SH3D21 is expressed in low levels in most tissue.[4] Microarray analysis has shown SH3D21 expression to be decreased in TP63 knockout mice.[5] SH3D21 has been shown to be expressed highly in the superior cervical ganglion, the dorsal root ganglia and the trigeminal ganglion.[4][6] Transcription of SH3D21 is known to be upregulated in the presence of testosterone.[7]
# Protein
SH3D21 contains three SH3 domains.[3][8][9] These domains are located near the N-terminus of the protein. In humans, these SH3 domains have a common amino acid sequence Asp-Glu-Leu. This sequence motif is also conserved in other species. SH3D21 has been found to interact with Adenylate Kinase 2, Artemin, and Importin 13.[1] The human protein has two isoforms and no paralogs.[2] The second isoform is 645 amino acids long and is identical to the first isoform, except it is missing the first 111 amino acids.[10] Due to this, the second isoform is missing the first, and half of the second, N-terminal SH3 domain.[10] Secondary structure analysis of SH3D21 indicates a long alpha helical structure near the C-terminus.[11][12] The purpose of this structure is unknown. SH3D21 is predicted to have many phosphorylation sites and multiple sumolyation sites throughout the entirety of the protein.[13][14]
# Function
The function of this gene is still unclear. However, research has linked SH3D21 expression changes to male infertility and Ataxia Telangiectasia.[15][16]
Further studies have implicated the chromosomal region of 1p34.3 in Intracranial Aneurysm and as a negative prognosis sign in colorectal cancer.[17][18] These studies do not, however, directly mention SH3D21.
# Homology
SH3D21 is well-conserved in mammals. BLAST analysis found distant orthologs in Osteichthyes with a max identity of 28%.[19] Sequence identity was calculated using available sequence data and ALIGN software.[20] | https://www.wikidoc.org/index.php/SH3D21 | |
323ce9279a65593e2d61eb62b31738dd94ee9139 | wikidoc | SH3TC2 | SH3TC2
SH3 domain and tetratricopeptide repeats-containing protein 2 is a protein that in humans is encoded by the SH3TC2 gene. It is believed to be expressed in the Schwann cells that wrap the myelin sheath around nerves.
# Function
This gene encodes a protein with two N-terminal Src homology 3 (SH3) domains and 10 tetratricopeptide repeat (TPR) motifs, and is a member of a small gene family. The gene product has been proposed to be an adapter or docking molecule.
The mouse version (orthologue) of SH3TC2 is believed to be expressed in Schwann cells. The tagged protein localizes to the plasma membrane and to the perinuclear endocytic recycling compartment. Mice lacking Sh3tc2 have an abnormal organization of the node of Ranvier consistent with the idea that the protein might have a role in myelination or in axon – glial cell interactions.
# Clinical significance
Mutations in this gene result in autosomal recessive Charcot-Marie-Tooth disease type 4C, a childhood-onset neurodegenerative disease characterized by demyelination of motor and sensory neurons. | SH3TC2
SH3 domain and tetratricopeptide repeats-containing protein 2 is a protein that in humans is encoded by the SH3TC2 gene.[1][2] It is believed to be expressed in the Schwann cells that wrap the myelin sheath around nerves.
# Function
This gene encodes a protein with two N-terminal Src homology 3 (SH3) domains and 10 tetratricopeptide repeat (TPR) motifs, and is a member of a small gene family. The gene product has been proposed to be an adapter or docking molecule.[2]
The mouse version (orthologue) of SH3TC2 is believed to be expressed in Schwann cells. The tagged protein localizes to the plasma membrane and to the perinuclear endocytic recycling compartment. Mice lacking Sh3tc2 have an abnormal organization of the node of Ranvier consistent with the idea that the protein might have a role in myelination or in axon – glial cell interactions.[3][4]
# Clinical significance
Mutations in this gene result in autosomal recessive Charcot-Marie-Tooth disease type 4C, a childhood-onset neurodegenerative disease characterized by demyelination of motor and sensory neurons.[2] | https://www.wikidoc.org/index.php/SH3TC2 | |
50ade955c0e9ae8af31b143d255b29a99160b6fe | wikidoc | SHANK2 | SHANK2
SH3 and multiple ankyrin repeat domains protein 2 is a protein that in humans is encoded by the SHANK2 gene. Two alternative splice variants, encoding distinct isoforms, are reported. Additional splice variants exist but their full-length nature has not been determined.
# Function
This gene encodes a protein that is a member of the Shank family of synaptic proteins that may function as molecular scaffolds in the postsynaptic density (PSD). Shank proteins contain multiple domains for protein-protein interaction, including ankyrin repeats, an SH3 domain, a PSD-95/Dlg/ZO-1 domain, a sterile alpha motif domain, and a proline-rich region. This particular family member contains a PDZ domain, a consensus sequence for cortactin SH3 domain-binding peptides and a sterile alpha motif. The alternative splicing demonstrated in Shank genes has been suggested as a mechanism for regulating the molecular structure of Shank and the spectrum of Shank-interacting proteins in the PSDs of adult and developing brain.
It is thought that SHANK2 might play a role in synaptogenesis by attaching metabotropic glutamate receptors (mGluRs) to an existing pool of NMDA receptors (NMDA-R), bylinking to the NMDA-R through PSD-95, and the mGluRs through HOMER1. An alternative hypothesis is that the Homer/Shank/GKAP/PSD-95 assembly mediates physical association of the NMDAR with IP3R/RYR and intracellular Ca2+ stores.
# Interactions
SHANK2 has been shown to interact with:
- ARHGEF7,
- Cortactin,
- DLG4,
- DLGAP1, and
- DNM2. | SHANK2
SH3 and multiple ankyrin repeat domains protein 2 is a protein that in humans is encoded by the SHANK2 gene.[1][2] Two alternative splice variants, encoding distinct isoforms, are reported. Additional splice variants exist but their full-length nature has not been determined.[2]
# Function
This gene encodes a protein that is a member of the Shank family of synaptic proteins that may function as molecular scaffolds in the postsynaptic density (PSD). Shank proteins contain multiple domains for protein-protein interaction, including ankyrin repeats, an SH3 domain, a PSD-95/Dlg/ZO-1 domain, a sterile alpha motif domain, and a proline-rich region. This particular family member contains a PDZ domain, a consensus sequence for cortactin SH3 domain-binding peptides and a sterile alpha motif. The alternative splicing demonstrated in Shank genes has been suggested as a mechanism for regulating the molecular structure of Shank and the spectrum of Shank-interacting proteins in the PSDs of adult and developing brain.[2]
It is thought that SHANK2 might play a role in synaptogenesis by attaching metabotropic glutamate receptors (mGluRs) to an existing pool of NMDA receptors (NMDA-R), bylinking to the NMDA-R through PSD-95, and the mGluRs through HOMER1.[3] An alternative hypothesis is that the Homer/Shank/GKAP/PSD-95 assembly mediates physical association of the NMDAR with IP3R/RYR and intracellular Ca2+ stores.
# Interactions
SHANK2 has been shown to interact with:
- ARHGEF7,[4]
- Cortactin,[5]
- DLG4,[6][7]
- DLGAP1,[6][7] and
- DNM2.[8] | https://www.wikidoc.org/index.php/SHANK2 | |
8de00c3c81305cdd3f6bb031f65168fff8546b6d | wikidoc | SHANK3 | SHANK3
SH3 and multiple ankyrin repeat domains 3 (Shank3), also known as proline-rich synapse-associated protein 2 (ProSAP2), is a protein that in humans is encoded by the SHANK3 gene on chromosome 22. Additional isoforms have been described for this gene but they have not yet been experimentally verified.
# Function
This gene is a member of the Shank gene family. The gene encodes a protein that contains 5 interaction domains or motifs including the ankyrin repeats domain (ANK), a src 3 domain (SH3), a proline-rich domain, a PDZ domain and a SAM (sterile α motif) domain. Shank proteins are multidomain scaffold proteins of the postsynaptic density that connect neurotransmitter receptors, ion channels, and other membrane proteins to the actin cytoskeleton and G-protein-coupled signaling pathways. Shank proteins also play a role in synapse formation and dendritic spine maturation.
# Clinical significance
Mutations in this gene are associated with autism spectrum disorder. This gene is often missing in patients with 22q13.3 deletion syndrome, although not in all cases.
# Interactions
SHANK3 has been shown to interact with ARHGEF7.
# Mouse models
Mouse models of SHANK3 include N-terminal knock-outs and a PDZ domain knock-out all of which also show social interaction deficits and variable other phenotypes. Most of these mice are homozygous knock-outs whereas all the human Shank3 mutations have been heterozygous.
In an inducible knockout, restoration of Shank3 expression in adult mice promoted dendritic spine growth and recovered normal grooming behaviour and voluntary social interaction. However, the reduced locomotion, anxiety and rotarod deficits remained. Germline restoration of the gene's expression rescued all measured phenotypes. Experiments on different developmental windows suggested that early intervention was more effective in restoring behavioural traits.
# Rat Models
A rat model of SHANK3 was developed using zinc finger nucleases targeting exon 6 of the ankyrin (ANK) repeat domain. The deletion (-68bp) resulted in reduction of the full length SHANK3a protein. It is unclear if the expression of other isoforms (b and c) of SHANK3 is affected in this rodent model. The shank3 mutant rats have deficits in long-term social recognition memory but not short-term social recognition memory as well as deficits in attention. These mutant also have impaired synaptic plasticity. In humans, 5 patients have been described harboring varying mutations in exon 6 of the SHANK3 protein. | SHANK3
SH3 and multiple ankyrin repeat domains 3 (Shank3), also known as proline-rich synapse-associated protein 2 (ProSAP2), is a protein that in humans is encoded by the SHANK3 gene on chromosome 22.[1] Additional isoforms have been described for this gene but they have not yet been experimentally verified.
# Function
This gene is a member of the Shank gene family. The gene encodes a protein that contains 5 interaction domains or motifs including the ankyrin repeats domain (ANK), a src 3 domain (SH3), a proline-rich domain, a PDZ domain and a SAM (sterile α motif) domain[2]. Shank proteins are multidomain scaffold proteins of the postsynaptic density that connect neurotransmitter receptors, ion channels, and other membrane proteins to the actin cytoskeleton and G-protein-coupled signaling pathways. Shank proteins also play a role in synapse formation and dendritic spine maturation.[3]
# Clinical significance
Mutations in this gene are associated with autism spectrum disorder. This gene is often missing in patients with 22q13.3 deletion syndrome,[4] although not in all cases.[5]
# Interactions
SHANK3 has been shown to interact with ARHGEF7.[6]
# Mouse models
Mouse models of SHANK3 include N-terminal knock-outs[7][8] and a PDZ domain knock-out[9] all of which also show social interaction deficits and variable other phenotypes. Most of these mice are homozygous knock-outs whereas all the human Shank3 mutations have been heterozygous.
In an inducible knockout, restoration of Shank3 expression in adult mice promoted dendritic spine growth and recovered normal grooming behaviour and voluntary social interaction.[10] However, the reduced locomotion, anxiety and rotarod deficits remained. Germline restoration of the gene's expression rescued all measured phenotypes. Experiments on different developmental windows suggested that early intervention was more effective in restoring behavioural traits.
# Rat Models
A rat model of SHANK3 was developed using zinc finger nucleases targeting exon 6 of the ankyrin (ANK) repeat domain. The deletion (-68bp) resulted in reduction of the full length SHANK3a protein. It is unclear if the expression of other isoforms (b and c) of SHANK3 is affected in this rodent model. The shank3 mutant rats have deficits in long-term social recognition memory but not short-term social recognition memory as well as deficits in attention. These mutant also have impaired synaptic plasticity. In humans, 5 patients have been described harboring varying mutations in exon 6 of the SHANK3 protein. | https://www.wikidoc.org/index.php/SHANK3 | |
465e85605395ac59cf1d1b88b402247a692a0d3f | wikidoc | SKIV2L | SKIV2L
Helicase SKI2W is an enzyme that in humans is encoded by the SKIV2L gene. This enzyme is a human homologue of yeast SKI2, which may be involved in antiviral activity by blocking translation of poly(A) deficient mRNAs. The SKIV2L gene is located in the class III region of the major histocompatibility complex.
DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division.
# Identification of gene
A novel human cDNA, homologous to the yeast gene SKI2, was identified in 1995. Researchers localised the corresponding gene to chromosome 6p.21.
The SKIV2L gene, also known as SKI2W or Ski2-like RNA Helicase, spans 11Kb and contains 28 exons. Located between RD and RP1 gene in MHC III on the short arm of chromosome 6, it has 16 transcripts on Ensembl, 3 of which are protein coding. One of these proteins, SKI2W, has 1246 amino acids and a helicase binding domain between amino acids 319-475, and is thought to be involved in exosome RNA mediated RNA decay.
The presence of the DEVH-box at position 423-426 within SKI2W infers that it is a member of the SF-II helicase family.
The human protein was named SKI2W because of its similarity to yeast protein Ski2, which has highly homologous (nearly identical) regions at the helicase domain and the C terminal.
SKIV2L transcripts are expressed in most, if not all, human tissue tested including spleen, thymus, small intestine, colon, heart, brain and liver.
# Function
The majority of the eukaryotic genome is transcribed into RNA molecules, which generates pools of RNA that require processing and surveillance in order to control abundant and damaged material. The RNA exosome multiprotein complex performs this function and is dependent on cofactors. The exosome was initially discovered in yeast but is also present in higher eukaryotes. It has activity in both the nucleus and cytoplasm for normal mRNA decay and for RNA surveillance and quality control through nonsense mediated; non-stop and no-go decay.
SKI2W is part of the tetraprotein ski complex which is an obligatory cytoplasmic cofactor of the RNA exosome and consists of SKI2W, TTC37 and 2 subunits of WD40 (encoded by WDR61), as pictured in Figure 1. Much of the information on SKI2W function is from yeast studies, where the homologue for SKI2W is ski2. In yeast, ski2 forms a ski complex with ski3 and 2 subunits of ski8. The ski2 (the SKI2W homolog in yeast) contains DEVH-box proteins which suggests it is the only protein in the ski complex to have an enzymatic helicase function. The exact interactions are not well described, however DEVH-box helicases are shown to separate nucleic strands in an energy dependent manner. The yeast ski complex has been more extensively studied than the human homologue, and a crystal structure of the RNA exosome and its interactions has been created that supports a role in non-stop decay, to thereby protect the cell from aberrant proteins.
Ski2 protein in yeast is also thought to have a role in antiviral defence, probably via its role in RNA turnover or through control of RNA degradation.
SKIV2L has been shown to be a negative regulator of the Rig-I like receptors (RLRs) that detect RNA. The authors found that the cytosolic RNA exosome, defined by the SKIV2L RNA helicase, is important for limiting the activation of RLRs and the antiviral response. If the endogenous RNAs fail to be processed, the cell undergoes an unfolded protein response which triggers an antiviral interferon (IFN) response. Human cells with SKIV2L deficiency are shown to have a strong IFN signature suggestive of a chronic antiviral response. The authors suggest that patients could subsequently be more prone to autoimmune disorders, although this has not been shown as yet, possibly due to the high mortality of patients. However this finding does suggest a link between SKIV2L and immune response.
