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http://www.ncbi.nlm.nih.gov/pubmed/27821050 | 1. BMC Genomics. 2016 Nov 7;17(1):887. doi: 10.1186/s12864-016-3167-3.
Stringent comparative sequence analysis reveals SOX10 as a putative inhibitor of
glial cell differentiation.
Gopinath C(1), Law WD(2), Rodríguez-Molina JF(3), Prasad AB(4), Song L(5),
Crawford GE(5)(6), Mullikin JC(4), Svaren J(7)(8), Antonellis A(9)(10)(11).
Author information:
(1)Cellular and Molecular Biology Program, University of Michigan Medical
School, Ann Arbor, MI, 48109, USA.
(2)Department of Human Genetics, University of Michigan Medical School, Ann
Arbor, MI, 48109, USA.
(3)Cellular and Molecular Pathology Program, University of Wisconsin-Madison,
Madison, WI, 53706, USA.
(4)Genome Technology Branch, National Human Genome Research Institute, National
Institutes of Health, Bethesda, MD, 20892, USA.
(5)Center for Genomic and Computational Biology, Duke University Medical Center,
Durham, NC, 27708, USA.
(6)Department of Pediatrics, Duke University Medical Center, Durham, NC, 27708,
USA.
(7)Waisman Center, University of Wisconsin-Madison, Madison, WI, 53706, USA.
(8)Department of Comparative Biosciences, University of Wisconsin-Madison,
Madison, WI, 53706, USA.
(9)Cellular and Molecular Biology Program, University of Michigan Medical
School, Ann Arbor, MI, 48109, USA. [email protected].
(10)Department of Human Genetics, University of Michigan Medical School, Ann
Arbor, MI, 48109, USA. [email protected].
(11)Department of Neurology, University of Michigan Medical School, Ann Arbor,
MI, 48109, USA. [email protected].
BACKGROUND: The transcription factor SOX10 is essential for all stages of
Schwann cell development including myelination. SOX10 cooperates with other
transcription factors to activate the expression of key myelin genes in Schwann
cells and is therefore a context-dependent, pro-myelination transcription
factor. As such, the identification of genes regulated by SOX10 will provide
insight into Schwann cell biology and related diseases. While genome-wide
studies have successfully revealed SOX10 target genes, these efforts mainly
focused on myelinating stages of Schwann cell development. We propose that
less-biased approaches will reveal novel functions of SOX10 outside of
myelination.
RESULTS: We developed a stringent, computational-based screen for genome-wide
identification of SOX10 response elements. Experimental validation of a pilot
set of predicted binding sites in multiple systems revealed that SOX10 directly
regulates a previously unreported alternative promoter at SOX6, which encodes a
transcription factor that inhibits glial cell differentiation. We further
explored the utility of our computational approach by combining it with
DNase-seq analysis in cultured Schwann cells and previously published SOX10
ChIP-seq data from rat sciatic nerve. Remarkably, this analysis enriched for
genomic segments that map to loci involved in the negative regulation of
gliogenesis including SOX5, SOX6, NOTCH1, HMGA2, HES1, MYCN, ID4, and ID2.
Functional studies in Schwann cells revealed that: (1) all eight loci are
expressed prior to myelination and down-regulated subsequent to myelination; (2)
seven of the eight loci harbor validated SOX10 binding sites; and (3) seven of
the eight loci are down-regulated upon repressing SOX10 function.
CONCLUSIONS: Our computational strategy revealed a putative novel function for
SOX10 in Schwann cells, which suggests a model where SOX10 activates the
expression of genes that inhibit myelination during non-myelinating stages of
Schwann cell development. Importantly, the computational and functional datasets
we present here will be valuable for the study of transcriptional regulation,
SOX protein function, and glial cell biology.
DOI: 10.1186/s12864-016-3167-3
PMCID: PMC5100263
PMID: 27821050 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26425553 | 1. Biomed Res Int. 2015;2015:757530. doi: 10.1155/2015/757530. Epub 2015 Sep 3.
Understanding Transcription Factor Regulation by Integrating Gene Expression and
DNase I Hypersensitive Sites.
Wang G(1), Wang F(2), Huang Q(2), Li Y(3), Liu Y(4), Wang Y(2).
Author information:
(1)School of Computer Science and Technology, Harbin Institute of Technology,
Harbin, Heilongjiang 150001, China ; Instrument Science and Technology, Harbin
Institute of Technology, Harbin, Heilongjiang 150001, China.
(2)School of Computer Science and Technology, Harbin Institute of Technology,
Harbin, Heilongjiang 150001, China.
(3)Instrument Science and Technology, Harbin Institute of Technology, Harbin,
Heilongjiang 150001, China ; School of Life Science and Technology, Harbin
Institute of Technology, Harbin, Heilongjiang 150001, China.
(4)Department of Medical and Molecular Genetics, Indiana University School of
Medicine, Indianapolis, IN 46202, USA ; Center for Computational Biology and
Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202,
USA.
Transcription factors are proteins that bind to DNA sequences to regulate gene
transcription. The transcription factor binding sites are short DNA sequences
(5-20 bp long) specifically bound by one or more transcription factors. The
identification of transcription factor binding sites and prediction of their
function continue to be challenging problems in computational biology. In this
study, by integrating the DNase I hypersensitive sites with known position
weight matrices in the TRANSFAC database, the transcription factor binding sites
in gene regulatory region are identified. Based on the global gene expression
patterns in cervical cancer HeLaS3 cell and HelaS3-ifnα4h cell (interferon
treatment on HeLaS3 cell for 4 hours), we present a model-based computational
approach to predict a set of transcription factors that potentially cause such
differential gene expression. Significantly, 6 out 10 predicted functional
factors, including IRF, IRF-2, IRF-9, IRF-1 and IRF-3, ICSBP, belong to
interferon regulatory factor family and upregulate the gene expression levels
responding to the interferon treatment. Another factor, ISGF-3, is also a
transcriptional activator induced by interferon alpha. Using the different
transcription factor binding sites selected criteria, the prediction result of
our model is consistent. Our model demonstrated the potential to computationally
identify the functional transcription factors in gene regulation.
DOI: 10.1155/2015/757530
PMCID: PMC4573618
PMID: 26425553 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29315345 | 1. PLoS One. 2018 Jan 9;13(1):e0190834. doi: 10.1371/journal.pone.0190834.
eCollection 2018.
Identification and functional analysis of SOX10 phosphorylation sites in
melanoma.
Cronin JC(1), Loftus SK(1), Baxter LL(1), Swatkoski S(2), Gucek M(2), Pavan
WJ(1).
Author information:
(1)Genetic Disease Research Branch, National Human Genome Research Institute,
National Institutes of Health, Bethesda, MD, United States of America.
(2)Proteomics Core, National Heart, Lung, and Blood Institute, National
Institutes of Health, Bethesda, MD, United States of America.
The transcription factor SOX10 plays an important role in vertebrate neural
crest development, including the establishment and maintenance of the melanocyte
lineage. SOX10 is also highly expressed in melanoma tumors, and SOX10 expression
increases with tumor progression. The suppression of SOX10 in melanoma cells
activates TGF-β signaling and can promote resistance to BRAF and MEK inhibitors.
Since resistance to BRAF/MEK inhibitors is seen in the majority of melanoma
patients, there is an immediate need to assess the underlying biology that
mediates resistance and to identify new targets for combinatorial therapeutic
approaches. Previously, we demonstrated that SOX10 protein is required for tumor
initiation, maintenance and survival. Here, we present data that support
phosphorylation as a mechanism employed by melanoma cells to tightly regulate
SOX10 expression. Mass spectrometry identified eight phosphorylation sites
contained within SOX10, three of which (S24, S45 and T240) were selected for
further analysis based on their location within predicted MAPK/CDK binding
motifs. SOX10 mutations were generated at these phosphorylation sites to assess
their impact on SOX10 protein function in melanoma cells, including
transcriptional activation on target promoters, subcellular localization, and
stability. These data further our understanding of SOX10 protein regulation and
provide critical information for identification of molecular pathways that
modulate SOX10 protein levels in melanoma, with the ultimate goal of discovering
novel targets for more effective combinatorial therapeutic approaches for
melanoma patients.
DOI: 10.1371/journal.pone.0190834
PMCID: PMC5760019
PMID: 29315345 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/21908409 | 1. Nucleic Acids Res. 2012 Jan;40(1):88-101. doi: 10.1093/nar/gkr734. Epub 2011
Sep 9.
Transcription factor Sox10 orchestrates activity of a neural crest-specific
enhancer in the vicinity of its gene.
Wahlbuhl M(1), Reiprich S, Vogl MR, Bösl MR, Wegner M.
Author information:
(1)Institut für Biochemie, Emil-Fischer-Zentrum, Universität Erlangen-Nürnberg,
D-91054 Erlangen, Germany.