# Clinical significance
Pathogenic variants in SKIV2L has been linked to Tricho-hepato-enteric syndrome (THES), also known as syndromic diarrhoea (SD) or phenotypic diarrhoea (PD). First described by Stankler et al (1982) as Stankler syndrome, this condition was renamed THES in 1994. THES is rare, with an estimated prevalence of 1:1,000,000. It is characterised by intractable diarrhoea, beginning in first few weeks of life; characteristic hair abnormalities, ”woolly" and brittle hair, intrauterine growth restriction and characteristic facial dysmorphisms. Other associations are hepatic dysfunction, skin abnormalities, intellectual disability and immunodeficiency. Less common findings include platelet abnormalities and congenital heart defects.
There are two causative genes, SKIV2L (in 1/3 of patients) and TTC37 (2/3 of patients), both encode for proteins in the Ski complex and clinically they are indistinguishable from each other.
Inherited in an autosomal recessive manner with complete penetrance, approximately 2/3rd of patients are homozygotes and 1/3rd are compound heterozygous. Mutations are spread throughout the gene with no identifiable hotspot and generally consist of frameshift, missense and nonsense mutations; a smaller number are splice site mutations. There is no clear genotype/phenotype correlation with overall disease severity, even siblings with the same homozygous mutation display variable phenotypes. Patients have been described globally in Europe, Saudi Arabia, Malaysia, China and Japan.
Intractable watery diarrhoea is a near consistent feature in almost all described cases, almost always starting soon after birth and commonly requiring parenteral nutrition. In cases which do not require parenteral nutrition an elemental diet and supplemental feeding is required.
The majority of SKIV2L pathogenic variant harbouring patients are small at birth (90% of patients and are described as woolly, brittle hair that is easily removed.
Facial dysmorphisms are found in most patients and become more apparent with age. These include a large forehead, broad base of the nose and hypertelorism. Overall the facial features are described as “coarse”.
Liver disease is reported frequently in SKIV2L patients (>80%), ranging from fibrosis, cirrhosis, hepatomegaly and raised liver enzymes. Histopathology when performed shows iron overload and can be consistent with haemochromatosis.
Skin abnormalities are frequently reported and are variable including café au lait lesions, haemangiomas and xerosis. A report from Saudi Arabia suggested the skin changes were more frequent in the lower limb and pelvic region of their regional cohort.
Immunodeficiency is reported in some patients. It is poorly delineated and mainly consists of low immunoglobulins and inadequate vaccine responses, however hyper IgA has also been reported. Immunoglobulin therapy has been shown to lower rates of infection.
Less commonly congenital cardiac defects have been reported, mostly ventricular septal defects (VSD), atrial septal defects (ASD), and rarely Tetralogy of Fallot and peripheral pulmonary stenosis.
## Mortality rate
Initially reported as high as 62.5% with most deaths in the first year, more recent reports have estimated mortality of around 30%, which is similar to other disorders which are dependent on parenteral nutrition.
# Recommended treatment and surveillance
No specific treatments are available for THES. The goal is to maximise weight gain and reduce infection rates.
Most children require parenteral nutrition (PN) which can be combined with oral feeding, most commonly a semi-elemental diet which allows patients to become independent of PN over time. Nutrition and growth should be closely monitored. If PN is not required, reports have described the use of an amino acid based formula, although it is unclear if weight gain was adequate.
Immunoglobulin levels and vaccine responses should be tested. If any abnormalities are found then a paediatric immunologist should be consulted and intravenous immunoglobulin (IVIG) can be considered to reduce chance of systemic infections. Infection was reported as a cause of death in 20% of a large cohort of French patients.
A recent study looked at immunodeficiency in 9 THES patients, of which 3 had SKIV2L pathogenic variants. The authors reported that the degranulation and number of IFN-γ producing NK cells were reduced in most patients (although it is unclear if this included the SKIV2L patients) and proposed that this could lead to susceptibility to RNA viruses, with 4/9 patients harbouring a chronic EBV infection and one patient dying of measles.
Regular liver assessment should include ultrasound and hepatic enzymes and developmental assessment should be performed.
Steroids, immunosuppressants and haematopoietic stem cell transplant has been THES with no success and therefore it is not recommended.
Genetic counselling should be offered as a sibling recurrence is 25% with each conception.
# Age related macular degeneration (ARMD)
An intronic single nucleotide polymorphism (SNP) in SKIV2L on genome wide association studies has been shown to be protective for age related macular degeneration. 3’UTR variant in SKIV2L has recently been reported to exert a protective effect in polypoidal choroidal vasculopathy, a haemorrhagic macular disease that shares some features with neovascular ARMD. As the variants would not affect structure of the protein, it was proposed that it affects regulation of oxidative stress pathways.
Conversely another study showed a genetic variant rs429608 to be strongly associated with the development of ARMD in the Han Chinese population, however further studies are needed to investigate the biological role of SKIV2L and pathogenesis. | SKIV2L
Helicase SKI2W is an enzyme that in humans is encoded by the SKIV2L gene.[1][2][3] This enzyme is a human homologue of yeast SKI2, which may be involved in antiviral activity by blocking translation of poly(A) deficient mRNAs. The SKIV2L gene is located in the class III region of the major histocompatibility complex.[2]
DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division.
# Identification of gene
A novel human cDNA, homologous to the yeast gene SKI2, was identified in 1995. Researchers localised the corresponding gene to chromosome 6p.21.[4]
The SKIV2L gene, also known as SKI2W or Ski2-like RNA Helicase, spans 11Kb and contains 28 exons.[5] Located between RD and RP1 gene in MHC III on the short arm of chromosome 6, it has 16 transcripts on Ensembl, 3 of which are protein coding. One of these proteins, SKI2W, has 1246 amino acids and a helicase binding domain between amino acids 319-475, and is thought to be involved in exosome RNA mediated RNA decay.[6]
The presence of the DEVH-box at position 423-426 within SKI2W infers that it is a member of the SF-II helicase family.
The human protein was named SKI2W because of its similarity to yeast protein Ski2, which has highly homologous (nearly identical) regions at the helicase domain and the C terminal.[7]
SKIV2L transcripts are expressed in most, if not all, human tissue tested including spleen, thymus, small intestine, colon, heart, brain and liver.[8]
# Function
The majority of the eukaryotic genome is transcribed into RNA molecules, which generates pools of RNA that require processing and surveillance in order to control abundant and damaged material. The RNA exosome multiprotein complex performs this function and is dependent on cofactors. The exosome was initially discovered in yeast but is also present in higher eukaryotes. It has activity in both the nucleus and cytoplasm for normal mRNA decay and for RNA surveillance and quality control through nonsense mediated; non-stop and no-go decay.[9]
SKI2W is part of the tetraprotein ski complex which is an obligatory cytoplasmic cofactor of the RNA exosome and consists of SKI2W, TTC37 and 2 subunits of WD40 (encoded by WDR61), as pictured in Figure 1.[10] Much of the information on SKI2W function is from yeast studies, where the homologue for SKI2W is ski2. In yeast, ski2 forms a ski complex with ski3 and 2 subunits of ski8. The ski2 (the SKI2W homolog in yeast) contains DEVH-box proteins which suggests it is the only protein in the ski complex to have an enzymatic helicase function.[11] The exact interactions are not well described, however DEVH-box helicases are shown to separate nucleic strands in an energy dependent manner. The yeast ski complex has been more extensively studied than the human homologue, and a crystal structure of the RNA exosome and its interactions has been created that supports a role in non-stop decay, to thereby protect the cell from aberrant proteins.[11]
Ski2 protein in yeast is also thought to have a role in antiviral defence, probably via its role in RNA turnover or through control of RNA degradation.[13]
SKIV2L has been shown to be a negative regulator of the Rig-I like receptors (RLRs) that detect RNA. The authors found that the cytosolic RNA exosome, defined by the SKIV2L RNA helicase, is important for limiting the activation of RLRs and the antiviral response. If the endogenous RNAs fail to be processed, the cell undergoes an unfolded protein response which triggers an antiviral interferon (IFN) response. Human cells with SKIV2L deficiency are shown to have a strong IFN signature suggestive of a chronic antiviral response. The authors suggest that patients could subsequently be more prone to autoimmune disorders, although this has not been shown as yet, possibly due to the high mortality of patients. However this finding does suggest a link between SKIV2L and immune response.[14]
# Clinical significance
Pathogenic variants in SKIV2L has been linked to Tricho-hepato-enteric syndrome (THES), also known as syndromic diarrhoea (SD) or phenotypic diarrhoea (PD). First described by Stankler et al (1982) as Stankler syndrome, this condition was renamed THES in 1994.[15] THES is rare, with an estimated prevalence of 1:1,000,000.[16] It is characterised by intractable diarrhoea, beginning in first few weeks of life; characteristic hair abnormalities, ”woolly" and brittle hair, intrauterine growth restriction and characteristic facial dysmorphisms. Other associations are hepatic dysfunction, skin abnormalities, intellectual disability and immunodeficiency. Less common findings include platelet abnormalities and congenital heart defects.[17]
There are two causative genes, SKIV2L (in 1/3 of patients) and TTC37 (2/3 of patients), both encode for proteins in the Ski complex and clinically they are indistinguishable from each other.[9]
Inherited in an autosomal recessive manner with complete penetrance, approximately 2/3rd of patients are homozygotes and 1/3rd are compound heterozygous. Mutations are spread throughout the gene with no identifiable hotspot and generally consist of frameshift, missense and nonsense mutations; a smaller number are splice site mutations.[10] There is no clear genotype/phenotype correlation with overall disease severity, even siblings with the same homozygous mutation display variable phenotypes. Patients have been described globally in Europe, Saudi Arabia, Malaysia, China and Japan.[18][19][20][21]
Intractable watery diarrhoea is a near consistent feature in almost all described cases, almost always starting soon after birth and commonly requiring parenteral nutrition. In cases which do not require parenteral nutrition an elemental diet and supplemental feeding is required.[10]
The majority of SKIV2L pathogenic variant harbouring patients are small at birth (<10th centile) and remain growth restricted despite increased nutrition. Hair abnormalities are seen in >90% of patients and are described as woolly, brittle hair that is easily removed.[10]
Facial dysmorphisms are found in most patients and become more apparent with age. These include a large forehead, broad base of the nose and hypertelorism. Overall the facial features are described as “coarse”.
Liver disease is reported frequently in SKIV2L patients (>80%), ranging from fibrosis, cirrhosis, hepatomegaly and raised liver enzymes. Histopathology when performed shows iron overload and can be consistent with haemochromatosis.[22]
Skin abnormalities are frequently reported and are variable including café au lait lesions, haemangiomas and xerosis. A report from Saudi Arabia suggested the skin changes were more frequent in the lower limb and pelvic region of their regional cohort.[19]
Immunodeficiency is reported in some patients. It is poorly delineated and mainly consists of low immunoglobulins and inadequate vaccine responses, however hyper IgA has also been reported. Immunoglobulin therapy has been shown to lower rates of infection.[23]
Less commonly congenital cardiac defects have been reported, mostly ventricular septal defects (VSD), atrial septal defects (ASD), and rarely Tetralogy of Fallot and peripheral pulmonary stenosis.
## Mortality rate
Initially reported as high as 62.5% with most deaths in the first year, more recent reports have estimated mortality of around 30%, which is similar to other disorders which are dependent on parenteral nutrition.
# Recommended treatment and surveillance
No specific treatments are available for THES. The goal is to maximise weight gain and reduce infection rates.
Most children require parenteral nutrition (PN) which can be combined with oral feeding, most commonly a semi-elemental diet which allows patients to become independent of PN over time. Nutrition and growth should be closely monitored. If PN is not required, reports have described the use of an amino acid based formula, although it is unclear if weight gain was adequate.
Immunoglobulin levels and vaccine responses should be tested. If any abnormalities are found then a paediatric immunologist should be consulted and intravenous immunoglobulin (IVIG) can be considered to reduce chance of systemic infections.[17][24] Infection was reported as a cause of death in 20% of a large cohort of French patients.[10]
A recent study looked at immunodeficiency in 9 THES patients, of which 3 had SKIV2L pathogenic variants. The authors reported that the degranulation and number of IFN-γ producing NK cells were reduced in most patients (although it is unclear if this included the SKIV2L patients) and proposed that this could lead to susceptibility to RNA viruses, with 4/9 patients harbouring a chronic EBV infection and one patient dying of measles.[23]
Regular liver assessment should include ultrasound and hepatic enzymes and developmental assessment should be performed.[25]
Steroids, immunosuppressants and haematopoietic stem cell transplant has been THES with no success and therefore it is not recommended.
Genetic counselling should be offered as a sibling recurrence is 25% with each conception.
# Age related macular degeneration (ARMD)
An intronic single nucleotide polymorphism (SNP) in SKIV2L on genome wide association studies has been shown to be protective for age related macular degeneration. 3’UTR variant in SKIV2L has recently been reported to exert a protective effect in polypoidal choroidal vasculopathy, a haemorrhagic macular disease that shares some features with neovascular ARMD. As the variants would not affect structure of the protein, it was proposed that it affects regulation of oxidative stress pathways.[26]
Conversely another study showed a genetic variant rs429608 to be strongly associated with the development of ARMD in the Han Chinese population,[27] however further studies are needed to investigate the biological role of SKIV2L and pathogenesis. | https://www.wikidoc.org/index.php/SKIV2L | |
a452604291fa68519b294177b1e1c5add4cb619b | wikidoc | SLAMF1 | SLAMF1
Signaling lymphocytic activation molecule 1 is a protein that in humans is encoded by the SLAMF1 gene. Recently SLAMF1 has also been designated CD150 (cluster of differentiation 150).
SLAMF1 belongs to the signaling lymphocytic activation molecule family. The interaction of SLAMF1 promoter and enhancers with the Early B-cell factor 1 (EBF1) is required for the expression of SLAMF1 gene in B cells. STAT6, IRF4, and NF-kB factors involved in the transfer of the signals from the B-cell receptor, its co-receptors and IL-4R, also play important role in the regulation of SLAMF1 expression.
# Interactions
SLAMF1 has been shown to interact with PTPN11, SH2D1A and SH2D1B. | SLAMF1
Signaling lymphocytic activation molecule 1 is a protein that in humans is encoded by the SLAMF1 gene.[1][2] Recently SLAMF1 has also been designated CD150 (cluster of differentiation 150).
SLAMF1 belongs to the signaling lymphocytic activation molecule family. The interaction of SLAMF1 promoter and enhancers with the Early B-cell factor 1 (EBF1) is required for the expression of SLAMF1 gene in B cells. STAT6, IRF4, and NF-kB factors involved in the transfer of the signals from the B-cell receptor, its co-receptors and IL-4R, also play important role in the regulation of SLAMF1 expression.[3]
# Interactions
SLAMF1 has been shown to interact with PTPN11,[4][5] SH2D1A[4][6] and SH2D1B.[5] | https://www.wikidoc.org/index.php/SLAMF1 | |
293c7cb2b6676b59720cfad7c9132785e73e0b36 | wikidoc | SLC1A2 | SLC1A2
Excitatory amino acid transporter 2 (EAAT2) also known as solute carrier family 1 member 2 (SLC1A2) and glutamate transporter 1 (GLT-1) is a protein that in humans is encoded by the SLC1A2 gene. Alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known.
# Function
SLC1A2 / EAAT2 is a member of a family of the solute carrier family of proteins. The membrane-bound protein is the principal transporter that clears the excitatory neurotransmitter glutamate from the extracellular space at synapses in the central nervous system. Glutamate clearance is necessary for proper synaptic activation and to prevent neuronal damage from excessive activation of glutamate receptors. EAAT2 is responsible for over 90% of glutamate reuptake within the brain.
# Clinical significance
Mutations in and decreased expression of this protein are associated with amyotrophic lateral sclerosis (ALS). The drug riluzole approved for the treatment of ALS upregulates EAAT2.
Ceftriaxone, an antibiotic, has been shown to induce/enhance the expression of EAAT2, resulting in reduced glutamate activity. Ceftriaxone has been shown to reduce the development and expression of tolerance to opiates and other drugs of abuse. EAAT2 may possess an important role in drug addiction and tolerance to addictive drugs.
Upregulation of EAAT2 (GLT-1) causes impairment of prepulse inhibition, a sensory gating deficit present in schizophrenics and schizophrenia animal models. Some antipsychotics have been shown to reduce the expression of EAAT2.
# Interactions
SLC1A2 has been shown to interact with JUB.
# As a drug target
EAAT2/GLT-1, being the most abundant subtype of glutamate transporter in the CNS, plays a key role in regulation of glutamate neurotransmission. Dysfunction of EAAT2 has been correlated with various pathologies such as traumatic brain injury, stroke, Amyotrophic lateral sclerosis (ALS), Alzheimer's disease, among others. Therefore, activators of the function or enhancers of the expression of EAAT2/GLT-1 could serve as a potential therapy for these conditions. Translational activators of EAAT2/GLT-1, such as ceftriaxone and LDN/OSU-0212320, have been described to have significant protective effects in animal models of ALS and epilepsy. In addition, pharmacological activators of the activity of EAAT2/GLT-1 have been explored for decades and are currently emerging as promising tools for neuroprotection, having potential advantages over expression activators.
DL-TBOA, WAY-213613, and dihydrokainic acid are known inhibitors of the protein, and function as excitotoxins. They can be considered a novel class of nerve agent toxins, inducing toxic levels of glutamate through transport inhibition in a manner analogous to the effect of sarin on acetylcholine transporters. Antidotes for such a poisoning have never been formally tested for efficacy and are not readily available for medical use.
Addiction to certain addictive drugs (e.g., cocaine, heroin, alcohol, and nicotine) is correlated with a persistent reduction in the expression of EAAT2 in the nucleus accumbens (NAcc); the reduced expression of EAAT2 in this region is implicated in addictive drug-seeking behavior. In particular, the long-term dysregulation of glutamate neurotransmission in the NAcc of addicts is associated with an increase in vulnerability to relapse after re-exposure to the addictive drug or its associated drug cues. Drugs which help to normalize the expression of EAAT2 in this region, such as N-acetylcysteine, have been proposed as an adjunct therapy for the treatment of addiction to cocaine, nicotine, alcohol, and other drugs. | SLC1A2
Excitatory amino acid transporter 2 (EAAT2) also known as solute carrier family 1 member 2 (SLC1A2) and glutamate transporter 1 (GLT-1) is a protein that in humans is encoded by the SLC1A2 gene.[1][2] Alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known.[2]
# Function
SLC1A2 / EAAT2 is a member of a family of the solute carrier family of proteins. The membrane-bound protein is the principal transporter that clears the excitatory neurotransmitter glutamate from the extracellular space at synapses in the central nervous system. Glutamate clearance is necessary for proper synaptic activation and to prevent neuronal damage from excessive activation of glutamate receptors.[2] EAAT2 is responsible for over 90% of glutamate reuptake within the brain.[3][4]
# Clinical significance
Mutations in and decreased expression of this protein are associated with amyotrophic lateral sclerosis (ALS).[2] The drug riluzole approved for the treatment of ALS upregulates EAAT2.[5]
Ceftriaxone, an antibiotic, has been shown to induce/enhance the expression of EAAT2, resulting in reduced glutamate activity.[6] Ceftriaxone has been shown to reduce the development and expression of tolerance to opiates and other drugs of abuse. EAAT2 may possess an important role in drug addiction and tolerance to addictive drugs.[7]
Upregulation of EAAT2 (GLT-1) causes impairment of prepulse inhibition, a sensory gating deficit present in schizophrenics and schizophrenia animal models.[8][9] Some antipsychotics have been shown to reduce the expression of EAAT2.[10][11]
# Interactions
SLC1A2 has been shown to interact with JUB.[12]
# As a drug target
EAAT2/GLT-1, being the most abundant subtype of glutamate transporter in the CNS, plays a key role in regulation of glutamate neurotransmission. Dysfunction of EAAT2 has been correlated with various pathologies such as traumatic brain injury, stroke, Amyotrophic lateral sclerosis (ALS), Alzheimer's disease, among others. Therefore, activators of the function or enhancers of the expression of EAAT2/GLT-1 could serve as a potential therapy for these conditions. Translational activators of EAAT2/GLT-1, such as ceftriaxone and LDN/OSU-0212320, have been described to have significant protective effects in animal models of ALS and epilepsy. In addition, pharmacological activators of the activity of EAAT2/GLT-1 have been explored for decades and are currently emerging as promising tools for neuroprotection, having potential advantages over expression activators.[13]
DL-TBOA, WAY-213613, and dihydrokainic acid are known inhibitors of the protein, and function as excitotoxins. They can be considered a novel class of nerve agent toxins, inducing toxic levels of glutamate through transport inhibition in a manner analogous to the effect of sarin on acetylcholine transporters. Antidotes for such a poisoning have never been formally tested for efficacy and are not readily available for medical use.[14]
Addiction to certain addictive drugs (e.g., cocaine, heroin, alcohol, and nicotine) is correlated with a persistent reduction in the expression of EAAT2 in the nucleus accumbens (NAcc);[15] the reduced expression of EAAT2 in this region is implicated in addictive drug-seeking behavior.[15] In particular, the long-term dysregulation of glutamate neurotransmission in the NAcc of addicts is associated with an increase in vulnerability to relapse after re-exposure to the addictive drug or its associated drug cues.[15] Drugs which help to normalize the expression of EAAT2 in this region, such as N-acetylcysteine, have been proposed as an adjunct therapy for the treatment of addiction to cocaine, nicotine, alcohol, and other drugs.[15] | https://www.wikidoc.org/index.php/SLC1A2 | |
382cc63b8adf4703d716d6c229de169015780465 | wikidoc | SLC2A9 | SLC2A9
Solute carrier family 2, facilitated glucose transporter member 9 is a protein that in humans is encoded by the SLC2A9 gene.
This gene encodes a member of the SLC2A facilitative glucose transporter family. Members of this family play a significant role in maintaining glucose homeostasis. The encoded protein may play a role in the development and survival of chondrocytes in cartilage matrices. Two transcript variants encoding distinct isoforms have been identified for this gene.
SLC2A9 has also recently been found to transport uric acid, and genetic variants of the transporter have been linked to increased risk of development of both hyperuricemia, gout and Alzheimer's disease. | SLC2A9
Solute carrier family 2, facilitated glucose transporter member 9 is a protein that in humans is encoded by the SLC2A9 gene.[1][2][3]
This gene encodes a member of the SLC2A facilitative glucose transporter family. Members of this family play a significant role in maintaining glucose homeostasis. The encoded protein may play a role in the development and survival of chondrocytes in cartilage matrices. Two transcript variants encoding distinct isoforms have been identified for this gene.[3]
SLC2A9 has also recently been found to transport uric acid, and genetic variants of the transporter have been linked to increased risk of development of both hyperuricemia, gout and Alzheimer's disease.[4][5][6] | https://www.wikidoc.org/index.php/SLC2A9 | |
3c63d441b9b4dd651acb6292e69b92d429d72c3d | wikidoc | SLC3A2 | SLC3A2
4F2 cell-surface antigen heavy chain is a protein that in humans is encoded by the SLC3A2 (solute carrier family 3 member 2) gene.
SLC3A2 comprises the heavy subunit of the large neutral amino acid transporter (LAT1) that is also known as CD98 (cluster of differentiation 98).
# Function
SLC3A2 is a member of the solute carrier family and encodes a cell surface, transmembrane protein with an alpha-amylase domain. The protein exists as the heavy chain of a heterodimer, covalently bound through di-sulfide bonds to one of several possible light chains. It associates with integrins and mediates integrin-dependent signaling related to normal cell growth and tumorigenesis. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.
LAT1 is a heterodimeric membrane transport protein that preferentially transports neutral branched (valine, leucine, isoleucine) and aromatic (tryptophan, tyrosine) amino acids. LAT is highly expressed in brain capillaries (which form the blood brain barrier) relative to other tissues.
A functional LAT1 transporter is composed of two proteins encoded by two distinct genes:
- 4F2hc/CD98 heavy subunit protein encoded by the SLC3A2 gene (this gene)
- CD98 light subunit protein encoded by the SLC7A5 gene
# Interactions
SLC3A2 has been shown to interact with SLC7A7.
Additionally, SLC3A2 is a constituent member of the system xc- cystine/glutamate antiporter, complexing with SLC7A11. | SLC3A2
4F2 cell-surface antigen heavy chain is a protein that in humans is encoded by the SLC3A2 (solute carrier family 3 member 2) gene.[1][2]
SLC3A2 comprises the heavy subunit of the large neutral amino acid transporter (LAT1) that is also known as CD98 (cluster of differentiation 98).[3][4]
# Function
SLC3A2 is a member of the solute carrier family and encodes a cell surface, transmembrane protein with an alpha-amylase domain. The protein exists as the heavy chain of a heterodimer, covalently bound through di-sulfide bonds to one of several possible light chains. It associates with integrins and mediates integrin-dependent signaling related to normal cell growth and tumorigenesis. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.[2]
LAT1 is a heterodimeric membrane transport protein that preferentially transports neutral branched (valine, leucine, isoleucine) and aromatic (tryptophan, tyrosine) amino acids.[5] LAT is highly expressed in brain capillaries (which form the blood brain barrier) relative to other tissues.[5]
A functional LAT1 transporter is composed of two proteins encoded by two distinct genes:
- 4F2hc/CD98 heavy subunit protein encoded by the SLC3A2 gene (this gene)[6]
- CD98 light subunit protein encoded by the SLC7A5 gene[7]
# Interactions
SLC3A2 has been shown to interact with SLC7A7.[8]
Additionally, SLC3A2 is a constituent member of the system xc- cystine/glutamate antiporter, complexing with SLC7A11. | https://www.wikidoc.org/index.php/SLC3A2 | |
576868b77e0a000fb0fff4ba7ca3395c9e530aee | wikidoc | SLC4A2 | SLC4A2
Anion exchange protein 2 (AE2) is a membrane transport protein that in humans is encoded by the SLC4A2 gene. AE2 is functionally similar to the Band 3 Cl−/HCO3− exchange protein.
Mice have been used to explore the function of AE2. AE2 contributes to basolateral membrane HCO3− transport in the gastrointestinal tract. AE2 is required for spermiogenesis in mice. AE2 is required for normal osteoclast function. The activity of AE2 is sensitive to pH.
AE3 has been suggested as a target for prevention of diabetic vasculopathy. | SLC4A2
Anion exchange protein 2 (AE2) is a membrane transport protein that in humans is encoded by the SLC4A2 gene.[1][2] AE2 is functionally similar to the Band 3 Cl−/HCO3− exchange protein.
Mice have been used to explore the function of AE2. AE2 contributes to basolateral membrane HCO3− transport in the gastrointestinal tract.[3] AE2 is required for spermiogenesis in mice.[4] AE2 is required for normal osteoclast function.[5][6] The activity of AE2 is sensitive to pH.[7]
AE3 has been suggested as a target for prevention of diabetic vasculopathy.[8] | https://www.wikidoc.org/index.php/SLC4A2 | |
3f4574730eaf743f7b8f6e63afc8d27944e79912 | wikidoc | SLC4A4 | SLC4A4
Electrogenic sodium bicarbonate cotransporter 1 is a membrane transport protein that in humans is encoded by the SLC4A4 gene.
# Function
Sodium bicarbonate cotransporters (NBCs) mediate the coupled movement of sodium and bicarbonate ions across the plasma membrane of many cells. This is an electrogenic process with an apparent stoichiometry of 3 bicarbonate ions per sodium ion. Sodium bicarbonate cotransport is involved in bicarbonate secretion/absorption and intracellular pH regulation. Romero and Boron (1999) reviewed NBCs. Soleimani and Burnham (2000) reviewed NBCs and their regulation in physiologic and pathophysiologic states.
# Clinical significance
NBCe1 may participate in regulation of brain extracellular space pH. Some mutations in NBCe1 have been associated with Familial hemiplegic migraine. Other NBCe1 mutations disrupt kidney bicarbonate transport and cause proximal renal tubular acidosis.
# Splice variants
NBCe1-A aka kNBC1 (mainly expressed in the kidney)
NBCe1-B aka pNBC1 (expressed in the pancreas and elsewhere)
NBCe1-C (expressed in the brain)
# Distribution
The renal SLC4A4 gene product NBCe1-A is specifically expressed in the basolateral membranes of proximal tubule epithelia. | SLC4A4
Electrogenic sodium bicarbonate cotransporter 1 is a membrane transport protein that in humans is encoded by the SLC4A4 gene.[1][2][3]
# Function
Sodium bicarbonate cotransporters (NBCs) mediate the coupled movement of sodium and bicarbonate ions across the plasma membrane of many cells. This is an electrogenic process with an apparent stoichiometry of 3 bicarbonate ions per sodium ion. Sodium bicarbonate cotransport is involved in bicarbonate secretion/absorption and intracellular pH regulation. Romero and Boron (1999) reviewed NBCs. Soleimani and Burnham (2000) reviewed NBCs and their regulation in physiologic and pathophysiologic states.[supplied by OMIM][3]
# Clinical significance
NBCe1 may participate in regulation of brain extracellular space pH. Some mutations in NBCe1 have been associated with Familial hemiplegic migraine.[4] Other NBCe1 mutations disrupt kidney bicarbonate transport and cause proximal renal tubular acidosis.[5]
# Splice variants
NBCe1-A aka kNBC1 (mainly expressed in the kidney)
NBCe1-B aka pNBC1 (expressed in the pancreas and elsewhere)
NBCe1-C (expressed in the brain)
# Distribution
The renal SLC4A4 gene product NBCe1-A is specifically expressed in the basolateral membranes of proximal tubule epithelia. | https://www.wikidoc.org/index.php/SLC4A4 | |
68b2a95ff278b8cc307ae55b1e0a955b34e0befd | wikidoc | SLC4A5 | SLC4A5
Electrogenic sodium bicarbonate cotransporter 4 is a protein that in humans is encoded by the SLC4A5 gene.