The Sox10 transcription factor is a central regulator of vertebrate neural crest
and nervous system development. Its expression is likely controlled by multiple
enhancer elements, among them U3 (alternatively known as MCS4). Here we analyze
U3 activity to obtain deeper insights into Sox10 function and expression in the
neural crest and its derivatives. U3 activity strongly depends on the presence
of Sox10 that regulates its own expression as commonly observed for important
developmental regulators. Sox10 bound directly as monomer to at least three
sites in U3, whereas a fourth site preferred dimers. Deletion of these sites
efficiently reduced U3 activity in transfected cells and transgenic mice. In
stimulating the U3 enhancer, Sox10 synergized with many other transcription
factors present in neural crest and developing peripheral nervous system
including Pax3, FoxD3, AP2α, Krox20 and Sox2. In case of FoxD3, synergism
involved Sox10-dependent recruitment to the U3 enhancer, while Sox10 and AP2α
each had to bind to the regulatory region. Our study points to the importance of
autoregulatory activity and synergistic interactions for maintenance of Sox10
expression and functional activity of Sox10 in the neural crest regulatory
network.
DOI: 10.1093/nar/gkr734
PMCID: PMC3245941
PMID: 21908409 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12138193 | 1. Mol Cell Biol. 2002 Aug;22(16):5826-34. doi: 10.1128/MCB.22.16.5826-5834.2002.
Sox10 is an active nucleocytoplasmic shuttle protein, and shuttling is crucial
for Sox10-mediated transactivation.
Rehberg S(1), Lischka P, Glaser G, Stamminger T, Wegner M, Rosorius O.
Author information:
(1)Institut für Biochemie, Universität Erlangen-Nürnberg, D-91054 Erlangen,
Germany.
Sox10 belongs to a family of transcription regulators characterized by a
DNA-binding domain known as the HMG box. It plays fundamental roles in neural
crest development, peripheral gliogenesis, and terminal differentiation of
oligodendrocytes. In accord with its function as transcription factor, Sox10
contains two nuclear localization signals and is most frequently detected in the
nucleus. In this study, we report that Sox10 is an active nucleocytoplasmic
shuttle protein, competent of both entering and exiting the nucleus. We
identified a functional Rev-type nuclear export signal within the DNA-binding
domain of Sox10. Mutational inactivation of this nuclear export signal or
treatment of cells with the CRM1-specific export inhibitor leptomycin B
inhibited nuclear export and consequently nucleocytoplasmic shuttling of Sox10.
Importantly, the inhibition of the nuclear export of Sox10 led to decreased
transactivation of transfected reporters and endogenous target genes, arguing
that continuous nucleocytoplasmic shuttling is essential for the function of
Sox10. To our knowledge this is the first time that nuclear export has been
reported and shown to be functionally relevant for any Sox protein.
DOI: 10.1128/MCB.22.16.5826-5834.2002
PMCID: PMC133963
PMID: 12138193 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19304657 | 1. J Biol Chem. 2009 May 15;284(20):13629-13640. doi: 10.1074/jbc.M901177200.
Epub 2009 Mar 20.
The armadillo repeat-containing protein, ARMCX3, physically and functionally
interacts with the developmental regulatory factor Sox10.
Mou Z(1), Tapper AR(1), Gardner PD(2).
Author information:
(1)Brudnick Neuropsychiatric Research Institute, Department of Psychiatry,
University of Massachusetts Medical School, Worcester, Massachusetts 01604.
(2)Brudnick Neuropsychiatric Research Institute, Department of Psychiatry,
University of Massachusetts Medical School, Worcester, Massachusetts 01604.
Electronic address: [email protected].
Sox10 is a member of the group E Sox transcription factor family and plays key
roles in neural crest development and subsequent cellular differentiation. Sox10
binds to regulatory sequences in target genes via its conserved high mobility
group domain. In most cases, Sox10 exerts its transcriptional effects in concert
with other DNA-binding factors, adaptor proteins, and nuclear import proteins.
These interactions can lead to synergistic gene activation and can be cell
type-specific. In earlier work, we demonstrated that Sox10 transactivates the
nicotinic acetylcholine receptor alpha3 and beta4 subunit genes and does so only
in neuronal-like cell lines, raising the possibility that Sox10 mediates its
effects via interactions with co-regulatory factors. Here we describe the
identification of the armadillo repeat-containing protein, ARMCX3, as a
Sox10-interacting protein. Biochemical analyses indicate that ARMCX3 is an
integral membrane protein of the mitochondrial outer membrane. Others have shown
that Sox10 is a nucleocytoplasmic shuttling protein. We extend this observation
and demonstrate that, in the cytoplasm, Sox10 is peripherally associated with
the mitochondrial outer membrane. Both Sox10 and ARMCX3 are expressed in mouse
brain and spinal cord as well as several cell lines. Overexpression of ARMCX3
increased the amount of mitochondrially associated Sox10. In addition, although
ARMCX3 does not possess intrinsic transcriptional activity, it does enhance
transactivation of the nicotinic acetylcholine receptor alpha3 and beta4 subunit
gene promoters by Sox10. These results suggest that Sox10 is a
membrane-associated factor whose transcriptional function is increased by direct
interactions with ARMCX3 and raise the possibility of a signal transduction
cascade between the nucleus and mitochondria through Sox10/ARMCX3 interactions.
DOI: 10.1074/jbc.M901177200
PMCID: PMC2679464
PMID: 19304657 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9412504 | 1. J Neurosci. 1998 Jan 1;18(1):237-50. doi: 10.1523/JNEUROSCI.18-01-00237.1998.
Sox10, a novel transcriptional modulator in glial cells.
Kuhlbrodt K(1), Herbarth B, Sock E, Hermans-Borgmeyer I, Wegner M.
Author information:
(1)Zentrum für Molekulare Neurobiologie, Universität Hamburg, D-20246 Hamburg,
Germany.
Sox proteins are characterized by possession of a DNA-binding domain with
similarity to the high-mobility group domain of the sex determining factor SRY.
Here, we report on Sox10, a novel protein with predominant expression in glial
cells of the nervous system. During development Sox10 first appeared in the
forming neural crest and continued to be expressed as these cells contributed to
the forming PNS and finally differentiated into Schwann cells. In the CNS, Sox10
transcripts were originally confined to glial precursors and later detected in
oligodendrocytes of the adult brain. Functional studies failed to reveal
autonomous transcriptional activity for Sox10. Instead, Sox10 functioned
synergistically with the POU domain protein Tst-1/Oct6/SCIP with which it is
coexpressed during certain stages of Schwann cell development. Synergy depended
on binding to adjacent sites in target promoters, was mediated by the N-terminal
regions of both proteins, and could not be observed between Sox10 and several
other POU domain proteins. Interestingly, Sox10 also modulated the function of
Pax3 and Krox-20, two other transcription factors involved in Schwann cell
development. We propose a role for Sox10 in conferring cell specificity to the
function of other transcription factors in developing and mature glia.
DOI: 10.1523/JNEUROSCI.18-01-00237.1998
PMCID: PMC6793382
PMID: 9412504 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18786246 | 1. BMC Genomics. 2008 Sep 11;9:408. doi: 10.1186/1471-2164-9-408.
Identification of direct regulatory targets of the transcription factor Sox10
based on function and conservation.
Lee KE(1), Nam S, Cho EA, Seong I, Limb JK, Lee S, Kim J.
Author information:
(1)Division of Life and Pharmaceutical Sciences and the Center for Cell
Signaling & Drug Discovery Research, Ewha Womans University, 11-1 Daehyun-dong,
Seodaemun-gu, Seoul, 120-750, Korea. [email protected]
BACKGROUND: Sox10, a member of the Sry-related HMG-Box gene family, is a
critical transcription factor for several important cell lineages, most notably
the neural crest stem cells and the derivative peripheral glial cells and
melanocytes. Thus far, only a handful of direct target genes are known for this
transcription factor limiting our understanding of the biological network it
governs.
RESULTS: We describe identification of multiple direct regulatory target genes
of Sox10 through a procedure based on function and conservation. By combining
RNA interference technique and DNA microarray technology, we have identified a
set of genes that show significant down-regulation upon introduction of Sox10
specific siRNA into Schwannoma cells. Subsequent comparative genomics analyses
led to potential binding sites for Sox10 protein conserved across several
mammalian species within the genomic region proximal to these genes. Multiple
sites belonging to 4 different genes (proteolipid protein, Sox10, extracellular
superoxide dismutase, and pleiotrophin) were shown to directly interact with
Sox10 by chromatin immunoprecipitation assay. We further confirmed the direct
regulation through the identified cis-element for one of the genes,
extracellular superoxide dismutase, using electrophoretic mobility shift assay
and reporter assay.
CONCLUSION: In sum, the process of combining differential expression profiling
and comparative genomics successfully led to further defining the role of Sox10,
a critical transcription factor for the development of peripheral glia. Our
strategy utilizing relatively accessible techniques and tools should be
applicable to studying the function of other transcription factors.
DOI: 10.1186/1471-2164-9-408
PMCID: PMC2556353
PMID: 18786246 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12885557 | 1. Dev Biol. 2003 Aug 1;260(1):79-96. doi: 10.1016/s0012-1606(03)00247-1.
Sox10 is required for the early development of the prospective neural crest in
Xenopus embryos.
Honoré SM(1), Aybar MJ, Mayor R.
Author information:
(1)Millennium Nucleus in Developmental Biology, Facultad de Ciencias,
Universidad de Chile, Casilla 653, Santiago, Chile.
The Sox family of transcription factors has been implicated in the development
of different tissues during embryogenesis. Several mutations in humans, mice,
and zebrafish have shown that depletion of Sox10 activity produces defects in
the development of neural crest derivatives, such as melanocytes, ganglia of the
peripheral nervous system, and some specific cell types as glia. We have
isolated the Xenopus homologue of the Sox10 gene. It is expressed in prospective
neural crest and otic placode regions from the earliest stages of neural crest
specification and in migrating cranial and trunk neural crest cells.
Loss-of-function experiments using morpholino antisense oligos against Sox10
produce a loss of neural crest precursors and an enlargement of the surrounding
neural plate and epidermis. This effect of Sox10 depletion is produced during
some of the earliest steps of neural crest specification, as is shown by the
inhibition in the expression of Slug and FoxD3, which are early markers of
neural crest specification. In addition, we show that Sox10 depletion leads to
an increase in apoptosis and a decrease in cell proliferation in the neural
folds, suggesting that Sox10 could work as a survival as well as a specification
factor in neural crest precursors during premigratory stages. Although some of
the deficiencies found in the Waardenburg syndrome and in the Hirschprung
disease could be associated with a failure of the development of crest
derivatives during the late phase of its development, or even during adulthood,
our results suggest that inhibition of Sox10 activity produces an earlier
failure of neural crest precursors. In experiments where melanocytes and ganglia
were induced in vivo and in vitro, we were able to block their development by
inhibiting Sox10 activity. These results are compatible with an additional late
role of Sox10 on development of neural crest derivatives, as it has been
previously proposed. We show that Sox10 expression is dependent on FGF and Wnt
activity, both in the neural crest and in the otic placode territories. Finally,
in order to establish the position of Sox10 in the hierarchical cascade of gene
activation required for neural crest specification, we used inducible forms of
the wild type and dominant negatives for the Snail and Slug genes. Our results
show that Snail is able to control Sox10 expression. However, the overexpression
of Slug was not able to upregulate Sox10 expression. Taken together, these
results indicate that Sox10 may lie between Snail and Slug in the genetic
cascade that controls neural crest development.
DOI: 10.1016/s0012-1606(03)00247-1
PMID: 12885557 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33566433 | 1. Glia. 2021 Jun;69(6):1464-1477. doi: 10.1002/glia.23973. Epub 2021 Feb 10.
Formation of the node of Ranvier by Schwann cells is under control of
transcription factor Sox10.
Saur AL(1), Fröb F(1), Weider M(1)(2), Wegner M(1).
Author information:
(1)Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität
Erlangen-Nürnberg, Erlangen, Germany.
(2)Zahnklinik 3 - Kieferorthopädie, Universitätsklinikum Erlangen,
Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
The transcription factor Sox10 is an essential regulator of genes that code for
structural components of the myelin sheath and for lipid metabolic enzymes in
both types of myelinating glia in the central and peripheral nervous systems. In
an attempt to characterize additional Sox10 target genes in Schwann cells, we
identified in this study a strong influence of Sox10 on the expression of genes
associated with adhesion in the MSC80 Schwann cell line. These included the
genes for Gliomedin, Neuronal cell adhesion molecule and Neurofascin that
together constitute essential Schwann cell contributions to paranode and node of
Ranvier. Using bioinformatics and molecular biology techniques we provide
evidence that Sox10 directly activates these genes by binding to conserved
regulatory regions. For activation, Sox10 cooperates with Krox20, a
transcription factor previously identified as the central regulator of Schwann
cell myelination. Both the activating function of Sox10 as well as its
cooperation with Krox20 were confirmed in vivo. We conclude that the employment
of Sox10 and Krox20 as regulators of structural myelin sheath components and
genes associated with the node of Ranvier is one way of ensuring a biologically
meaningful coordinated formation of both structures during peripheral
myelination.
© 2021 The Authors. Glia published by Wiley Periodicals LLC.
DOI: 10.1002/glia.23973
PMID: 33566433 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33082503 | 1. Sci Rep. 2020 Oct 20;10(1):17807. doi: 10.1038/s41598-020-74664-y.
The transcription factor Sox10 is an essential determinant of branching
morphogenesis and involution in the mouse mammary gland.
Mertelmeyer S(1), Weider M(1)(2), Baroti T(1), Reiprich S(1), Fröb F(1), Stolt
CC(1), Wagner KU(3)(4), Wegner M(5).
Author information:
(1)Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität
Erlangen-Nürnberg, Fahrstrasse 17, 91054, Erlangen, Germany.
(2)Zahnklinik 3 - Kieferorthopädie, Universitätsklinikum Erlangen, FAU
Erlangen-Nürnberg, Glückstrasse 6, 91054, Erlangen, Germany.
(3)Barbara Ann Karmanos Cancer Institute, Detroit, USA.
(4)Wayne State University School of Medicine, Detroit, MI, USA.
(5)Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität
Erlangen-Nürnberg, Fahrstrasse 17, 91054, Erlangen, Germany.
[email protected].
The high mobility group-domain containing transcription factor Sox10 is an
essential regulator of developmental processes and homeostasis in the neural
crest, several neural crest-derived lineages and myelinating glia. Recent
studies have also implicated Sox10 as an important factor in mammary stem and
precursor cells. Here we employ a series of mouse mutants with constitutive and
conditional Sox10 deficiencies to show that Sox10 has multiple functions in the
developing mammary gland. While there is no indication for a requirement of
Sox10 in the specification of the mammary placode or descending mammary bud, it
is essential for both the prenatal hormone-independent as well as the pubertal
hormone-dependent branching of the mammary epithelium and for proper
alveologenesis during pregnancy. It furthermore acts in a dosage-dependent
manner. Sox10 also plays a role during the involution process at the end of the
lactation period. Whereas its effect on epithelial branching and alveologenesis
are likely causally related to its function in mammary stem and precursor cells,
this is not the case for its function during involution where Sox10 seems to
work at least in part through regulation of the miR-424(322)/503 cluster.
DOI: 10.1038/s41598-020-74664-y
PMCID: PMC7575560
PMID: 33082503 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/18950534 | 1. BMC Dev Biol. 2008 Oct 26;8:105. doi: 10.1186/1471-213X-8-105.
An evolutionarily conserved intronic region controls the spatiotemporal
expression of the transcription factor Sox10.
Dutton JR(1), Antonellis A, Carney TJ, Rodrigues FS, Pavan WJ, Ward A, Kelsh RN.
Author information:
(1)Centre for Regenerative Medicine, Department of Biology and Biochemistry,
University of Bath, Bath, BA2 7AY, UK. [email protected]
BACKGROUND: A major challenge lies in understanding the complexities of gene
regulation. Mutation of the transcription factor SOX10 is associated with
several human diseases. The disease phenotypes reflect the function of SOX10 in
diverse tissues including the neural crest, central nervous system and otic
vesicle. As expected, the SOX10 expression pattern is complex and highly
dynamic, but little is known of the underlying mechanisms regulating its
spatiotemporal pattern. SOX10 expression is highly conserved between all
vertebrates characterised.
RESULTS: We have combined in vivo testing of DNA fragments in zebrafish and
computational comparative genomics to identify the first regulatory regions of
the zebrafish sox10 gene. Both approaches converged on the 3' end of the
conserved 1st intron as being critical for spatial patterning of sox10 in the
embryo. Importantly, we have defined a minimal region crucial for this function.
We show that this region contains numerous binding sites for transcription
factors known to be essential in early neural crest induction, including
Tcf/Lef, Sox and FoxD3. We show that the identity and relative position of these
binding sites are conserved between zebrafish and mammals. A further region,
partially required for oligodendrocyte expression, lies in the 5' region of the
same intron and contains a putative CSL binding site, consistent with a role for
Notch signalling in sox10 regulation. Furthermore, we show that beta-catenin,
Notch signalling and Sox9 can induce ectopic sox10 expression in early embryos,
consistent with regulatory roles predicted from our transgenic and computational
results.
CONCLUSION: We have thus identified two major sites of sox10 regulation in
vertebrates and provided evidence supporting a role for at least three factors
in driving sox10 expression in neural crest, otic epithelium and oligodendrocyte
domains.
DOI: 10.1186/1471-213X-8-105
PMCID: PMC2601039
PMID: 18950534 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11543611 | 1. Dev Biol. 2001 Sep 15;237(2):245-57. doi: 10.1006/dbio.2001.0372.
Analysis of SOX10 function in neural crest-derived melanocyte development:
SOX10-dependent transcriptional control of dopachrome tautomerase.
Potterf SB(1), Mollaaghababa R, Hou L, Southard-Smith EM, Hornyak TJ, Arnheiter
H, Pavan WJ.
Author information:
(1)Genetic Disease Research Branch, National Human Genome Research Institute,
Bethesda, Maryland 20892, USA.