# Function
This gene encodes a member of the sodium bicarbonate cotransporter (NBC) family, part of the bicarbonate transporter superfamily. Sodium bicarbonate cotransporters are involved in intracellular pH regulation and electroneural or electrogenic sodium bicarbonate transport. This protein is thought to be an integral membrane protein. Multiple transcript variants encoding different isoforms have been found for this gene, but the biological validity of some variants has not been determined.
# Clinical significance
This human gene has been identified as a hypertension susceptibility gene based on the association of single nucleotide polymorphisms with blood pressure (BP) levels and hypertension status. | SLC4A5
Electrogenic sodium bicarbonate cotransporter 4 is a protein that in humans is encoded by the SLC4A5 gene.[1][2][3]
# Function
This gene encodes a member of the sodium bicarbonate cotransporter (NBC) family, part of the bicarbonate transporter superfamily. Sodium bicarbonate cotransporters are involved in intracellular pH regulation and electroneural or electrogenic sodium bicarbonate transport. This protein is thought to be an integral membrane protein. Multiple transcript variants encoding different isoforms have been found for this gene, but the biological validity of some variants has not been determined.[3]
# Clinical significance
This human gene has been identified as a hypertension susceptibility gene based on the association of single nucleotide polymorphisms with blood pressure (BP) levels and hypertension status.[4] | https://www.wikidoc.org/index.php/SLC4A5 | |
c11c73e5c577f1b8394e4ef39ee9269762b76af4 | wikidoc | SLC5A1 | SLC5A1
Sodium/glucose cotransporter 1 also known as solute carrier family 5 member 1 is a protein that in humans is encoded by the SLC5A1 gene.
# Function
Glucose transporters are integral membrane proteins that mediate the transport of glucose and structurally related substances across cellular membranes. The role of the sodium-glucose cotransporters is to not only absorb glucose, but to also absorb sodium and to then reabsorb the sodium and glucose from the tubule of the nephron. Two families of glucose transporter have been identified: the facilitated diffusion glucose transporter family (GLUT family), also known as 'uniporters,' and the sodium-dependent glucose transporter family (SGLT family), also known as 'cotransporters' or 'symporters. The SLC5A1 gene encodes a protein that is involved in the active transport of glucose and galactose into eukaryotic and some prokaryotic cells.
# Cloning
Co-transport proteins of mammalian cell membranes had eluded efforts of purification with classical biochemical methods until the late 1980s. These proteins had proven difficult to isolate because they contain hydrophilic and hydrophobic sequences and exist in membranes only in very low abundance (<0.2% of membrane proteins). The rabbit form of SGLT1 was the first mammalian co-transport protein ever to be cloned and sequenced, and this was reported in 1987. To circumvent the difficulties with traditional isolation methods, a novel expression cloning technique was used. Size-fractionation of large amounts of rabbit intestinal mRNA with preparative gel electrophoresis were then sequentially injected into Xenopus oocytes to ultimately find the RNA species that induced the expression of sodium-glucose cotransport.
# Mutations
SLC5A1 is important because of its role in the absorption of glucose and sodium, however, mutations in the gene can cause serious effects. A mutation in the SLC5A1 gene can cause problems creating the SGLT1 protein, leading to a rare glucose-galactose malabsorption disease. Glucose-galactose malabsorption occurs when the lining of the intestinal cells can't take in glucose and galactose which prevents the use of those molecules in catabolism and anabolism. The disease has symptoms that consist of watery and/or acidic diarrhea which is the result of water retention in the intestinal lumen and osmotic loss created by non-absorbed glucose, galactose and sodium. Glucose-Galactose malabsorption can cause death, due to loss of water from diarrhea, if the disease isn't treated soon. To counteract the disease, oral rehydration therapy is performed using sodium, glucose, and water for intestinal reabsorption.
# Tissue distribution
The SLC5A1 cotransporter is mainly expressed in the lumen of the small intestine, kidney, parotid glands, submandibular glands and in the heart. | SLC5A1
Sodium/glucose cotransporter 1 also known as solute carrier family 5 member 1 is a protein that in humans is encoded by the SLC5A1 gene.[1][2]
# Function
Glucose transporters are integral membrane proteins that mediate the transport of glucose and structurally related substances across cellular membranes. The role of the sodium-glucose cotransporters is to not only absorb glucose, but to also absorb sodium and to then reabsorb the sodium and glucose from the tubule of the nephron.[3] Two families of glucose transporter have been identified: the facilitated diffusion glucose transporter family (GLUT family), also known as 'uniporters,' and the sodium-dependent glucose transporter family (SGLT family), also known as 'cotransporters' or 'symporters.[4] The SLC5A1 gene encodes a protein that is involved in the active transport of glucose and galactose into eukaryotic and some prokaryotic cells.[2]
# Cloning
Co-transport proteins of mammalian cell membranes had eluded efforts of purification with classical biochemical methods until the late 1980s. These proteins had proven difficult to isolate because they contain hydrophilic and hydrophobic sequences and exist in membranes only in very low abundance (<0.2% of membrane proteins). The rabbit form of SGLT1 was the first mammalian co-transport protein ever to be cloned and sequenced, and this was reported in 1987.[5] To circumvent the difficulties with traditional isolation methods, a novel expression cloning technique was used. Size-fractionation of large amounts of rabbit intestinal mRNA with preparative gel electrophoresis were then sequentially injected into Xenopus oocytes to ultimately find the RNA species that induced the expression of sodium-glucose cotransport.[5]
# Mutations
SLC5A1 is important because of its role in the absorption of glucose and sodium, however, mutations in the gene can cause serious effects. A mutation in the SLC5A1 gene can cause problems creating the SGLT1 protein, leading to a rare glucose-galactose malabsorption disease. Glucose-galactose malabsorption occurs when the lining of the intestinal cells can't take in glucose and galactose which prevents the use of those molecules in catabolism and anabolism. The disease has symptoms that consist of watery and/or acidic diarrhea which is the result of water retention in the intestinal lumen and osmotic loss created by non-absorbed glucose, galactose and sodium.[6] Glucose-Galactose malabsorption can cause death, due to loss of water from diarrhea, if the disease isn't treated soon. To counteract the disease, oral rehydration therapy is performed using sodium, glucose, and water for intestinal reabsorption.
# Tissue distribution
The SLC5A1 cotransporter is mainly expressed in the lumen of the small intestine, kidney, parotid glands, submandibular glands and in the heart.[7] | https://www.wikidoc.org/index.php/SLC5A1 | |
6d5eaf5017193628dbeae456c4f2cb6c35de2611 | wikidoc | SLC7A9 | SLC7A9
Solute carrier family 7 (cationic amino acid transporter, y+ system), member 9 also known as SLC7A9 is a protein which in humans is encoded by the SLC7A9 gene.
# Function
This gene encodes a protein that belongs to a family of light subunits of amino acid transporters. This protein plays a role in the high-affinity and sodium-independent transport of cystine and neutral and dibasic amino acids, and appears to function in the reabsorption of cystine in the kidney tubule. The protein associates with the protein coded for by SLC3A1.
# Clinical significance
Mutations in this gene cause non-type I cystinuria, a disease that leads to cystine stones in the urinary system due to impaired transport of cystine and dibasic amino acids. | SLC7A9
Solute carrier family 7 (cationic amino acid transporter, y+ system), member 9 also known as SLC7A9 is a protein which in humans is encoded by the SLC7A9 gene.[1]
# Function
This gene encodes a protein that belongs to a family of light subunits of amino acid transporters. This protein plays a role in the high-affinity and sodium-independent transport of cystine and neutral and dibasic amino acids, and appears to function in the reabsorption of cystine in the kidney tubule.[1] The protein associates with the protein coded for by SLC3A1.[2]
# Clinical significance
Mutations in this gene cause non-type I cystinuria, a disease that leads to cystine stones in the urinary system due to impaired transport of cystine and dibasic amino acids.[1] | https://www.wikidoc.org/index.php/SLC7A9 | |
4bb15e8afb48b6659d398479c8467ea4c433dfda | wikidoc | SLC9A8 | SLC9A8
Sodium/hydrogen exchanger 8 is a protein that in humans is encoded by the SLC9A8 gene.
# Model organisms
Model organisms have been used in the study of SLC9A8 function. A conditional knockout mouse line, called Slc9a8tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty one tests were carried out on mutant mice and one significant abnormality was observed: homozygous mutant animals had abnormal retinal morphology and pigmentation. | SLC9A8
Sodium/hydrogen exchanger 8 is a protein that in humans is encoded by the SLC9A8 gene.[1][2]
# Model organisms
Model organisms have been used in the study of SLC9A8 function. A conditional knockout mouse line, called Slc9a8tm1a(KOMP)Wtsi[6][7] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[8][9][10]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[4][11] Twenty one tests were carried out on mutant mice and one significant abnormality was observed: homozygous mutant animals had abnormal retinal morphology and pigmentation.[4] | https://www.wikidoc.org/index.php/SLC9A8 | |
51ccff2bbbe08d83676e60e82cbc0b67d8386920 | wikidoc | SLURP1 | SLURP1
Secreted Ly-6/uPAR-related protein 1 is a protein that in humans is encoded by the SLURP1 gene. It exerts anti-inflammatory effects and acts as a tumor suppressor and antagonist of nicotine.
# Function
The protein encoded by this gene is a member of the Ly6/uPAR family but lacks a GPI-anchoring signal sequence. It is secreted into the blood and binds to the α7-acetylcholine receptor. It is shown to act as an endogenous tumor suppressor by reducing cell migration and invasion by mediating its own anti-tumor effect and by antagonizing the pro-malignant effects of nicotine.
Mutations in this gene have been associated with Mal de Meleda, a rare autosomal recessive skin disorder characterized by an inflammatory palmoplantar hyperkeratosis. This is the consequence of a loss of SLURP1 which leads to a dysfunctional epithelial differentiation and an increased secretion of the inflammatory cytokines TNFα, IL1, IL-6, and IL-8.
This gene maps to the same chromosomal region as several members of the Ly6/uPAR family of glycoprotein receptors. | SLURP1
Secreted Ly-6/uPAR-related protein 1 is a protein that in humans is encoded by the SLURP1 gene.[1][2][3] It exerts anti-inflammatory effects and acts as a tumor suppressor and antagonist of nicotine[4].
# Function
The protein encoded by this gene is a member of the Ly6/uPAR family but lacks a GPI-anchoring signal sequence. It is secreted into the blood[2] and binds to the α7-acetylcholine receptor[4]. It is shown to act as an endogenous tumor suppressor by reducing cell migration and invasion by mediating its own anti-tumor effect and by antagonizing the pro-malignant effects of nicotine[4].
Mutations in this gene have been associated with Mal de Meleda, a rare autosomal recessive skin disorder characterized by an inflammatory palmoplantar hyperkeratosis. This is the consequence of a loss of SLURP1 which leads to a dysfunctional epithelial differentiation[5] and an increased secretion of the inflammatory cytokines TNFα, IL1, IL-6, and IL-8[6][7].
This gene maps to the same chromosomal region as several members of the Ly6/uPAR family of glycoprotein receptors.[3] | https://www.wikidoc.org/index.php/SLURP1 | |
bf967133b2daf48e916fdb6678bb76f2a12bde7d | wikidoc | SNAP23 | SNAP23
Synaptosomal-associated protein 23 is a protein that in humans is encoded by the SNAP23 gene. Two alternative transcript variants encoding different protein isoforms have been described for this gene.
# Function
Specificity of vesicular transport is regulated, in part, by the interaction of a vesicle-associated membrane protein termed synaptobrevin/VAMP with a target compartment membrane protein termed syntaxin. These proteins, together with SNAP25 (synaptosome-associated protein of 25 kDa), form a complex which serves as a binding site for the general membrane fusion machinery. Synaptobrevin/VAMP and syntaxin are believed to be involved in vesicular transport in most, if not all cells, while SNAP25 is present almost exclusively in the brain, suggesting that a ubiquitously expressed homolog of SNAP25 exists to facilitate transport vesicle/target membrane fusion in other tissues.
SNAP23 is structurally and functionally similar to SNAP25 and binds tightly to multiple syntaxins and synaptobrevins/VAMPs. It is an essential component of the high affinity receptor for the general membrane fusion machinery and is an important regulator of transport vesicle docking and fusion.
# Clinical significance
In individuals with insulin resistance, SNAP23 is found to be translocated from the plasma membrane to the cytosol where it becomes associated with lipid droplets and is therefore unable to translocate GLUT-4 to the membrane, hindering glucose transport.
# Interactions
SNAP23 has been shown to interact with:
- Cystic fibrosis transmembrane conductance regulator,
- KIF5B,
- NAPA,
- SNAPAP,
- STX11,
- STX1A,
- STX2,
- STX4,
- STX6,
- SYBL1,
- Syntaxin 3,
- VAMP2,
- VAMP3, and
- Vesicle-associated membrane protein 8. | SNAP23
Synaptosomal-associated protein 23 is a protein that in humans is encoded by the SNAP23 gene.[1][2] Two alternative transcript variants encoding different protein isoforms have been described for this gene.
# Function
Specificity of vesicular transport is regulated, in part, by the interaction of a vesicle-associated membrane protein termed synaptobrevin/VAMP with a target compartment membrane protein termed syntaxin. These proteins, together with SNAP25 (synaptosome-associated protein of 25 kDa), form a complex which serves as a binding site for the general membrane fusion machinery. Synaptobrevin/VAMP and syntaxin are believed to be involved in vesicular transport in most, if not all cells, while SNAP25 is present almost exclusively in the brain, suggesting that a ubiquitously expressed homolog of SNAP25 exists to facilitate transport vesicle/target membrane fusion in other tissues.
SNAP23 is structurally and functionally similar to SNAP25 and binds tightly to multiple syntaxins and synaptobrevins/VAMPs. It is an essential component of the high affinity receptor for the general membrane fusion machinery and is an important regulator of transport vesicle docking and fusion.[3]
# Clinical significance
In individuals with insulin resistance, SNAP23 is found to be translocated from the plasma membrane to the cytosol where it becomes associated with lipid droplets and is therefore unable to translocate GLUT-4 to the membrane, hindering glucose transport.
# Interactions
SNAP23 has been shown to interact with:
- Cystic fibrosis transmembrane conductance regulator,[4]
- KIF5B,[5]
- NAPA,[6]
- SNAPAP,[7]
- STX11,[6][8]
- STX1A,[2][9][10][11][12]
- STX2,[2][9][10][11]
- STX4,[2][9][10][11][13][14][12][15]
- STX6,[16]
- SYBL1,[17][18]
- Syntaxin 3,[2][9][11][12]
- VAMP2,[9][13][14]
- VAMP3,[9][13][15] and
- Vesicle-associated membrane protein 8.[9][13] | https://www.wikidoc.org/index.php/SNAP23 | |
088c01892987ed04fe2deccc0d2a66f94897c237 | wikidoc | SNAP25 | SNAP25
Synaptosomal nerve-associated protein 25 (SNAP-25) is a t-SNARE protein that is encoded by the SNAP25 gene in humans. SNAP-25 is a component of the trans-SNARE complex, which is proposed to account for the specificity of membrane fusion and to directly execute fusion by forming a tight complex that brings the synaptic vesicle and plasma membranes together.