SOX10 is a high-mobility-group transcription factor that plays a critical role
in the development of neural crest-derived melanocytes. At E11.5, mouse embryos
homozygous for the Sox10(Dom) mutation entirely lack neural crest-derived cells
expressing the lineage marker KIT, MITF, or DCT. Moreover, neural crest cell
cultures derived from homozygous embryos do not give rise to pigmented cells. In
contrast, in Sox10(Dom) heterozygous embryos, melanoblasts expressing KIT and
MITF do occur, albeit in reduced numbers, and pigmented cells eventually develop
in nearly normal numbers both in culture and in vivo. Intriguingly, however,
Sox10(Dom)/+ melanoblasts transiently lack Dct expression both in culture and in
vivo, suggesting that during a critical developmental period SOX10 may serve as
a transcriptional activator of Dct. Indeed, we found that SOX10 and DCT
colocalized in early melanoblasts and that SOX10 is capable of transactivating
the Dct promoter in vitro. Our data suggest that during early melanoblast
development SOX10 acts as a critical transactivator of Dct, that MITF, on its
own, is insufficient to stimulate Dct expression, and that delayed onset of Dct
expression is not deleterious to the melanocyte lineage.
DOI: 10.1006/dbio.2001.0372
PMID: 11543611 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23644063 | 1. Dev Biol. 2013 Oct 1;382(1):330-43. doi: 10.1016/j.ydbio.2013.04.024. Epub
2013 May 2.
The role of SOX10 during enteric nervous system development.
Bondurand N(1), Sham MH.
Author information:
(1)INSERM, U955, Equipe 11, Hôpital Henri Mondor, 51 Avenue du Maréchal de
Lattre de Tassigny, F-94000 Créteil, France; Université Paris Est, UMR_S955,
UPEC, Créteil, F-94000 Créteil, France. Electronic address:
[email protected].
The SOX10 transcription factor is a characteristic marker for migratory
multipotent neural crest (NC) progenitors as well as several of their
differentiated derivatives. The involvement of SOX10 in Waardenburg-Hirschsprung
disease (pigmentation defects, deafness and intestinal aganglionosis) and
studies of mutant animal models have contributed significantly to the
understanding of its function in neural crest cells (NCC) in general and in the
melanocytes and enteric nervous system (ENS) in particular. Cell-based studies
have further demonstrated the important roles of this transcription factor in
maintaining the NC progenitor cell number and in determining glial cell fate.
Phenotypic variability observed among patients presenting with SOX10 mutations
is in agreement with molecular genetics and animal model studies, which revealed
that SOX10 cooperates with different partner factors; a number of genetic
modifiers of SOX10 have been identified. This study reviews the expression,
regulation, and function of SOX10 in normal development of the ENS and in
disease conditions, as well as the genetic and molecular interactions of SOX10
with other ENS genes/factors. We also discuss future research areas. Further
understanding of SOX10 function will benefit from genomic and cell biological
studies that integrate the cell-intrinsic molecular mechanisms and the
interactions of the enteric NCC with the niche environment.
© 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ydbio.2013.04.024
PMID: 23644063 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22037207 | 1. Mol Cell Neurosci. 2012 Feb;49(2):85-96. doi: 10.1016/j.mcn.2011.10.004. Epub
2011 Oct 19.
SOX10 regulates expression of the SH3-domain kinase binding protein 1 (Sh3kbp1)
locus in Schwann cells via an alternative promoter.
Hodonsky CJ(1), Kleinbrink EL, Charney KN, Prasad M, Bessling SL, Jones EA,
Srinivasan R, Svaren J, McCallion AS, Antonellis A.
Author information:
(1)Department of Human Genetics, University of Michigan Medical School, Ann
Arbor, MI, USA.
The transcription factor SOX10 has essential roles in neural crest-derived cell
populations, including myelinating Schwann cells-specialized glial cells
responsible for ensheathing axons in the peripheral nervous system. Importantly,
SOX10 directly regulates the expression of genes essential for proper myelin
function. To date, only a handful of SOX10 target loci have been characterized
in Schwann cells. Addressing this lack of knowledge will provide a better
understanding of Schwann cell biology and candidate loci for relevant diseases
such as demyelinating peripheral neuropathies. We have identified a
highly-conserved SOX10 binding site within an alternative promoter at the
SH3-domain kinase binding protein 1 (Sh3kbp1) locus. The genomic segment
identified at Sh3kbp1 binds to SOX10 and displays strong promoter activity in
Schwann cells in vitro and in vivo. Mutation of the SOX10 binding site ablates
promoter activity, and ectopic expression of SOX10 in SOX10-negative cells
promotes the expression of endogenous Sh3kbp1. Combined, these data reveal
Sh3kbp1 as a novel target of SOX10 and raise important questions regarding the
function of SH3KBP1 isoforms in Schwann cells.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.mcn.2011.10.004
PMCID: PMC3277675
PMID: 22037207 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20130826 | 1. J Mol Med (Berl). 2010 May;88(5):507-14. doi: 10.1007/s00109-010-0592-7. Epub
2010 Feb 4.
Involvement of SOX10 in the pathogenesis of Hirschsprung disease: report of a
truncating mutation in an isolated patient.
Sánchez-Mejías A(1), Watanabe Y, M Fernández R, López-Alonso M, Antiñolo G,
Bondurand N, Borrego S.
Author information:
(1)Unidad de Gestión Clínica de Genética, Reproducción y Medicina Fetal,
Hospital Universitario Virgen del Rocío, Avda. Manuel Siurot s/n, 41013,
Seville, Spain.
SOX10 protein is a key transcription factor during neural crest development.
Mutations in SOX10 are associated with several neurocristopathies such as
Waardenburg syndrome type IV (WS4), a congenital disorder characterized by the
association of hearing loss, pigmentary abnormalities, and absence of ganglion
cells in the myenteric and submucosal plexus of the gastrointestinal tract, also
known as aganglionic megacolon or Hirschsprung disease (HSCR). Several mutations
at this locus are known to cause a high percentage of WS4 cases, but no SOX10
mutations had been ever reported associated to isolated HSCR patient. Therefore,
nonsyndromic HSCR was initially thought not to be associated to mutations at
this particular locus. In the present study, we describe the evaluation of the
SOX10 gene in a series of 196 isolated HSCR cases, the largest patient series
evaluated so far, and report a truncating c.153-155del mutation. This is the
first time that a SOX10 mutation is detected in an isolated HSCR patient, which
completely changes the scenario for the implications of SOX10 mutations in human
disease, giving us a new tool for genetic counseling.
DOI: 10.1007/s00109-010-0592-7
PMCID: PMC3235085
PMID: 20130826 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18184726 | 1. Development. 2008 Feb;135(4):637-46. doi: 10.1242/dev.010454. Epub 2008 Jan 9.
Sox9 and Sox10 influence survival and migration of oligodendrocyte precursors in
the spinal cord by regulating PDGF receptor alpha expression.
Finzsch M(1), Stolt CC, Lommes P, Wegner M.
Author information:
(1)Institut für Biochemie, Emil-Fischer-Zentrum, Universität Erlangen,
Fahrstrasse 17, D-91054 Erlangen, Germany.
Specification of the myelin-forming oligodendrocytes of the central nervous
system requires the Sox9 transcription factor, whereas terminal differentiation
depends on the closely related Sox10. Between specification and terminal
differentiation, Sox9 and Sox10 are co-expressed in oligodendrocyte precursors
and are believed to exert additional functions. To identify such functions, we
have deleted Sox9 specifically in already specified oligodendrocyte precursors
of the spinal cord. In the absence of Sox9, oligodendrocyte precursors developed
normally and started terminal differentiation on schedule. However, when Sox10
was additionally deleted, oligodendrocyte precursors exhibited an altered
migration pattern and were present in reduced numbers because of increased
apoptosis rates. Remaining precursors continued to express many characteristic
oligodendroglial markers. Aberrant expression of astrocytic and neuronal markers
was not observed. Strikingly, we failed to detect PDGF receptor alpha expression
in the mutant oligodendrocyte precursors, arguing that PDGF receptor alpha is
under transcriptional control of Sox9 and Sox10. Altered PDGF receptor alpha
expression is furthermore sufficient to explain the observed phenotype, as PDGF
is both an important survival factor and migratory cue for oligodendrocyte
precursors. We thus conclude that Sox9 and Sox10 are required in a functionally
redundant manner in oligodendrocyte precursors for PDGF-dependent survival and
migration.
DOI: 10.1242/dev.010454
PMID: 18184726 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29181082 | 1. Arch Med Sci. 2017 Oct;13(6):1493-1503. doi: 10.5114/aoms.2016.60655. Epub
2016 Jun 17.
SOX10-MITF pathway activity in melanoma cells.
Tudrej KB(1), Czepielewska E(1), Kozłowska-Wojciechowska M(1).
Author information:
(1)Department of Clinical Pharmacology and Pharmaceutical Care, Medical
University of Warsaw, Warsaw, Poland.
Melanoma is one of the most dangerous and lethal skin cancers, with a
considerable metastatic potential and drug resistance. It involves a malignant
transformation of melanocytes. The exact course of events in which melanocytes
become melanoma cells remains unclear. Nevertheless, this process is said to be
dependent on the occurrence of cells with the phenotype of progenitor cells -
cells characterized by expression of proteins such as nestin, CD-133 or CD-271.
The development of these cells and their survival were found to be potentially
dependent on the neural crest stem cell transcription factor SOX10. This is just
one of the possible roles of SOX10, which contributes to melanomagenesis by
regulating the SOX10-MITF pathway, but also to melanoma cell survival,
proliferation and metastasis formation. The aim of this review is to describe
the broad influence of the SOX10-MITF pathway on melanoma cells.
DOI: 10.5114/aoms.2016.60655
PMCID: PMC5701683
PMID: 29181082 |
http://www.ncbi.nlm.nih.gov/pubmed/16214168 | 1. J Mol Biol. 2005 Nov 11;353(5):1033-42. doi: 10.1016/j.jmb.2005.09.013. Epub
2005 Sep 23.
The high-mobility group transcription factor Sox10 interacts with the
N-myc-interacting protein Nmi.
Schlierf B(1), Lang S, Kosian T, Werner T, Wegner M.
Author information:
(1)Institut für Biochemie, Universität Erlangen-Nürnberg, D-91054 Erlangen,
Germany.
The high-mobility group transcription factor Sox10 exerts many different roles
during development of the neural crest and nervous system. To unravel its
complex transcriptional functions, we have started to look for interaction
partners. Here, we identify an association of Sox10 with the N-myc interactor
Nmi, which was mediated by the high-mobility group of Sox10 and the central
region of Nmi. In vivo relevance of this interaction is indicated by the fact
that both proteins were co-expressed in glial cells, gliomas and in the spinal
cord. Additionally, subcellular localization of Nmi in C6 glioma depended on the
presence of Sox10 such that nuclear Nmi was more frequent in Sox10-expressing
cells. Importantly, Nmi modulated the transcriptional activity of Sox10 in
reporter gene assays. Nmi effects varied between different Sox10 target gene
promoters, indicating that Nmi function in vivo may be promoter-specific.
DOI: 10.1016/j.jmb.2005.09.013
PMID: 16214168 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11156606 | 1. Genes Dev. 2001 Jan 1;15(1):66-78. doi: 10.1101/gad.186601.
The transcription factor Sox10 is a key regulator of peripheral glial
development.
Britsch S(1), Goerich DE, Riethmacher D, Peirano RI, Rossner M, Nave KA,
Birchmeier C, Wegner M.
Author information:
(1)Max-Delbrück-Center for Molecular Medicine, D-13122 Berlin, Germany.
The molecular mechanisms that determine glial cell fate in the vertebrate
nervous system have not been elucidated. Peripheral glial cells differentiate
from pluripotent neural crest cells. We show here that the transcription factor
Sox10 is a key regulator in differentiation of peripheral glial cells. In mice
that carry a spontaneous or a targeted mutation of Sox10, neuronal cells form in
dorsal root ganglia, but Schwann cells or satellite cells are not generated. At
later developmental stages, this lack of peripheral glial cells results in a
severe degeneration of sensory and motor neurons. Moreover, we show that Sox10
controls expression of ErbB3 in neural crest cells. ErbB3 encodes a Neuregulin
receptor, and down-regulation of ErbB3 accounts for many changes in development
of neural crest cells observed in Sox10 mutant mice. Sox10 also has functions
not mediated by ErbB3, for instance in the melanocyte lineage. Phenotypes
observed in heterozygous mice that carry a targeted Sox10 null allele reproduce
those observed in heterozygous Sox10(Dom) mice. Haploinsufficiency of Sox10 can
thus cause pigmentation and megacolon defects, which are also observed in
Sox10(Dom)/+ mice and in patients with Waardenburg-Hirschsprung disease caused
by heterozygous SOX10 mutations.
DOI: 10.1101/gad.186601
PMCID: PMC312607
PMID: 11156606 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23935512 | 1. PLoS Genet. 2013;9(7):e1003644. doi: 10.1371/journal.pgen.1003644. Epub 2013
Jul 25.
A dual role for SOX10 in the maintenance of the postnatal melanocyte lineage and
the differentiation of melanocyte stem cell progenitors.
Harris ML(1), Buac K, Shakhova O, Hakami RM, Wegner M, Sommer L, Pavan WJ.
Author information:
(1)Genetic Disease Research Branch, National Human Genome Institute, National
Institutes of Health, Bethesda, Maryland, United States of America.
During embryogenesis, the transcription factor, Sox10, drives the survival and
differentiation of the melanocyte lineage. However, the role that Sox10 plays in
postnatal melanocytes is not established. We show in vivo that melanocyte stem
cells (McSCs) and more differentiated melanocytes express SOX10 but that McSCs
remain undifferentiated. Sox10 knockout (Sox10(fl); Tg(Tyr::CreER)) results in
loss of both McSCs and differentiated melanocytes, while overexpression of Sox10
(Tg(DctSox10)) causes premature differentiation and loss of McSCs, leading to
hair graying. This suggests that levels of SOX10 are key to normal McSC function
and Sox10 must be downregulated for McSC establishment and maintenance. We
examined whether the mechanism of Tg(DctSox10) hair graying is through increased
expression of Mitf, a target of SOX10, by asking if haploinsufficiency for Mitf
(Mitf(vga9) ) can rescue hair graying in Tg(DctSox10) animals. Surprisingly,
Mitf(vga9) does not mitigate but exacerbates Tg(DctSox10) hair graying
suggesting that MITF participates in the negative regulation of Sox10 in McSCs.
These observations demonstrate that while SOX10 is necessary to maintain the
postnatal melanocyte lineage it is simultaneously prevented from driving
differentiation in the McSCs. This data illustrates how tissue-specific stem
cells can arise from lineage-specified precursors through the regulation of the
very transcription factors important in defining that lineage.
DOI: 10.1371/journal.pgen.1003644
PMCID: PMC3723529
PMID: 23935512 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/28012818 | 1. Dev Biol. 2017 Feb 1;422(1):47-57. doi: 10.1016/j.ydbio.2016.12.004. Epub 2016
Dec 22.
Tissue specific regulation of the chick Sox10E1 enhancer by different Sox family
members.
Murko C(1), Bronner ME(2).
Author information:
(1)Division of Biology and Biological Engineering, California Institute of
Technology, Pasadena, CA 91125, United States.
(2)Division of Biology and Biological Engineering, California Institute of
Technology, Pasadena, CA 91125, United States. Electronic address:
[email protected].
The transcription factor Sox10 is a key regulator of vertebrate neural crest
development and serves crucial functions in the differentiation of multiple
neural crest lineages. In the chick neural crest, two cis-regulatory elements
have been identified that mediate Sox10 expression: Sox10E2, which initiates
expression in cranial neural crest; Sox10E1 driving expression in vagal and
trunk neural crest. Both also mediate Sox10 expression in the otic placode.
Here, we have dissected and analyzed the Sox10E1 enhancer element to identify
upstream regulatory inputs. Via mutational analysis, we found two critical Sox
sites with differential impact on trunk versus otic Sox10E1 mediated reporter
expression. Mutation of a combined SoxD/E motif was sufficient to completely
abolish neural crest but not ear enhancer activity. However, mutation of both
the SoxD/E and another SoxE site eliminated otic Sox10E1 expression.
Loss-of-function experiments reveal Sox5 and Sox8 as critical inputs for trunk
neural crest enhancer activity, but only Sox8 for its activity in the ear.
Finally, we show by ChIP and co-immunoprecipitation that Sox5 directly binds to
the SoxD/E site, and that it can interact with Sox8, further supporting their
combinatorial role in activation of Sox10E1 in the trunk neural crest. The
results reveal important tissue-specific inputs into Sox10 expression in the
developing embryo.
Copyright © 2016 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ydbio.2016.12.004
PMCID: PMC5810587
PMID: 28012818 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27466180 | 1. Hum Mol Genet. 2016 Sep 15;25(18):3925-3936. doi: 10.1093/hmg/ddw233. Epub
2016 Jul 27.
SOX10 regulates an alternative promoter at the Charcot-Marie-Tooth disease locus
MTMR2.
Fogarty EA(1), Brewer MH(2), Rodriguez-Molina JF(3), Law WD(2), Ma KH(3),
Steinberg NM(2), Svaren J(4)(5), Antonellis A(6)(2)(7).
Author information:
(1)Neuroscience Graduate Program.
(2)Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
(3)Cellular and Molecular Pathology (CMP) Program.
(4)Waisman Center.
(5)Department of Comparative Biosciences, University of Wisconsin-Madison,
Madison, WI, USA.
(6)Neuroscience Graduate Program [email protected].
(7)Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
Schwann cells are the myelinating glia of the peripheral nervous system and
dysfunction of these cells causes motor and sensory peripheral neuropathy. The
transcription factor SOX10 is critical for Schwann cell development and
maintenance, and many SOX10 target genes encode proteins required for Schwann
cell function. Loss-of-function mutations in the gene encoding
myotubularin-related protein 2 (MTMR2) cause Charcot-Marie-Tooth disease type
4B1 (CMT4B1), a severe demyelinating peripheral neuropathy characterized by
myelin outfoldings along peripheral nerves. Previous reports indicate that MTMR2
is ubiquitously expressed making it unclear how loss of this gene causes a
Schwann cell-specific phenotype. To address this, we performed computational and
functional analyses at MTMR2 to identify transcriptional regulatory elements
important for Schwann cell expression. Through these efforts, we identified an
alternative, SOX10-responsive promoter at MTMR2 that displays strong regulatory
activity in immortalized rat Schwann (S16) cells. This promoter directs
transcription of a previously unidentified MTMR2 transcript that is enriched in
mouse Schwann cells compared to immortalized mouse motor neurons (MN-1), and is
predicted to encode an N-terminally truncated protein isoform. The expression of
the endogenous transcript is induced in a heterologous cell line by ectopically
expressing SOX10, and is nearly ablated in Schwann cells by impairing SOX10
function. Intriguingly, overexpressing the two MTMR2 protein isoforms in HeLa
cells revealed that both localize to nuclear puncta and the shorter isoform
displays higher nuclear localization compared to the longer isoform. Combined,
our data warrant further investigation of the truncated MTMR2 protein isoform in
Schwann cells and in CMT4B1 pathogenesis.