# Structure and function
SNAP-25, a Q-SNARE protein, is anchored to the cytosolic face of membranes via palmitoyl side chains covalently bound to cysteine amino acid residues in the middle of the molecule. This means that SNAP-25 does not contain a trans-membrane domain.
SNAP-25 has been identified in contributing two α-helices to the SNARE complex, a four-α-helix domain complex. The SNARE complex participates in vesicle fusion, which involves the docking and merging of a vesicle with the cell membrane to bring about an exocytotic event. Synaptobrevin, a protein that is a part of the vesicle-associated membrane protein (VAMP) family, and syntaxin-1 also help form the SNARE complex by each contributing one α-helix. SNAP-25 assembles with synaptobrevin and syntaxin-1 and the selective binding of these proteins enables vesicle docking and fusion to occur at the correct location.
To form the SNARE complex, synaptobrevin, syntaxin-1, and SNAP-25 associate and begin to wrap around each other to form a coiled coil quaternary structure. The α-helices of both synaptobrevin and syntaxin-1 bind to those of SNAP-25. Synaptobrevin binds the α-helix near SNAP-25's C-terminal side, while syntaxin-1 binds the α-helix near the N-terminus.
SNAP-25 inhibits presynaptic P-, Q-, and L-type voltage-gated calcium channels and interacts with the synaptotagmin C2B domain in Ca2+-independent fashion. In glutamatergic synapses, SNAP-25 decreases the Ca2+ responsiveness, while it is naturally absent in GABAergic synapses.
Two isoforms (mRNA splice variants) of SNAP-25 exist, which are labeled A and B. There are nine amino acid residue differences between the two isoforms, including a re-localization of one of the four cysteine residues. The major characteristics of these two forms are outlined in the table below.
# Clinical significance
Consistent with the regulation of synaptic Ca2+ responsiveness, heterozygous deletion of the SNAP-25 gene in mice results in a hyperactive phenotype similar to attention deficit hyperactivity disorder (ADHD). In heterozygous mice, a decrease in hyperactivity is observed with dextroamphetamine (or Dexedrine), an active ingredient in the ADHD drug Adderall. Homozygous deletions of the SNAP-25 gene are lethal. Subsequent studies have suggested that at least some of the SNAP-25 gene mutations in humans might predispose to ADHD.
A genome wide association study pointed to the rs362584 polymorphism in the gene as possibly associated with the personality trait neuroticism. Botulinum toxins A, C and E cleave SNAP-25, leading to paralysis in clinically developed botulism.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "NicotineDopaminergic_WP1602"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
# Interactions
SNAP-25 has been shown to interact with:
- CPLX1,
- ITSN1,
- KIF5B,
- SNAPAP and
- STX11,
- STX1A,
- STX2,
- STX4,
- SYT1,
- Syntaxin 3,
- TRIM9, and
- VAMP2. | SNAP25
Synaptosomal nerve-associated protein 25 (SNAP-25) is a t-SNARE protein that is encoded by the SNAP25 gene in humans.[1] SNAP-25 is a component of the trans-SNARE complex, which is proposed to account for the specificity of membrane fusion and to directly execute fusion by forming a tight complex that brings the synaptic vesicle and plasma membranes together.[2]
# Structure and function
SNAP-25, a Q-SNARE protein, is anchored to the cytosolic face of membranes via palmitoyl side chains covalently bound to cysteine amino acid residues in the middle of the molecule. This means that SNAP-25 does not contain a trans-membrane domain.[4]
SNAP-25 has been identified in contributing two α-helices to the SNARE complex, a four-α-helix domain complex.[5] The SNARE complex participates in vesicle fusion, which involves the docking and merging of a vesicle with the cell membrane to bring about an exocytotic event. Synaptobrevin, a protein that is a part of the vesicle-associated membrane protein (VAMP) family, and syntaxin-1 also help form the SNARE complex by each contributing one α-helix. SNAP-25 assembles with synaptobrevin and syntaxin-1 and the selective binding of these proteins enables vesicle docking and fusion to occur at the correct location.[6]
To form the SNARE complex, synaptobrevin, syntaxin-1, and SNAP-25 associate and begin to wrap around each other to form a coiled coil quaternary structure. The α-helices of both synaptobrevin and syntaxin-1 bind to those of SNAP-25. Synaptobrevin binds the α-helix near SNAP-25's C-terminal side, while syntaxin-1 binds the α-helix near the N-terminus.[4]
SNAP-25 inhibits presynaptic P-, Q-, and L-type voltage-gated calcium channels[7] and interacts with the synaptotagmin C2B domain in Ca2+-independent fashion.[8] In glutamatergic synapses, SNAP-25 decreases the Ca2+ responsiveness, while it is naturally absent in GABAergic synapses.[9]
Two isoforms (mRNA splice variants) of SNAP-25 exist, which are labeled A and B. There are nine amino acid residue differences between the two isoforms, including a re-localization of one of the four cysteine residues.[10] The major characteristics of these two forms are outlined in the table below.
# Clinical significance
Consistent with the regulation of synaptic Ca2+ responsiveness, heterozygous deletion of the SNAP-25 gene in mice results in a hyperactive phenotype similar to attention deficit hyperactivity disorder (ADHD). In heterozygous mice, a decrease in hyperactivity is observed with dextroamphetamine (or Dexedrine), an active ingredient in the ADHD drug Adderall. Homozygous deletions of the SNAP-25 gene are lethal. Subsequent studies have suggested that at least some of the SNAP-25 gene mutations in humans might predispose to ADHD.[12][13]
A genome wide association study pointed to the rs362584 polymorphism in the gene as possibly associated with the personality trait neuroticism.[14] Botulinum toxins A, C and E cleave SNAP-25,[15] leading to paralysis in clinically developed botulism.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "NicotineDopaminergic_WP1602"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
# Interactions
SNAP-25 has been shown to interact with:
- CPLX1,[16][17]
- ITSN1,[18]
- KIF5B,[19]
- SNAPAP[20] and
- STX11,[21][22]
- STX1A,[16][20][21][23][24][25][26][27][28][29][30]
- STX2,[23][24]
- STX4,[23][24][25][31]
- SYT1,[32][33]
- Syntaxin 3,[23][24][25]
- TRIM9,[29] and
- VAMP2.[16][29][34] | https://www.wikidoc.org/index.php/SNAP25 | |
15167116a754ee835587c649a097276666d189f6 | wikidoc | SNAP29 | SNAP29
Synaptosomal-associated protein 29 is a protein that in humans is encoded by the SNAP29 gene.
# Function
This gene, a member of the SNAP25 gene family, encodes a protein involved in multiple membrane trafficking steps. Two other members of this gene family, SNAP23 and SNAP25, encode proteins that bind a syntaxin protein and mediate synaptic vesicle membrane docking and fusion to the plasma membrane. The protein encoded by this gene binds tightly to multiple syntaxins and is localized to intracellular membrane structures rather than to the plasma membrane. While the protein is mostly membrane-bound, a significant fraction of it is found free in the cytoplasm. Use of multiple polyadenylation sites has been noted for this gene.
# Model organisms
Model organisms have been used in the study of SNAP29 function. A conditional knockout mouse line, called Snap29tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program—a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on mutant mice and two significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no significant abnormalities were observed in these animals.
# Interactions
SNAP29 has been shown to interact with Syntaxin 3 and EHD1. | SNAP29
Synaptosomal-associated protein 29 is a protein that in humans is encoded by the SNAP29 gene.[1][2][3]
# Function
This gene, a member of the SNAP25 gene family, encodes a protein involved in multiple membrane trafficking steps. Two other members of this gene family, SNAP23 and SNAP25, encode proteins that bind a syntaxin protein and mediate synaptic vesicle membrane docking and fusion to the plasma membrane. The protein encoded by this gene binds tightly to multiple syntaxins and is localized to intracellular membrane structures rather than to the plasma membrane. While the protein is mostly membrane-bound, a significant fraction of it is found free in the cytoplasm. Use of multiple polyadenylation sites has been noted for this gene.[3]
# Model organisms
Model organisms have been used in the study of SNAP29 function. A conditional knockout mouse line, called Snap29tm1a(EUCOMM)Wtsi[8][9] was generated as part of the International Knockout Mouse Consortium program—a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[10][11][12]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[6][13] Twenty five tests were carried out on mutant mice and two significant abnormalities were observed.[6] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no significant abnormalities were observed in these animals.[6]
# Interactions
SNAP29 has been shown to interact with Syntaxin 3[1] and EHD1.[14] | https://www.wikidoc.org/index.php/SNAP29 | |
a55f0836a38fcb2ddad863e7d6c582986ea011ae | wikidoc | SNAPAP | SNAPAP
SNARE-associated protein Snapin is a protein that in humans is encoded by the SNAPIN gene.
# Function
SNAPAP is a component of the SNARE complex of proteins that is required for synaptic vesicle docking and fusion. SNAPAP is also a component of the ubiquitously expressed BLOC1 multisubunit protein complex. BLOC1 is required for normal biogenesis of specialized organelles of the endosomal-lysosomal system, such as melanosomes and platelet dense granules.
Snapin has been established to be a promoter of vesicle docking, as it plays a role in binding to SNAP-25, which together stabilize and favor SNARE complex assembly and vesicle docking. Specifically, the degree to which snapin is necessary for proper synaptic release varies across species. The functions of snapin have been reported to be independent of synaptotagmin, and works through the SNAP-25 pathway to stabilize, prime, and dock vesicles.
# Interactions
SNAPAP has been shown to interact with:
- BLOC1S1,
- BLOC1S2,
- Dysbindin,
- PLDN,
- RGS7,
- SNAP-25,
- SNAP23, and
- TRPV1. | SNAPAP
SNARE-associated protein Snapin is a protein that in humans is encoded by the SNAPIN gene.[1][2][3]
# Function
SNAPAP is a component of the SNARE complex of proteins that is required for synaptic vesicle docking and fusion.[1] SNAPAP is also a component of the ubiquitously expressed BLOC1 multisubunit protein complex. BLOC1 is required for normal biogenesis of specialized organelles of the endosomal-lysosomal system, such as melanosomes and platelet dense granules.[3][4]
Snapin has been established to be a promoter of vesicle docking, as it plays a role in binding to SNAP-25, which together stabilize and favor SNARE complex assembly and vesicle docking.[5] Specifically, the degree to which snapin is necessary for proper synaptic release varies across species. The functions of snapin have been reported to be independent of synaptotagmin, and works through the SNAP-25 pathway to stabilize, prime, and dock vesicles.[5]
# Interactions
SNAPAP has been shown to interact with:
- BLOC1S1,[4]
- BLOC1S2,[4]
- Dysbindin,[4]
- PLDN,[4]
- RGS7,[2]
- SNAP-25,[1]
- SNAP23,[6] and
- TRPV1.[7] | https://www.wikidoc.org/index.php/SNAPAP | |
b02b47540a131337f1c89fc502ef97172b01e569 | wikidoc | SNAPC4 | SNAPC4
snRNA-activating protein complex subunit 4 is a protein that in humans is encoded by the SNAPC4 gene.
# Model organisms
Model organisms have been used in the study of SNAPC4 function. A conditional knockout mouse line, called Snapc4tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty six tests were carried out on mutant mice and two significant abnormalities were observed. No homozygous mutant embryos were recorded during gestation and, in a separate study, no homozygous animals were observed at weaning. The remaining tests were carried out on adult heterozygous mutant animals and no further abnormalities were observed.
# Interactions
SNAPC4 has been shown to interact with SNAPC1, POU2F1 and SNAPC2. | SNAPC4
snRNA-activating protein complex subunit 4 is a protein that in humans is encoded by the SNAPC4 gene.[1][2]
# Model organisms
Model organisms have been used in the study of SNAPC4 function. A conditional knockout mouse line, called Snapc4tm1a(KOMP)Wtsi[7][8] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[9][10][11]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[5][12] Twenty six tests were carried out on mutant mice and two significant abnormalities were observed. No homozygous mutant embryos were recorded during gestation and, in a separate study, no homozygous animals were observed at weaning. The remaining tests were carried out on adult heterozygous mutant animals and no further abnormalities were observed.[5]
# Interactions
SNAPC4 has been shown to interact with SNAPC1,[13] POU2F1[1][14] and SNAPC2.[1][13] | https://www.wikidoc.org/index.php/SNAPC4 | |
385cb6cbcd407a871a1cd71de245d7c18173a33d | wikidoc | SNC-80 | SNC-80
SNC-80 is an opioid analgesic drug used in scientific research. It was invented in 1994.
SNC-80 was the first non-peptide drug developed that is a highly selective agonist for the δ-opioid receptor.
It has been shown to produce useful analgesic, antidepressant and anxiolytic effects in animal studies, but its usefulness is limited by producing convulsions at high doses, and so SNC-80 is not used medically, although it is a useful drug in scientific research. | SNC-80
SNC-80 is an opioid analgesic drug used in scientific research.[1] It was invented in 1994.[2]
SNC-80 was the first non-peptide drug developed that is a highly selective agonist for the δ-opioid receptor.[3][4]
It has been shown to produce useful analgesic,[5] antidepressant[6] and anxiolytic effects in animal studies,[7][8] but its usefulness is limited by producing convulsions at high doses,[9] and so SNC-80 is not used medically, although it is a useful drug in scientific research.
Template:Pharm-stub | https://www.wikidoc.org/index.php/SNC-80 | |
d6ad7d5e8e4eecfaffe4e5c43dc56c5155f85702 | wikidoc | SNCAIP | SNCAIP
Synphilin-1 is a protein that in humans is encoded by the SNCAIP gene. SNCAIP stands for "synuclein, alpha interacting protein" and can be signified by SNCAP_HUMAN, synphilin 1, synuclein, alpha interacting protein (synphilin), and SYPH1.
# Function
This gene encodes a protein containing several protein-protein interaction domains, including ankyrin-like repeats, a coiled-coil domain, and an ATP/GTP-binding motif. The encoded protein interacts with alpha-synuclein in neuronal tissue and may play a role in the formation of cytoplasmic inclusions and neurodegeneration. A mutation in this gene has been associated with Parkinson's disease. Alternatively spliced transcript variants encoding different isoforms of this gene have been described, but their full-length nature has yet to be determined.
The SNCAIP gene provides instructions for making a protein called synphilin-1 and a slightly different version of this protein called synphilin-1A. These proteins are produced in the brain. They are usually located in specialized structures called presynaptic terminals, found at the tips of nerve cells. In nerve cells, synphilin-1 and synphilin-1A interact with another protein called alpha-synuclein. The functions of synphilin-1 and synphilin-1A, however, are unknown.
# Interactions
SNCAIP has been shown to interact with:
- Alpha-synuclein and
- Parkin (ligase). | SNCAIP
Synphilin-1 is a protein that in humans is encoded by the SNCAIP gene.[1][2] SNCAIP stands for "synuclein, alpha interacting protein" and can be signified by SNCAP_HUMAN, synphilin 1, synuclein, alpha interacting protein (synphilin), and SYPH1.