© The Author 2016. Published by Oxford University Press. All rights reserved.
For Permissions, please email: [email protected].
DOI: 10.1093/hmg/ddw233
PMCID: PMC5291229
PMID: 27466180 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11731238 | 1. Mech Dev. 2001 Dec;109(2):253-65. doi: 10.1016/s0925-4773(01)00547-0.
Development and degeneration of dorsal root ganglia in the absence of the
HMG-domain transcription factor Sox10.
Sonnenberg-Riethmacher E(1), Miehe M, Stolt CC, Goerich DE, Wegner M,
Riethmacher D.
Author information:
(1)Zentrum für Molekulare Neurobiologie, Universität Hamburg, Falkenried 94,
20251, Hamburg, Germany.
The HMG-domain transcription factor Sox10 is essential for the development of
various neural crest derived lineages including glia and neurons of the
peripheral nervous system (PNS). Within the PNS the most striking defect is the
complete absence of glial differentiation whereas neurogenesis seemed initially
normal. A degeneration of motoneurons and sensory neurons occurred later in
development. The mechanism that leads to the dramatic effects on the neural
crest derived cell lineages in the dorsal root ganglia (DRG), however, has not
been examined up to now. Here, we provide a detailed analysis of proliferation
and apoptosis in the DRG during the time of their generation and lineage
segregation (between E 9.5 and E 11.5). We show that both increased apoptosis as
well as decreased proliferation of neural crest cells contribute to the observed
hypomorphism.
DOI: 10.1016/s0925-4773(01)00547-0
PMID: 11731238 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16494873 | 1. FEBS Lett. 2006 Mar 6;580(6):1635-41. doi: 10.1016/j.febslet.2006.02.011. Epub
2006 Feb 17.
Sumoylation of the SOX10 transcription factor regulates its transcriptional
activity.
Girard M(1), Goossens M.
Author information:
(1)INSERM U654, Bases Moléculaires et Cellulaires des Maladies Génétiques,
France.
SRY-related HMG box-containing factor 10 (SOX10) is a transcription factor
essential for neural crest development and differentiation, and involved in
Waardenburg syndrome type IV and PCWH syndrome. Here we show that the SOX10
protein is modified by sumoylation, a highly dynamic post-translational
modification that affects stability, activity and localisation of some specific
transcription factors. Three sumoylation consensus sites were found in the SOX10
protein, all of them are functional and modulate SOX10 activity. Sumoylation
does not affect SOX10 sub-cellular localisation, but represses its
transcriptional activity on two of its target genes, GJB1 and MITF, and
modulates its synergy with its cofactors EGR2 and PAX3 on these promoters.
DOI: 10.1016/j.febslet.2006.02.011
PMID: 16494873 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25629959 | 1. PLoS Genet. 2015 Jan 28;11(1):e1004877. doi: 10.1371/journal.pgen.1004877.
eCollection 2015 Jan.
Antagonistic cross-regulation between Sox9 and Sox10 controls an
anti-tumorigenic program in melanoma.
Shakhova O(1), Cheng P(2), Mishra PJ(3), Zingg D(1), Schaefer SM(1), Debbache
J(1), Häusel J(1), Matter C(4), Guo T(3), Davis S(3), Meltzer P(3), Mihic-Probst
D(5), Moch H(5), Wegner M(6), Merlino G(3), Levesque MP(2), Dummer R(2), Santoro
R(7), Cinelli P(8), Sommer L(1).
Author information:
(1)Cell and Developmental Biology, Institute of Anatomy, University of Zurich,
Zurich, Switzerland.
(2)Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
(3)Laboratory of Cancer Biology and Genetics, National Cancer Institute,
Bethesda, Maryland, United States of America.
(4)Department of Oncology, University Hospital Zurich, Schlieren, Switzerland.
(5)Department of Pathology, Institute of Surgical Pathology, University Hospital
Zurich, Zurich, Switzerland.
(6)Institute of Biochemistry, Emil Fischer Center, FAU University of
Erlangen-Nuernberg, Erlangen, Germany.
(7)Institute of Veterinary Biochemistry and Molecular Biology, University of
Zurich, Zurich, Switzerland.
(8)Division of Trauma Surgery, Center for Clinical Research, University Hospital
Zurich, Zurich, Switzerland.
Melanoma is the most fatal skin cancer, but the etiology of this devastating
disease is still poorly understood. Recently, the transcription factor Sox10 has
been shown to promote both melanoma initiation and progression. Reducing SOX10
expression levels in human melanoma cells and in a genetic melanoma mouse model,
efficiently abolishes tumorigenesis by inducing cell cycle exit and apoptosis.
Here, we show that this anti-tumorigenic effect functionally involves SOX9, a
factor related to SOX10 and upregulated in melanoma cells upon loss of SOX10.
Unlike SOX10, SOX9 is not required for normal melanocyte stem cell function, the
formation of hyperplastic lesions, and melanoma initiation. To the contrary,
SOX9 overexpression results in cell cycle arrest, apoptosis, and a gene
expression profile shared by melanoma cells with reduced SOX10 expression.
Moreover, SOX9 binds to the SOX10 promoter and induces downregulation of SOX10
expression, revealing a feedback loop reinforcing the SOX10 low/SOX9 high
ant,m/ii-tumorigenic program. Finally, SOX9 is required in vitro and in vivo for
the anti-tumorigenic effect achieved by reducing SOX10 expression. Thus, SOX10
and SOX9 are functionally antagonistic regulators of melanoma development.
DOI: 10.1371/journal.pgen.1004877
PMCID: PMC4309598
PMID: 25629959 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/25724000 | 1. Am J Surg Pathol. 2015 Jun;39(6):826-35. doi: 10.1097/PAS.0000000000000398.
Sox10--a marker for not only schwannian and melanocytic neoplasms but also
myoepithelial cell tumors of soft tissue: a systematic analysis of 5134 tumors.
Miettinen M(1), McCue PA, Sarlomo-Rikala M, Biernat W, Czapiewski P, Kopczynski
J, Thompson LD, Lasota J, Wang Z, Fetsch JF.
Author information:
(1)*Laboratory of Pathology, NCI/NIH, Bethesda #Joint Pathology Center of the
Capital Region, Silver Spring, MD †Department of Pathology, Kimmel Medical
College of Thomas Jefferson University, Philadelphia, PA ¶Southern California
Permanente Medical Group, Woodland Hills, CA ‡University of Helsinki and
HUSLab/Pathology, Helsinki, Finland §Department of Pathology, Medical University
of Gdansk, Gdansk ∥Holy Cross Cancer Center, Kielce, Poland.
Sox10 transcription factor is expressed in schwannian and melanocytic lineages
and is important in their development and can be used as a marker for
corresponding tumors. In addition, it has been reported in subsets of
myoepithelial/basal cell epithelial neoplasms, but its expression remains
incompletely characterized. In this study, we examined Sox10 expression in 5134
human neoplasms spanning a wide spectrum of neuroectodermal, mesenchymal,
lymphoid, and epithelial tumors. A new rabbit monoclonal antibody (clone EP268)
and Leica Bond Max automation were used on multitumor block libraries containing
30 to 70 cases per slide. Sox10 was consistently expressed in benign Schwann
cell tumors of soft tissue and the gastrointestinal tract and in metastatic
melanoma and was variably present in malignant peripheral nerve sheath tumors.
In contrast, Sox10 was absent in many potential mimics of nerve sheath tumors
such as cellular neurothekeoma, meningioma, gastrointestinal stromal tumors,
perivascular epithelioid cell tumor and a variety of
fibroblastic-myofibroblastic tumors. Sox10 was virtually absent in mesenchymal
tumors but occasionally seen in alveolar rhabdomyosarcoma. In epithelial tumors
of soft tissue, Sox10 was expressed only in myoepitheliomas, although often
absent in malignant variants. Carcinomas, other than basal cell-type breast
cancers, were only rarely positive but included 6% of squamous carcinomas of
head and neck and 7% of pulmonary small cell carcinomas. Furthermore, Sox10 was
often focally expressed in embryonal carcinoma reflecting a primitive
Sox10-positive phenotype or neuroectodermal differentiation. Expression of Sox10
in entrapped non-neoplastic Schwann cells or melanocytes in various neoplasms
has to be considered in diagnosing Sox10-positive tumors. The Sox10 antibody
belongs in a modern immunohistochemical panel for the diagnosis of soft tissue
and epithelial tumors.
DOI: 10.1097/PAS.0000000000000398
PMCID: PMC4431945
PMID: 25724000 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11641219 | 1. Development. 2001 Oct;128(20):3949-61. doi: 10.1242/dev.128.20.3949.