# Function
This gene encodes a protein containing several protein-protein interaction domains, including ankyrin-like repeats, a coiled-coil domain, and an ATP/GTP-binding motif. The encoded protein interacts with alpha-synuclein in neuronal tissue and may play a role in the formation of cytoplasmic inclusions and neurodegeneration. A mutation in this gene has been associated with Parkinson's disease. Alternatively spliced transcript variants encoding different isoforms of this gene have been described, but their full-length nature has yet to be determined.[2]
The SNCAIP gene provides instructions for making a protein called synphilin-1 and a slightly different version of this protein called synphilin-1A. These proteins are produced in the brain. They are usually located in specialized structures called presynaptic terminals, found at the tips of nerve cells. In nerve cells, synphilin-1 and synphilin-1A interact with another protein called alpha-synuclein. The functions of synphilin-1 and synphilin-1A, however, are unknown.
# Interactions
SNCAIP has been shown to interact with:
- Alpha-synuclein[1][3][4][5] and
- Parkin (ligase).[6] | https://www.wikidoc.org/index.php/SNCAIP | |
82f4c4ff9bfe61d5ef19be738ef8907216a5b861 | wikidoc | SORBS1 | SORBS1
CAP/Ponsin protein, also known as Sorbin and SH3 domain-containing protein 1 is a protein that in humans is encoded by the SORBS1 gene. CAP/Ponsin is part of a small family of adaptor proteins that regulate cell adhesion, growth factor signaling and cytoskeletal formation. CAP/Ponsin is mainly expressed in heart, skeletal muscle, liver, adipose tissue, and macrophages; in striated muscle tissue, CAP/Ponsin is localized to costamere structures.
# Structure
CAP/Ponsin may exist as thirteen alternatively-spliced isoforms, ranging from 81 kDa to 142 kDa. CAP/Ponsin is part of an adaptor protein family, of which ArgBP2 and vinexin are also a part. These proteins contain a conserved sorbin homology (SOHO) domain and three SH3 domains, and CAP/Ponsin is expressed in heart, skeletal muscle, liver, adipose tissue, and macrophages.
# Function
In muscle, CAP/Ponsin plays a role in the formation of mature costameres from focal adhesion-like contacts during assembly of the contractile apparatus, as overexpression of CAP/Ponsin disrupted normal cell-matrix contact morphology. In a mouse model of viral myocarditis due to Coxsackievirus infection, CAP/Ponsin stabilized antiviral type I interferon production and was protective against apoptosis and cytotoxicity. CAP/Ponsin has also been shown to be a major regulator of insulin-stimulated signaling and regulation of glucose uptake, by potentiating insulin-induced phosphorylation and recruitment of CBL to a lipid raft signaling complex involving flotillin. A role for CAP/Ponsin in macrophage function was illuminated by the finding that mice harboring SORBS1-deficient macrophages in bone marrow was protective against high-fat diet-induced insulin resistance and showed reduced inflammation. In non-muscle cells, CAP/Ponsin inhibits cell spreading and focal adhesion turnover, as its siRNA-mediated knockdown resulted in enhanced PAK/MEK/ERK activation and cell migration.
# Clinical Significance
CAP/Ponsin was demonstrated to be down-regulated in end-stage heart failure patients; an effect that was restored upon mechanical unloading. A single nucleotide polymorphism in SORBS1 was found to be associated with type 2 diabetes and obesity.
# Interactions
SORBS1 has been shown to interact with:
- CBL,
- FLOT1,
- INPPL1,
- INSM1,
- MLLT4,
- PXN, and
- Vinculin. | SORBS1
CAP/Ponsin protein, also known as Sorbin and SH3 domain-containing protein 1 is a protein that in humans is encoded by the SORBS1 gene.[1][2][3] CAP/Ponsin is part of a small family of adaptor proteins that regulate cell adhesion, growth factor signaling and cytoskeletal formation. CAP/Ponsin is mainly expressed in heart, skeletal muscle, liver, adipose tissue, and macrophages; in striated muscle tissue, CAP/Ponsin is localized to costamere structures.
# Structure
CAP/Ponsin may exist as thirteen alternatively-spliced isoforms, ranging from 81 kDa to 142 kDa.[4] CAP/Ponsin is part of an adaptor protein family, of which ArgBP2 and vinexin are also a part.[5] These proteins contain a conserved sorbin homology (SOHO) domain and three SH3 domains, and CAP/Ponsin is expressed in heart, skeletal muscle, liver, adipose tissue, and macrophages.[4][6][7]
# Function
In muscle, CAP/Ponsin plays a role in the formation of mature costameres from focal adhesion-like contacts during assembly of the contractile apparatus, as overexpression of CAP/Ponsin disrupted normal cell-matrix contact morphology.[8] In a mouse model of viral myocarditis due to Coxsackievirus infection, CAP/Ponsin stabilized antiviral type I interferon production and was protective against apoptosis and cytotoxicity.[9] CAP/Ponsin has also been shown to be a major regulator of insulin-stimulated signaling and regulation of glucose uptake, by potentiating insulin-induced phosphorylation and recruitment of CBL to a lipid raft signaling complex involving flotillin.[10] A role for CAP/Ponsin in macrophage function was illuminated by the finding that mice harboring SORBS1-deficient macrophages in bone marrow was protective against high-fat diet-induced insulin resistance and showed reduced inflammation.[7] In non-muscle cells, CAP/Ponsin inhibits cell spreading and focal adhesion turnover, as its siRNA-mediated knockdown resulted in enhanced PAK/MEK/ERK activation and cell migration.[11]
# Clinical Significance
CAP/Ponsin was demonstrated to be down-regulated in end-stage heart failure patients; an effect that was restored upon mechanical unloading.[8] A single nucleotide polymorphism in SORBS1 was found to be associated with type 2 diabetes and obesity.[12]
# Interactions
SORBS1 has been shown to interact with:
- CBL,[13][14]
- FLOT1,[2][13][15]
- INPPL1,[14]
- INSM1,[16]
- MLLT4,[1]
- PXN,[8] and
- Vinculin.[1] | https://www.wikidoc.org/index.php/SORBS1 | |
cb7d4f745e230541cb334673a36fd4bb1d8afbda | wikidoc | SORBS2 | SORBS2
ArgBP2 protein, also referred to as Sorbin and SH3 domain-containing protein 2 is a protein that in humans is encoded by the SORBS2 gene. ArgBP2 belongs to the a small family of adaptor proteins having sorbin homology (SOHO) domains. ArgBP2 is highly abundant in cardiac muscle cells at sarcomeric Z-disc structures, and is expressed in other cells at actin stress fibers and the nucleus.
# Structure
ArgBP2 may exist in as many as 9 unique isoforms ranging from 52 kDa to 117 kDa (492 to 1100 amino acids). ArgBP2 belongs to the a small family of adaptor proteins having sorbin homology (SOHO) domains and three SH3 domains, which regulate cell adhesion, cytoskeletal organization and growth factor signaling; other members include CAP/ponsin and vinexin. The three SH3 domains are C-terminal, a serine-threonine rich domain resides in the middle, and the sorbin homology (SoHo) domain is N-terminal. The SH3 domains interact with Arg/Abl, vinculin. The SOHO domain interacts with flotillin found in lipid rafts.
# Function
The subcellular localization of this protein in epithelial and cardiac muscle cells suggests that ArgBP2 functions as an adapter protein to assemble signaling complexes in stress fibers, and that it is a potential link between Abl family kinases and the actin cytoskeleton. ArgBP2 contains several potential Abl phosphorylation sites; Arg and c-Abl represent the mammalian members of the Abelson family of non-receptor protein-tyrosine kinases. In non-muscle cells, ArgBP2 bids Cbl which enhances the degradation of c-Abl; and also Pyk2 which promotes cytoskeletal remodeling. ArgBP2 binding with flotillin at lipid rafts may indicate a role for ArgBP2 in vesicle trafficking and signal transduction. flotillin in skeletal muscle cells exhibits a striated pattern suggesting localization to T-tubules or sarcoplasmic reticular cisternae, though no precise role has been determined in cardiac cells. In cardiac muscle cells, pull-down experiments discovered ArgBP2 in complex with alpha actinin-2, vinculin, spectrin, paxillin, Pyk2 and flotillin, suggesting that ArgBP2 may be involved in myofibril assembly and Z-band signaling in cardiomyocytes, though functional studies are necessary to elucidate specific mechanisms. ArgBP2 has been linked to hyertrophic signaling, as a potent paracrine-acting RNA molecule shown to induce cardiac hypertrophy in mice, miR-21, acts on both ArgBP2 and PDLIM5 to trigger the hypertrophic response.
# Clinical Significance
Elevated levels of serum ArgBP2 and coordinate decreases in ArgBP2 in myocardial tissue were detected in the very early phase from patients post-myocardial infarction who died within 7 hours of the insult. Chromosome 4 pericentric inversion has been observed in 10 patients, with associated cardiac defects linked to terminal 4q35.1 deletions, which may affect SORBS2.
# Interactions
ArgBP2 has been shown to interact with:
- ABL,
- ABL2,
- ACTC1,
- CBL,
- FLOT1,
- PTK2B,
- PLDN, and
- VCL. | SORBS2
ArgBP2 protein, also referred to as Sorbin and SH3 domain-containing protein 2 is a protein that in humans is encoded by the SORBS2 gene.[1][2] ArgBP2 belongs to the a small family of adaptor proteins having sorbin homology (SOHO) domains. ArgBP2 is highly abundant in cardiac muscle cells at sarcomeric Z-disc structures, and is expressed in other cells at actin stress fibers and the nucleus.
# Structure
ArgBP2 may exist in as many as 9 unique isoforms ranging from 52 kDa to 117 kDa (492 to 1100 amino acids).[2] ArgBP2 belongs to the a small family of adaptor proteins having sorbin homology (SOHO) domains and three SH3 domains, which regulate cell adhesion, cytoskeletal organization and growth factor signaling; other members include CAP/ponsin and vinexin.[3] The three SH3 domains are C-terminal, a serine-threonine rich domain[4] resides in the middle, and the sorbin homology (SoHo) domain is N-terminal. The SH3 domains interact with Arg/Abl, vinculin.[3] The SOHO domain interacts with flotillin found in lipid rafts.[5]
# Function
The subcellular localization of this protein in epithelial and cardiac muscle cells suggests that ArgBP2 functions as an adapter protein to assemble signaling complexes in stress fibers, and that it is a potential link between Abl family kinases and the actin cytoskeleton. ArgBP2 contains several potential Abl phosphorylation sites;[4] Arg and c-Abl represent the mammalian members of the Abelson family of non-receptor protein-tyrosine kinases. In non-muscle cells, ArgBP2 bids Cbl which enhances the degradation of c-Abl;[6] and also Pyk2 which promotes cytoskeletal remodeling.[7] ArgBP2 binding with flotillin at lipid rafts may indicate a role for ArgBP2 in vesicle trafficking and signal transduction. flotillin in skeletal muscle cells exhibits a striated pattern[8] suggesting localization to T-tubules or sarcoplasmic reticular cisternae, though no precise role has been determined in cardiac cells. In cardiac muscle cells, pull-down experiments discovered ArgBP2 in complex with alpha actinin-2, vinculin, spectrin, paxillin, Pyk2 and flotillin, suggesting that ArgBP2 may be involved in myofibril assembly and Z-band signaling in cardiomyocytes,[9] though functional studies are necessary to elucidate specific mechanisms. ArgBP2 has been linked to hyertrophic signaling, as a potent paracrine-acting RNA molecule shown to induce cardiac hypertrophy in mice, miR-21, acts on both ArgBP2 and PDLIM5 to trigger the hypertrophic response.[10]
# Clinical Significance
Elevated levels of serum ArgBP2 and coordinate decreases in ArgBP2 in myocardial tissue were detected in the very early phase from patients post-myocardial infarction who died within 7 hours of the insult.[11] Chromosome 4 pericentric inversion has been observed in 10 patients, with associated cardiac defects linked to terminal 4q35.1 deletions, which may affect SORBS2.[12]
# Interactions
ArgBP2 has been shown to interact with:
- ABL,[1][13]
- ABL2,[1]
- ACTC1,[9][14]
- CBL,[13][15]
- FLOT1,[16]
- PTK2B,[15]
- PLDN,[17] and
- VCL.[9][18] | https://www.wikidoc.org/index.php/SORBS2 | |
e984f2786c3337f8d9eeb48972ed57c5a5883d2d | wikidoc | SPATS1 | SPATS1
Spermatogenesis associated serine rich 1 (SPATS1) is a protein which in humans is encoded by the SPATS1 gene. It is also known by the aliases Dishevelled-DEP domain interacting protein (DDIP), Spermatogenesis Associated 8 (SPATA8), and serin-rich spermatogenic protein 1 (SRSP1). A general idea of its chemical structure, subcellular localization, expression, and conservation is known. Research suggests SPATS1 may play a role in the canonical Wnt Signaling pathway and in the first spermatogenic wave.
# Gene
The human SPATS1 gene contains 1150 nucleotides, coding for 300 amino acids. It's located on the positive strand of chromosome 6 in the 21p1 region. As of now there are no known single nucleotide polymorphisms (SNPs) that prove to be clinically significant.
# Protein
## Structure
The protein in its longest form has 8 exons. There is another possible isoform, but experimental confirmation is lacking – possibly due to it being produced at low levels because of an immature stop codon. Bioinformatic analysis suggests that the protein does not have transmembrane structure and is composed of both alpha helixes and beta sheets. There have been conflicting numbers for SPATS1 isoelectric points. Several sources have said 6.68, while two others suggested that it is higher, 7.04 and 7.47.
## Subcellular location
Studies have suggested that most of the expression is found in the cytoplasm of the cell, but there is also evidence of expression in the nucleus. Expression in the nucleus may be supported by the fact that the rat homolog of the SPATS1 gene was experimentally found to have a probable bipartite nuclear localization signal. In addition, bioinformatic tools have identified a bipartite nuclear localization signal with high probability in the human protein at amino acids 174 - 191.
## Post-translational modifications
Bioinformatic analysis suggests that it undergoes several post-transnational modifications. The more plausible ones propose a GPI – modification site at amino acid 280, N-glycosylation sites at amino acids 49 and 229, and a phosphorylation site at amino acid 113. There are 85 predicted sites of phosphorylation, 23 having an 80% or higher likelihood. Only the one located at amino acid 113 has been experimentally confirmed. There is also a high probability of a SASRP1 motif that spans amino acids 51 - 288.
## Protein interactions
Possible interacting proteins are listed in the table below. Note that these proteins have not been experimentally confirmed to interact with SPATS1. Instead, their interaction potential was determined by looking
at concurrence patterns and textmining.
# Expression
## Regulation
The expression of this protein has been found to greatly decline in adulthood, compared to expression levels measured in fetuses. Studies have shown some fluctuation during the gestation period, but overall remaining relatively high. There has also been evidence of high expression levels up until day 28 postpartum.
## Location
Expression of this protein has been found in peritubular myoid cells, gonocytes, pachytene spermatocytes, spermatogonia, myoid cells, and Sertoli cells.
Mouse brains have shown expression in various areas of the brain including the pituitary gland, the prefrontal coretx, the frontal lobe, the cerebellum, and the pariatal lobe. Highest expression levels have been found in the testes, the next highest levels being found in the trachea. A protein abundance histogram, which compares the abundance of a desired protein to other proteins, shows that SPATS1 is on the lower level of expression.
# Function
The specific function of SPATS1 is still being studied. Research has indicated that it may play a role in initiation of the first spermatogenic wave as well as the first male meiotic division. Another study suggests that it acts as a negative regulator in the canonical Wnt signaling pathway. Several microaary studies have studied the effects of knocking out different proteins and enzymes and the resulting effects on SPATS1 expression. Epigentic factors, specifically histone methylation, have also been looked at. The effects of knockout on phenotypes have also been done in several studies.
# Conservation
SPATS1 protein is conserved in species as early as Oxytricha trifallax. No orthologues have been found for this protein in archaea or bacteria. Nor have orthologs been found in birds. There is a high level of conservation among mammals and other close orthologs in the coding region. There is conservation among distant orthologs in non-coding regions, including the promoter, 5' UTR, and 3' UTR. These convservations are kept through either the same nucleotide, or a chemically similar nucleotide. Below is a table of orthologs along with the percent similarity and their date of divergence. | SPATS1
Spermatogenesis associated serine rich 1 (SPATS1) is a protein which in humans is encoded by the SPATS1 gene. It is also known by the aliases Dishevelled-DEP domain interacting protein (DDIP), Spermatogenesis Associated 8 (SPATA8), and serin-rich spermatogenic protein 1 (SRSP1).[1] A general idea of its chemical structure, subcellular localization, expression, and conservation is known. Research suggests SPATS1 may play a role in the canonical Wnt Signaling pathway and in the first spermatogenic wave.
# Gene
The human SPATS1 gene contains 1150 nucleotides, coding for 300 amino acids. It's located on the positive strand of chromosome 6 in the 21p1 region.[1] As of now there are no known single nucleotide polymorphisms (SNPs) that prove to be clinically significant.[2]
# Protein
## Structure
The protein in its longest form has 8 exons. There is another possible isoform, but experimental confirmation is lacking – possibly due to it being produced at low levels because of an immature stop codon.[3] Bioinformatic analysis suggests that the protein does not have transmembrane structure and is composed of both alpha helixes and beta sheets. There have been conflicting numbers for SPATS1 isoelectric points. Several sources have said 6.68, while two others suggested that it is higher, 7.04 and 7.47.[4][5][6]
## Subcellular location
Studies have suggested that most of the expression is found in the cytoplasm of the cell, but there is also evidence of expression in the nucleus.[7] Expression in the nucleus may be supported by the fact that the rat homolog of the SPATS1 gene was experimentally found to have a probable bipartite nuclear localization signal.[8] In addition, bioinformatic tools have identified a bipartite nuclear localization signal with high probability in the human protein at amino acids 174 - 191.[9]
## Post-translational modifications
Bioinformatic analysis suggests that it undergoes several post-transnational modifications. The more plausible ones propose a GPI – modification site at amino acid 280, N-glycosylation sites at amino acids 49 and 229, and a phosphorylation site at amino acid 113. There are 85 predicted sites of phosphorylation, 23 having an 80% or higher likelihood.[10] Only the one located at amino acid 113 has been experimentally confirmed.[1] There is also a high probability of a SASRP1 motif that spans amino acids 51 - 288.[11]
## Protein interactions
Possible interacting proteins are listed in the table below. Note that these proteins have not been experimentally confirmed to interact with SPATS1. Instead, their interaction potential was determined by looking
at concurrence patterns and textmining.[12]
# Expression
## Regulation
The expression of this protein has been found to greatly decline in adulthood, compared to expression levels measured in fetuses.[7] Studies have shown some fluctuation during the gestation period, but overall remaining relatively high. There has also been evidence of high expression levels up until day 28 postpartum.[13]
## Location
Expression of this protein has been found in peritubular myoid cells, gonocytes, pachytene spermatocytes, spermatogonia, myoid cells, and Sertoli cells.[7]
Mouse brains have shown expression in various areas of the brain including the pituitary gland, the prefrontal coretx, the frontal lobe, the cerebellum, and the pariatal lobe.[14] Highest expression levels have been found in the testes, the next highest levels being found in the trachea. A protein abundance histogram, which compares the abundance of a desired protein to other proteins, shows that SPATS1 is on the lower level of expression.[1]
# Function
The specific function of SPATS1 is still being studied. Research has indicated that it may play a role in initiation of the first spermatogenic wave as well as the first male meiotic division.[7] Another study suggests that it acts as a negative regulator in the canonical Wnt signaling pathway.[8] Several microaary studies have studied the effects of knocking out different proteins and enzymes and the resulting effects on SPATS1 expression. Epigentic factors, specifically histone methylation, have also been looked at. The effects of knockout on phenotypes have also been done in several studies.[1]
# Conservation
SPATS1 protein is conserved in species as early as Oxytricha trifallax. No orthologues have been found for this protein in archaea or bacteria. Nor have orthologs been found in birds.[15] There is a high level of conservation among mammals and other close orthologs in the coding region. There is conservation among distant orthologs in non-coding regions, including the promoter, 5' UTR, and 3' UTR. These convservations are kept through either the same nucleotide, or a chemically similar nucleotide.[16] Below is a table of orthologs along with the percent similarity and their date of divergence.[15][17] | https://www.wikidoc.org/index.php/SPATS1 | |
353d81d7843a2bb5ffabb7e5064417ed8cf41d9c | wikidoc | SPRED1 | SPRED1
Sprouty-related, EVH1 domain-containing protein 1 (Spread-1) is a protein that in humans is encoded by the SPRED1 gene located on chromosome 15q13.2 and has seven coding exons.
# Function
Spread-1 is a member of the Sprouty family of proteins and is phosphorylated by tyrosine kinase in response to several growth factors. The encoded protein can act as a homodimer or as a heterodimer with SPRED2 to regulate activation of the MAP kinase cascade.
# Clinical associations
Defects in this gene are a cause of neurofibromatosis type 1-like syndrome (NFLS).
Mutations in this gene are associated with
- Legius syndrome.
- Childhood leukemia
# Mutations
The following mutations have been observed:
- An exon 3 c.46C>T mutation leading to p.Arg16Stop. This mutation may result in a truncated nonfunctional protein. Blast cells analysis displayed the same abnormality as germline mutation with one mutated allele (no somatic SPRED1 single-point mutation or loss of heterozygosity was found). The M4/M5 phenotype of AML are most closely associated with Ras pathway mutations. Ras pathway mutations are also associated with monosomy 7.
- 3 Nonsense (R16X, E73X, R262X)
- 2 Frameshift (c.1048_c1049 delGG, c.149_1152del 4 bp)
- Missense (V44D)
- p.R18X and p.Q194X with phenotype altered pigmentation without tumoriginesis.
# Disease Database
SPRED1 gene variant database | SPRED1
Sprouty-related, EVH1 domain-containing protein 1 (Spread-1) is a protein that in humans is encoded by the SPRED1 gene located on chromosome 15q13.2 and has seven coding exons.[1]
# Function
Spread-1 is a member of the Sprouty family of proteins and is phosphorylated by tyrosine kinase in response to several growth factors. The encoded protein can act as a homodimer or as a heterodimer with SPRED2 to regulate activation of the MAP kinase cascade.[1]
# Clinical associations
Defects in this gene are a cause of neurofibromatosis type 1-like syndrome (NFLS).[1]
Mutations in this gene are associated with
- Legius syndrome.[2][3]
- Childhood leukemia[4]
# Mutations
The following mutations have been observed:
- An exon 3 c.46C>T mutation leading to p.Arg16Stop.[4] This mutation may result in a truncated nonfunctional protein. Blast cells analysis displayed the same abnormality as germline mutation with one mutated allele (no somatic SPRED1 single-point mutation or loss of heterozygosity was found). The M4/M5 phenotype of AML are most closely associated with Ras pathway mutations. Ras pathway mutations are also associated with monosomy 7.
- 3 Nonsense (R16X, E73X, R262X)[5]
- 2 Frameshift (c.1048_c1049 delGG, c.149_1152del 4 bp)[5]
- Missense (V44D)[5]
- p.R18X and p.Q194X with phenotype altered pigmentation without tumoriginesis.[6]
# Disease Database
SPRED1 gene variant database | https://www.wikidoc.org/index.php/SPRED1 | |
21e3223a4e408d10e93b654984f9c84048d34540 | wikidoc | SPTAN1 | SPTAN1
Alpha II-spectrin, also known as Spectrin alpha chain, brain is a protein that in humans is encoded by the SPTAN1 gene. Alpha II-spectrin is expressed in a variety of tissues, and is highly expressed in cardiac muscle at Z-disc structures, costameres and at the sarcolemma membrane. Mutations in alpha II-spectrin have been associated with early infantile epileptic encephalopathy-5, and alpha II-spectrin may be a valuable biomarker for Guillain–Barré syndrome and infantile congenital heart disease.
# Structure
Alternate splicing of alpha II-spectrin has been documented and results in multiple transcript variants; specifically, cardiomyocytes have four identified alpha II-spectrin splice variants. As opposed to alpha I-spectrin that is principally found in erythrocytes, alpha II-spectrin is expressed in most tissues. In cardiac tissue, alpha II-spectrin is found in myocytes at Z-discs, costameres, and the sarcolemma membrane, and in cardiac fibroblasts along the surface of the cytoskeletal network. Alpha II-spectrin most commonly exists in a heterodimer with alpha II and beta II spectrin subunits; and dimers typically self-associate and heterotetramerize.
# Function
The spectrins are a family of widely distributed cytoskeletal proteins which are involved in actin crosslinking, cell adhesion, intercellular communication and cell cycle regulation. Though a role in cardiac muscle is not well understood, it is likely that alpha II-spectrin is involved in organizing sub-sarcolemmal domains and stabilizing sarcolemmal membranes against the stresses associated with continuous cardiac contraction. Functional diversity of alpha II-spectrin is manifest through its four splice variants. First, a cardiac-specific, 21 amino acid sequence insert in the 21st spectrin repeat, termed alpha II-cardi+, was identified as an insert that modulates affinity of alpha II-spectrin for binding beta-spectrins and regulates myocyte growth and differentiation. Secondly, another insert of 20 amino acids in the 10th spectrin repeat, termed SH3i+, contains protein kinase A and protein kinase C phosphorylation sites and modulates Ca2+-dependent cleavage of spectrin and protein-protein interaction properties. Thirdly, an insert of five amino acids in the fifteenth spectrin motif bears a highly antigenic epitope resembling an ankyrin-like p53 binding protein binding site. Fourthly, a six amino acid insert in the twenty-first spectrin motif with unknown function has been reported.
Alpha II-spectrin gene expression has been shown to be upregulated in cardiac fibroblasts in response to Angiotensin II-induced cardiac remodeling.
In animal models of disease and injury, alpha II-spectrin has been implicated in diverse functions. In a canine model of hypothermic circulatory arrest, alpha II-spectrin breakdown products have shown to be relevant markers of neurologic injury post-cardiac surgery.
# Clinical significance
Mutations in SPTAN1 are the cause of early infantile epileptic encephalopathy-5.
Alpha II-spectrin has shown promising utility as a biomarker for brain necrosis and apoptosis in infants with congenital heart disease; breakdown products of alpha II-spectrin have been detected in the serum of neonates in the perioperative period and following open-heart surgery. Elevated protein expression of alpha II-spectrin has been detected in cerebrospinal fluid in patients with Guillain–Barré syndrome.
# Interactions
SPTAN1 has been shown to interact with:
- Abl gene,
- FANCA,
- Fanconi anemia, complementation group C,
- GRIA2,
- Plectin,
- SHANK1, and
- Vimentin. | SPTAN1
Alpha II-spectrin, also known as Spectrin alpha chain, brain is a protein that in humans is encoded by the SPTAN1 gene.[1][2][3] Alpha II-spectrin is expressed in a variety of tissues, and is highly expressed in cardiac muscle at Z-disc structures, costameres and at the sarcolemma membrane. Mutations in alpha II-spectrin have been associated with early infantile epileptic encephalopathy-5, and alpha II-spectrin may be a valuable biomarker for Guillain–Barré syndrome and infantile congenital heart disease.
# Structure
Alternate splicing of alpha II-spectrin has been documented and results in multiple transcript variants; specifically, cardiomyocytes have four identified alpha II-spectrin splice variants.[4][5] As opposed to alpha I-spectrin that is principally found in erythrocytes,[6] alpha II-spectrin is expressed in most tissues. In cardiac tissue, alpha II-spectrin is found in myocytes at Z-discs, costameres, and the sarcolemma membrane,[7][8][9] and in cardiac fibroblasts along the surface of the cytoskeletal network.[10] Alpha II-spectrin most commonly exists in a heterodimer with alpha II and beta II spectrin subunits; and dimers typically self-associate and heterotetramerize.[1][11][12]
# Function
The spectrins are a family of widely distributed cytoskeletal proteins which are involved in actin crosslinking, cell adhesion, intercellular communication and cell cycle regulation.[13][14][15] Though a role in cardiac muscle is not well understood, it is likely that alpha II-spectrin is involved in organizing sub-sarcolemmal domains and stabilizing sarcolemmal membranes against the stresses associated with continuous cardiac contraction.[12] Functional diversity of alpha II-spectrin is manifest through its four splice variants. First, a cardiac-specific, 21 amino acid sequence insert in the 21st spectrin repeat, termed alpha II-cardi+, was identified as an insert that modulates affinity of alpha II-spectrin for binding beta-spectrins and regulates myocyte growth and differentiation.[4] Secondly, another insert of 20 amino acids in the 10th spectrin repeat, termed SH3i+, contains protein kinase A and protein kinase C phosphorylation sites and modulates Ca2+-dependent cleavage of spectrin and protein-protein interaction properties.[16] Thirdly, an insert of five amino acids in the fifteenth spectrin motif bears a highly antigenic epitope resembling an ankyrin-like p53 binding protein binding site.[4][17] Fourthly, a six amino acid insert in the twenty-first spectrin motif with unknown function has been reported.[7][18]
Alpha II-spectrin gene expression has been shown to be upregulated in cardiac fibroblasts in response to Angiotensin II-induced cardiac remodeling.[19]
In animal models of disease and injury, alpha II-spectrin has been implicated in diverse functions. In a canine model of hypothermic circulatory arrest, alpha II-spectrin breakdown products have shown to be relevant markers of neurologic injury post-cardiac surgery.[20]
# Clinical significance
Mutations in SPTAN1 are the cause of early infantile epileptic encephalopathy-5.[21]
Alpha II-spectrin has shown promising utility as a biomarker for brain necrosis and apoptosis in infants with congenital heart disease; breakdown products of alpha II-spectrin have been detected in the serum of neonates in the perioperative period and following open-heart surgery.[22] Elevated protein expression of alpha II-spectrin has been detected in cerebrospinal fluid in patients with Guillain–Barré syndrome.[23]
# Interactions
SPTAN1 has been shown to interact with:
- Abl gene,[24]
- FANCA,[25][26][27]
- Fanconi anemia, complementation group C,[25][26]
- GRIA2,[28]
- Plectin,[29][30]
- SHANK1,[31] and
- Vimentin.[29] | https://www.wikidoc.org/index.php/SPTAN1 | |
b47d9fb3371aaa8ee15055edc591dacba1afab50 | wikidoc | SPTBN1 | SPTBN1
Spectrin beta chain, brain 1 is a protein that in humans is encoded by the SPTBN1 gene.