Survival and glial fate acquisition of neural crest cells are regulated by an
interplay between the transcription factor Sox10 and extrinsic combinatorial
signaling.
Paratore C(1), Goerich DE, Suter U, Wegner M, Sommer L.
Author information:
(1)Institute of Cell Biology, Swiss Federal Institute of Technology,
ETH-Hönggerberg, CH-8093 Zurich, Switzerland.
The transcription factor Sox10 is required for proper development of various
neural crest-derived cell types. Several lineages including melanocytes,
autonomic and enteric neurons, and all subtypes of peripheral glia are missing
in mice homozygous for Sox10 mutations. Moreover, haploinsufficiency of Sox10
results in neural crest defects that cause Waardenburg/Hirschsprung disease in
humans. We provide evidence that the cellular basis to these phenotypes is
likely to be a requirement for Sox10 by neural crest stem cells before lineage
segregation. Cell death is increased in undifferentiated, postmigratory neural
crest cells that lack Sox10, suggesting a role of Sox10 in the survival of
neural crest cells. This function is mediated by neuregulin, which acts as a
survival signal for postmigratory neural crest cells in a Sox10-dependent
manner. Furthermore, Sox10 is required for glial fate acquisition, as the
surviving mutant neural crest cells are unable to adopt a glial fate when
challenged with different gliogenic conditions. In Sox10 heterozygous mutant
neural crest cells, survival appears to be normal, while fate specifications are
drastically affected. Thereby, the fate chosen by a mutant neural crest cell is
context dependent. Our data indicate that combinatorial signaling by Sox10,
extracellular factors such as neuregulin 1, and local cell-cell interactions is
involved in fine-tuning lineage decisions by neural crest stem cells. Failures
in fate decision processes might thus contribute to the etiology of
Waardenburg/Hirschsprung disease.
DOI: 10.1242/dev.128.20.3949
PMID: 11641219 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22173870 | 1. Genesis. 2012 Jun;50(6):506-15. doi: 10.1002/dvg.22003. Epub 2012 Feb 20.
Sox10-iCreERT2 : a mouse line to inducibly trace the neural crest and
oligodendrocyte lineage.
Simon C(1), Lickert H, Götz M, Dimou L.
Author information:
(1)Physiological Genomics, Institute of Physiology, Ludwig-Maximilians
University, Munich, Germany.
SOX10 is a well-conserved and widely expressed transcription factor involved in
the regulation of embryonic development and in the determination of cell fate.
As it is expressed in neural crest cells, their derivatives and the
oligodendrocyte lineage, mutations of the protein contribute to a variety of
diseases like neurocristopathies, peripheral demyelinating neuropathies, and
melanoma. Here, we report the generation of an inducible Sox10-iCreER(T2) BAC
transgenic mouse line that labels, depending on the timepoint of induction,
distinct derivatives of the otic placode and the neural crest as well as cells
of the oligodendrocyte lineage. Surprisingly, we could show a neural crest
origin of pericytes in the brain. Besides its use for fate-mapping, the
Sox10-iCreER(T2) mouse line is a powerful tool to conditionally inactivate genes
in the neural crest cells, their progeny and/or the oligodendrocyte lineage in a
time-dependent fashion to gain further insights into their function and
contribution to diseases.
Copyright © 2011 Wiley Periodicals, Inc.
DOI: 10.1002/dvg.22003
PMID: 22173870 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27943102 | 1. Med Oncol. 2017 Jan;34(1):8. doi: 10.1007/s12032-016-0865-2. Epub 2016 Dec 10.
Clinicopathological evaluation of Sox10 expression in diffuse-type gastric
adenocarcinoma.
Kato M(1), Nishihara H(2)(3)(4), Hayashi H(5), Kimura T(6)(7), Ishida Y(7), Wang
L(6), Tsuda M(1), Tanino MA(1), Tanaka S(1)(6).
Author information:
(1)Department of Cancer Pathology, Hokkaido University Graduate School of
Medicine, N15W7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
(2)Department of Translational Pathology, Hokkaido University Graduate School of
Medicine, N15W7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
[email protected].
(3)Division of Clinical Cancer Genomics, Hokkaido University Hospital, N14W5,
Kita-ku, Sapporo, Hokkaido, 060-8648, Japan. [email protected].
(4)Clinical Research and Medical Innovation Cancer, Hokkaido University
Hospital, N14W5, Kita-ku, Sapporo, Hokkaido, 060-8648, Japan.
[email protected].
(5)Division of Clinical Cancer Genomics, Hokkaido University Hospital, N14W5,
Kita-ku, Sapporo, Hokkaido, 060-8648, Japan.
(6)Department of Translational Pathology, Hokkaido University Graduate School of
Medicine, N15W7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
(7)Clinical Research and Medical Innovation Cancer, Hokkaido University
Hospital, N14W5, Kita-ku, Sapporo, Hokkaido, 060-8648, Japan.
Sox10, one of the transcription factors, regulates Wnt/β-catenin signaling in
diverse developmental processes in normal tissues. Sox10 is also expressed in
variable solid tumors such as breast cancer, salivary tumor, hepatocellular
carcinoma, ovarian tumor, nasopharyngeal carcinoma, prostate cancer, and
digestive cancer. The role of Sox10 during tumorigenesis is still controversial,
especially in digestive cancers; thus, we performed clinicopathological
evaluation of Sox10 expression in 41 cases of diffuse-type gastric
adenocarcinoma (DGA). We examined the expression of Sox10 by immunohistochemical
staining and real-time quantitative reverse transcriptase PCR and evaluated the
correlation between Sox10 expression and clinicopathological factors. A
low-level expression of Sox10 was significantly associated with high-level
venous invasion by immunohistochemical evaluation, while it was significantly
associated with high-level lymphatic permeation when analyzed by real-time PCR
assay. Survival analysis of 41 cases indicated that high level of vascular
permeation was a statistically poor prognostic factor, suggesting that
derogation of Sox10 would lead to unfavorable patients' outcome through the
acceleration of vascular invasion. In this study, we revealed the clinical
benefit of evaluation of Sox10 expression to predict the risk of vascular
permeation which yields patients' poor prognosis in DGA.
DOI: 10.1007/s12032-016-0865-2
PMID: 27943102 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34385359 | 1. J Neurosci. 2021 Sep 29;41(39):8163-8180. doi: 10.1523/JNEUROSCI.2432-20.2021.
Epub 2021 Aug 12.
Akt Regulates Sox10 Expression to Control Oligodendrocyte Differentiation via
Phosphorylating FoxO1.
Wang H(1), Liu M(1), Ye Z(1), Zhou C(2), Bi H(1), Wang L(1), Zhang C(3), Fu
H(4), Shen Y(5), Yang JJ(6), Hu Y(7), Chen G(8).
Author information:
(1)Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study,
Model Animal Research Center, Jiangsu Key Laboratory of Molecular Medicine,
Medical School, Nanjing University, Nanjing 210061, People's Republic of China.
(2)Department of Anesthesiology, The Second Affiliated Changzhou People's
Hospital of Nanjing Medical University, Changzhou 213000, People's Republic of
China.
(3)School of Basic Medical Sciences, Beijing Key Laboratory of Neural
Regeneration and Repair, Advanced Innovation Center for Human Brain Protection,
Capital Medical University, Beijing 100069, People's Republic of China.
(4)School of Basic Medical Sciences, Wuhan University, Wuhan 430071, People's
Republic of China.
(5)Department of Neurobiology, Key Laboratory of Medical Neurobiology of the
Ministry of Health, Zhejiang University School of Medicine, Hangzhou 310058,
People's Republic of China.
(6)Department of Anesthesiology, Pain and Perioperative Medicine, The First
Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic
of China.
(7)Department of Anesthesiology, The Second Affiliated Changzhou People's
Hospital of Nanjing Medical University, Changzhou 213000, People's Republic of
China [email protected] [email protected].
(8)Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study,
Model Animal Research Center, Jiangsu Key Laboratory of Molecular Medicine,
Medical School, Nanjing University, Nanjing 210061, People's Republic of China
[email protected] [email protected].
Sox10 is a well known factor to control oligodendrocyte (OL) differentiation,
and its expression is regulated by Olig2. As an important protein kinase, Akt
has been implicated in diseases with white matter abnormalities. To study
whether and how Akt may regulate OL development, we generated OL lineage
cell-specific Akt1/Akt2/Akt3 triple conditional knock-out (Akt cTKO) mice. Both
male and female mice were used. These mutants exhibit a complete loss of mature
OLs and unchanged apoptotic cell death in the CNS. We show that the deletion of
Akt three isoforms causes downregulation of Sox10 and decreased levels of
phosphorylated FoxO1 in the brain. In vitro analysis reveals that the expression
of FoxO1 with mutations on phosphorylation sites for Akt significantly represses
the Sox10 promoter activity, suggesting that phosphorylation of FoxO1 by Akt is
important for Sox10 expression. We further demonstrate that mutant FoxO1 without
Akt phosphorylation epitopes is enriched in the Sox10 promoter. Together, this
study identifies a novel FoxO1 phosphorylation-dependent mechanism for Sox10
expression and OL differentiation.SIGNIFICANCE STATEMENT Dysfunction of Akt is
associated with white matter diseases including the agenesis of the corpus
callosum. However, it remains unknown whether Akt plays an important role in
oligodendrocyte differentiation. To address this question, we generated
oligodendrocyte lineage cell-specific Akt1/Akt2/Akt3 triple-conditional
knock-out mice. Akt mutants exhibit deficient white matter development, loss of
mature oligodendrocytes, absence of myelination, and unchanged apoptotic cell
death in the CNS. We demonstrate that deletion of Akt three isoforms leads to
downregulation of Sox10, and that phosphorylation of FoxO1 by Akt is critical
for Sox10 expression. Together, these findings reveal a novel mechanism to
regulate Sox10 expression. This study may provide insights into molecular
mechanisms for neurodevelopmental diseases caused by dysfunction of protein
kinases.