# Function
Spectrin is an actin crosslinking and molecular scaffold protein that links the plasma membrane to the actin cytoskeleton, and functions in the determination of cell shape, arrangement of transmembrane proteins, and organization of organelles. It is composed of two antiparallel dimers of alpha- and beta- subunits. This gene is one member of a family of beta-spectrin genes. The encoded protein contains an N-terminal actin-binding domain, and 17 spectrin repeats that are involved in dimer formation. Multiple transcript variants encoding different isoforms have been found for this gene.
# Interactions
SPTBN1 has been shown to interact with Merlin.
# Model organisms
Model organisms have been used in the study of spectrin function. A conditional knockout mouse line, called Spnb2tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty seven tests were carried out on mutant mice and four significant abnormalities were observed. Few homozygous mutant embryos were identified during gestation and those that were present displayed oedema. None survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice. These animals had a decreased length of long bones, while males also displayed hypoalbuminemia . | SPTBN1
Spectrin beta chain, brain 1 is a protein that in humans is encoded by the SPTBN1 gene.[1]
# Function
Spectrin is an actin crosslinking and molecular scaffold protein that links the plasma membrane to the actin cytoskeleton, and functions in the determination of cell shape, arrangement of transmembrane proteins, and organization of organelles. It is composed of two antiparallel dimers of alpha- and beta- subunits. This gene is one member of a family of beta-spectrin genes. The encoded protein contains an N-terminal actin-binding domain, and 17 spectrin repeats that are involved in dimer formation. Multiple transcript variants encoding different isoforms have been found for this gene.[1]
# Interactions
SPTBN1 has been shown to interact with Merlin.[2]
# Model organisms
Model organisms have been used in the study of spectrin function. A conditional knockout mouse line, called Spnb2tm1a(EUCOMM)Wtsi[8][9] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[10][11][12]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[6][13] Twenty seven tests were carried out on mutant mice and four significant abnormalities were observed.[6] Few homozygous mutant embryos were identified during gestation and those that were present displayed oedema. None survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice. These animals had a decreased length of long bones, while males also displayed hypoalbuminemia .[6] | https://www.wikidoc.org/index.php/SPTBN1 | |
13b86df57a805de0c87d26fde1d08833d5b94fd0 | wikidoc | SRD5A1 | SRD5A1
3-oxo-5α-steroid 4-dehydrogenase 1 is an enzyme that in humans is encoded by the SRD5A1 gene. It is one of three forms of 5α-reductase.
Steroid 5α-reductase (EC 1.3.99.5) catalyzes the conversion of testosterone into the more potent androgen, dihydrotestosterone (DHT). There are 3 isoforms of the enzyme: SRD5A1, SRD5A2, and SRD5A3.
# Regulation
ETV4 family members bind to ETS DNA-binding sites and both regulate their own expression and the transcription of a subset of genes that are dependent upon testicular luminal fluid factors, including Ggt_pr4, SRD5A1, and Gpx5.
6-month dietary vitamin E (VE) deficiency in rats resulted in a twofold increase in the mRNA level of SRD5A1 gene and a twofold decrease in the mRNA level of GCLM gene but is not directly mediated by changes in promoter DNA methylation.
Insulin increases the expression of 5α-reductase type 1 mRNA via Akt signalling suggest that elevated levels of 5α-reduced androgens seen in hyperinsulinemic conditions might be explained on the basis of a stimulatory effect of insulin on 5α-reductase in granulosa cells leading to impaired follicle growth and ovulation.
# Clinical significance
Hyperinsulinemia acutely enhances ACTH effects on both the androgen and glucocorticoid pathways leading to changes in steroid metabolites molar ratios that suggest insulin stimulation of 5 α-reductase activity.
PCOS is associated with enhanced androgen and cortisol metabolite excretion and increased 5α-reductase activity that cannot be explained by obesity alone. Increased adrenal corticosteroid production represents an important pathogenic pathway in PCOS.
Progression to castration-resistant prostate cancer (CRPC) is accompanied by increased expression of SRD5A1 over SRD5A2, which is otherwise the dominant isoenzyme expressed in the prostate. The dominant route of DHT synthesis in human CRPC bypasses testosterone, and instead requires 5α-reduction of androstenedione by SRD5A1 to 5α-androstanedione, which is then converted to DHT fuelling cancer growth. | SRD5A1
3-oxo-5α-steroid 4-dehydrogenase 1 is an enzyme that in humans is encoded by the SRD5A1 gene.[1] It is one of three forms of 5α-reductase.
Steroid 5α-reductase (EC 1.3.99.5) catalyzes the conversion of testosterone into the more potent androgen, dihydrotestosterone (DHT). There are 3 isoforms of the enzyme: SRD5A1, SRD5A2, and SRD5A3.[2][3]
# Regulation
ETV4 family members bind to ETS DNA-binding sites and both regulate their own expression and the transcription of a subset of genes that are dependent upon testicular luminal fluid factors, including Ggt_pr4, SRD5A1, and Gpx5.[4]
6-month dietary vitamin E (VE) deficiency in rats resulted in a twofold increase in the mRNA level of SRD5A1 gene and a twofold decrease in the mRNA level of GCLM gene but is not directly mediated by changes in promoter DNA methylation.[5]
Insulin increases the expression of 5α-reductase type 1 mRNA via Akt signalling suggest that elevated levels of 5α-reduced androgens seen in hyperinsulinemic conditions might be explained on the basis of a stimulatory effect of insulin on 5α-reductase in granulosa cells leading to impaired follicle growth and ovulation.[6]
# Clinical significance
Hyperinsulinemia acutely enhances ACTH effects on both the androgen and glucocorticoid pathways leading to changes in steroid metabolites molar ratios that suggest insulin stimulation of 5 α-reductase activity. [7]
PCOS is associated with enhanced androgen and cortisol metabolite excretion and increased 5α-reductase activity that cannot be explained by obesity alone. Increased adrenal corticosteroid production represents an important pathogenic pathway in PCOS.[8]
Progression to castration-resistant prostate cancer (CRPC) is accompanied by increased expression of SRD5A1 over SRD5A2, which is otherwise the dominant isoenzyme expressed in the prostate. The dominant route of DHT synthesis in human CRPC bypasses testosterone, and instead requires 5α-reduction of androstenedione by SRD5A1 to 5α-androstanedione, which is then converted to DHT fuelling cancer growth.[9] | https://www.wikidoc.org/index.php/SRD5A1 | |
f24f5be85e85b94d14833c64beddb6cc30cb49c0 | wikidoc | SRD5A2 | SRD5A2
3-oxo-5α-steroid 4-dehydrogenase 2 is an enzyme that in humans is encoded by the SRD5A2 gene. It is one of three forms of 5α-reductase.
Steroid 5α-reductase catalyzes the conversion of the male sex hormone testosterone into the more potent androgen, dihydrotestosterone.
This gene encodes a microsomal protein expressed at high levels in androgen-sensitive tissues such as the prostate. The encoded protein is active at acidic pH and is sensitive to the 4-azasteroid inhibitor finasteride. Deficiencies in this gene can result in male pseudohermaphroditism, specifically pseudovaginal perineoscrotal hypospadias (PPSH). | SRD5A2
3-oxo-5α-steroid 4-dehydrogenase 2 is an enzyme that in humans is encoded by the SRD5A2 gene.[1][2] It is one of three forms of 5α-reductase.
Steroid 5α-reductase catalyzes the conversion of the male sex hormone testosterone into the more potent androgen, dihydrotestosterone.
This gene encodes a microsomal protein expressed at high levels in androgen-sensitive tissues such as the prostate. The encoded protein is active at acidic pH and is sensitive to the 4-azasteroid inhibitor finasteride. Deficiencies in this gene can result in male pseudohermaphroditism, specifically pseudovaginal perineoscrotal hypospadias (PPSH).[2] | https://www.wikidoc.org/index.php/SRD5A2 | |
96a4085c0648dc0a2d51d1b5d0532b5b894f013d | wikidoc | SRGAP2 | SRGAP2
SLIT-ROBO Rho GTPase-activating protein 2 (srGAP2) also known as formin-binding protein 2 (FNBP2) is a protein that in humans is encoded by the SRGAP2 gene.
SRGAP2 is involved in neuronal migration and neuronal differentiation. SRGAP2 also plays a critical role in synaptic development, brain mass and the number of cortical neurons.
SRGAP2C slows maturation of some neurons and increases neuronal spine density.
Downregulation of srGAP2 inhibits cell-cell repulsion and enhances cell-cell contact duration.
# Gene duplication
This gene is one of the 23 genes that are duplicated in humans but not in other primates.
This protein in humans has been duplicated three times in the human genome in the past 3.4 million years: one duplication 3.4 million years ago (mya) called SRGAP2B, a second duplication 2.4 mya (called SRGAP2C), and one final duplication ~1 mya (SRGAP2D). The ancestral gene SRGAP2 is found in all mammals and the human copy has been renamed SRGAP2A. The 2.4 million year-old duplication (SRGAP2C) expresses a shortened version that 100% of humans possess. This shortened version SRGAP2C inhibits the function of the ancestral copy SRGAP2A and (1) allows faster migration of neurons by interfering with filopodia production and (2) slows the rate of synaptic maturation and increases the density of synapses in the cerebral cortex. | SRGAP2
SLIT-ROBO Rho GTPase-activating protein 2 (srGAP2) also known as formin-binding protein 2 (FNBP2) is a protein that in humans is encoded by the SRGAP2 gene.[1][2]
SRGAP2 is involved in neuronal migration and neuronal differentiation.[3] SRGAP2 also plays a critical role in synaptic development,[4] brain mass and the number of cortical neurons.[5]
SRGAP2C slows maturation of some neurons and increases neuronal spine density.
Downregulation of srGAP2 inhibits cell-cell repulsion and enhances cell-cell contact duration.
# Gene duplication
This gene is one of the 23 genes that are duplicated in humans but not in other primates.[6]
This protein in humans has been duplicated three times in the human genome in the past 3.4 million years: one duplication 3.4 million years ago (mya) called SRGAP2B, a second duplication 2.4 mya (called SRGAP2C), and one final duplication ~1 mya (SRGAP2D). The ancestral gene SRGAP2 is found in all mammals and the human copy has been renamed SRGAP2A. The 2.4 million year-old duplication (SRGAP2C) expresses a shortened version that 100% of humans possess.[7] This shortened version SRGAP2C inhibits the function of the ancestral copy SRGAP2A and (1) allows faster migration of neurons by interfering with filopodia production and (2) slows the rate of synaptic maturation and increases the density of synapses in the cerebral cortex.[4] | https://www.wikidoc.org/index.php/SRGAP2 | |
844e0dad53abe8d2c0f32e4906928e61b48e1447 | wikidoc | SS18L1 | SS18L1
SS18-like protein 1 is a protein that in humans is encoded by the SS18L1 gene.
# Function
Synovial sarcomas occur most frequently in the extremities around large joints. More than 90% of cases have a recurrent and specific chromosomal translocation, t(X;18)(p11.2;q11.2), in which the 5-prime end of the SS18 gene is fused in-frame to the 3-prime end of the SSX1, SSX2, or SSX4 gene. The SS18L1 gene is homologous to SS18.
# Interactions
SS18L1 has been shown to interact with CREB-binding protein. Biochemical pull down assays reveal SS18L1 to interact with several components of the human SWI/SNF chromatin remodeling complex. | SS18L1
SS18-like protein 1 is a protein that in humans is encoded by the SS18L1 gene.[1]
# Function
Synovial sarcomas occur most frequently in the extremities around large joints. More than 90% of cases have a recurrent and specific chromosomal translocation, t(X;18)(p11.2;q11.2), in which the 5-prime end of the SS18 gene is fused in-frame to the 3-prime end of the SSX1, SSX2, or SSX4 gene. The SS18L1 gene is homologous to SS18.[1]
# Interactions
SS18L1 has been shown to interact with CREB-binding protein.[2] Biochemical pull down assays reveal SS18L1 to interact with several components of the human SWI/SNF chromatin remodeling complex.[3] | https://www.wikidoc.org/index.php/SS18L1 | |
32fe5a4a77bd9a2288e77fba336c67f3dcd52224 | wikidoc | SSMEM1 | SSMEM1
Serine-rich single pass membrane protein 1 is a protein that in humans is encoded by the SSMEM1 gene.
# Gene
The gene and intron-exon structure were first predicted through analysis of the complete sequence of human chromosome 7, its initial designation being C7orf45. Human mRNA transcripts were identified through two large scale cDNA cloning efforts, an American effort run out of the Dana-Farber Cancer Institute and Harvard Medical School, and full-length long Japan effort. Later assigned the official symbol SSMEM1, the gene is located on the long arm of chromosome 7 (7q32.2) on the sense strand in humans. The human mRNA transcript is 1171 bp long with three exons.
## Aliases
In humans, SSMEM1 is also referred to as C7orf45. Human SSMEM1 has a clone name of FLJ40316.
## Expression
In humans, SSMEM1 is highly expressed in the testes. In mice, SSMEM1 is expressed in the brain.
# Protein
In humans, serine-rich single pass membrane protein 1 is 244 amino acids long with a transmembrane domain region spanning amino acids 35-55. This protein has a domain of unknown function (DUF4636) that spans almost all of the protein (amino acids 1-243). DUF4636 belongs to pfam15468 which is a part of the superfamily cl21285 that is found in eukaryotes and typically 196 to 244 amino acids long. The human protein has a molecular weight of 28036 Da and an isoelectric point of 7.64. | SSMEM1
Serine-rich single pass membrane protein 1 is a protein that in humans is encoded by the SSMEM1 gene.[1]
# Gene
The gene and intron-exon structure were first predicted through analysis of the complete sequence of human chromosome 7, its initial designation being C7orf45.[2][3] Human mRNA transcripts were identified through two large scale cDNA cloning efforts, an American effort run out of the Dana-Farber Cancer Institute and Harvard Medical School, and full-length long Japan effort. Later assigned the official symbol SSMEM1, the gene is located on the long arm of chromosome 7 (7q32.2) on the sense strand in humans.[4] The human mRNA transcript is 1171 bp long with three exons.[5]
## Aliases
In humans, SSMEM1 is also referred to as C7orf45.[4] Human SSMEM1 has a clone name of FLJ40316.[4]
## Expression
In humans, SSMEM1 is highly expressed in the testes.[6][not in citation given][7][8] In mice, SSMEM1 is expressed in the brain.[9]
# Protein
In humans, serine-rich single pass membrane protein 1 is 244 amino acids long with a transmembrane domain region spanning amino acids 35-55.[1] This protein has a domain of unknown function (DUF4636) that spans almost all of the protein (amino acids 1-243).[1] DUF4636 belongs to pfam15468 which is a part of the superfamily cl21285 that is found in eukaryotes and typically 196 to 244 amino acids long.[1] The human protein has a molecular weight of 28036 Da and an isoelectric point of 7.64.[1][10] | https://www.wikidoc.org/index.php/SSMEM1 |
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