Copyright © 2021 the authors.
DOI: 10.1523/JNEUROSCI.2432-20.2021
PMCID: PMC8482862
PMID: 34385359 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35546709 | 1. J Coll Physicians Surg Pak. 2022 May;32(5):671-673. doi:
10.29271/jcpsp.2022.05.671.
Neurological Recovery with Interferon-gamma Treatment in Friedreich's Ataxia.
Tekin HG(1), Levent E(2).
Author information:
(1)Department of Pediatric Neurology, Bakircay University Cigli Training and
Education Hospital, Yeni Mahalle Ata Sanayi, Cigli, Izmir, Turkey.
(2)Department of Pediatric Cardiology, Ege University, Ege Universitesi
Hastanesi Bornova, Izmir, Turkey.
Friedreich's ataxia (FA) is a rare, progressive, and degenerative hereditary
disorder caused by a deficiency of frataxin protein. This disease is
characterised by severe neurological dysfunction and life-threatening
cardiomyopathy. Various drugs are used to slow down / stop the neurodegenerative
progress. However, recent clinical trials and animal experiments demonstrate
that interferon-gamma (IFN-ɣ) treatment might improve signs of FA as well. A
9-year-old girl was admitted to our hospital with gait instability, mild
dysarthria, and sensorimotor polyneuropathy. Her genetic examination was
consistent with FA. IFN-ɣ treatment was started 3 times a week. The treatment
was evaluated by physical examination and side effects assessment. Friedreich
Ataxia Rating Scale (FARS), 9-hole peg test (9HPT), and time of 25-foot walk
(T25FW) were measured. Ataxia and cerebellar findings improved within 9
months. Although clinical neurological improvement was achieved, there was no
improvement in cardiomyopathy. Key Words: Interferon-gamma, Friedreich ataxia,
FARS, Children, Cardiomyopathy.
DOI: 10.29271/jcpsp.2022.05.671
PMID: 35546709 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35682973 | 1. Int J Mol Sci. 2022 Jun 4;23(11):6297. doi: 10.3390/ijms23116297.
Neuroinflammation in Friedreich's Ataxia.
Apolloni S(1), Milani M(1), D'Ambrosi N(1).
Author information:
(1)Department of Biology, Tor Vergata University of Rome, 00133 Roma, Italy.
Friedreich's ataxia (FRDA) is a rare genetic disorder caused by mutations in the
gene frataxin, encoding for a mitochondrial protein involved in iron handling
and in the biogenesis of iron-sulphur clusters, and leading to progressive
nervous system damage. Although the overt manifestations of FRDA in the nervous
system are mainly observed in the neurons, alterations in non-neuronal cells may
also contribute to the pathogenesis of the disease, as recently suggested for
other neurodegenerative disorders. In FRDA, the involvement of glial cells can
be ascribed to direct effects caused by frataxin loss, eliciting different
aberrant mechanisms. Iron accumulation, mitochondria dysfunction, and reactive
species overproduction, mechanisms identified as etiopathogenic in neurons in
FRDA, can similarly affect glial cells, leading them to assume phenotypes that
can concur to and exacerbate neuron loss. Recent findings obtained in FRDA
patients and cellular and animal models of the disease have suggested that
neuroinflammation can accompany and contribute to the neuropathology. In this
review article, we discuss evidence about the involvement of
neuroinflammatory-related mechanisms in models of FRDA and provide clues for the
modulation of glial-related mechanisms as a possible strategy to improve disease
features.
DOI: 10.3390/ijms23116297
PMCID: PMC9181348
PMID: 35682973 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/36198237 | 1. Differentiation. 2022 Nov-Dec;128:13-25. doi: 10.1016/j.diff.2022.09.001. Epub
2022 Sep 23.
Comparative role of SOX10 gene in the gliogenesis of central, peripheral, and
enteric nervous systems.
Bhattarai C(1), Poudel PP(1), Ghosh A(2), Kalthur SG(3).
Author information:
(1)Department of Anatomy, Kasturba Medical College, Manipal, Manipal Academy of
Higher Education (MAHE), 576104, Karnataka, India; Department of Anatomy,
Manipal College of Medical Sciences, Pokhara, Nepal.
(2)Department of Pathology, Manipal-TATA Medical College, Jamshedpur, India.
(3)Department of Anatomy, Kasturba Medical College, Manipal, Manipal Academy of
Higher Education (MAHE), 576104, Karnataka, India. Electronic address:
[email protected].
SOX10 gene and SOX10 protein are responsible for the gliogenesis of neuroglia
from the neural crest cells. Expression of SOX10 gene encodes SOX10 protein
which binds with DNA at its minor groove via its HMG domain upon activation.
SOX10 protein undergoes bending and changes its conformation after binding with
DNA. Via its transactivation domain and HMG domain, it further activates several
other transcription factors, these cause gliogenesis of the neural crest cells
into neuroglia. In literature, it is stated that the SOX10 gene helps in the
formation of schwann cells, oligodendrocytes, and enteric ganglia from neural
crest cells. Altered expression of the SOX10 gene results in agliogenesis,
dysmyelination, and demyelination in the nervous system as well as intestinal
aganglionosis. This review highlighted that there is a role of the SOX10 gene
and SOX10 protein in enteric gliogenesis from the neural crest cells.
Copyright © 2022 International Society of Differentiation. Published by Elsevier
B.V. All rights reserved.
DOI: 10.1016/j.diff.2022.09.001
PMID: 36198237 [Indexed for MEDLINE]
Conflict of interest statement: Declarations of competing interest None |
http://www.ncbi.nlm.nih.gov/pubmed/26338206 | 1. Orphanet J Rare Dis. 2015 Sep 4;10:108. doi: 10.1186/s13023-015-0328-4.
Friedreich ataxia in Norway - an epidemiological, molecular and clinical study.
Wedding IM(1)(2), Kroken M(3), Henriksen SP(4), Selmer KK(3)(5), Fiskerstrand
T(6)(7), Knappskog PM(6)(7), Berge T(4), Tallaksen CM(4)(5).
Author information:
(1)Department of Neurology, Oslo University Hospital, Ullevaal, 0407, Oslo,
Norway. [email protected].
(2)University of Oslo, Faculty of Medicine, Oslo, Norway.
[email protected].
(3)Department of Medical Genetics, Oslo University Hospital, Ullevaal, 0407,
Oslo, Norway.
(4)Department of Neurology, Oslo University Hospital, Ullevaal, 0407, Oslo,
Norway.
(5)University of Oslo, Faculty of Medicine, Oslo, Norway.
(6)Department of Clinical Science, University of Bergen, Bergen, Norway.
(7)Center for Medical Genetics and Molecular Medicine, Haukeland University
Hospital, Bergen, Norway.
BACKGROUND: Friedreich ataxia is an autosomal recessive hereditary
spinocerebellar disorder, characterized by progressive limb and gait ataxia due
to proprioceptive loss, often complicated by cardiomyopathy, diabetes and
skeletal deformities. Friedreich ataxia is the most common hereditary ataxia,
with a reported prevalence of 1:20 000 - 1:50 000 in Central Europe. Previous
reports from south Norway have found a prevalence varying from 1:100 000 - 1:1
350 000; no studies are previously done in the rest of the country.
METHODS: In this cross-sectional study, Friedreich ataxia patients were
identified through colleagues in neurological, pediatric and genetic
departments, hospital archives searches, patients' associations, and National
Centre for Rare Disorders. All included patients, carriers and controls were
investigated clinically and molecularly with genotype characterization including
size determination of GAA repeat expansions and frataxin measurements. 1376
healthy blood donors were tested for GAA repeat expansion for carrier frequency
analysis.
RESULTS: Twenty-nine Friedreich ataxia patients were identified in Norway, of
which 23 were ethnic Norwegian, corresponding to a prevalence of 1:176 000 and
1:191 000, respectively. The highest prevalence was seen in the north. Carrier
frequency of 1:196 (95 % CI = [1:752-1:112]) was found. Homozygous GAA repeat
expansions in the FXN gene were found in 27/29, while two patients were compound
heterozygous with c.467 T < C, L157P and the deletion (g.120032_122808del)
including exon 5a. Two additional patients were heterozygous for GAA repeat
expansions only. Significant differences in the level of frataxin were found
between the included patients (N = 27), carriers (N = 37) and controls (N = 27).
CONCLUSIONS: In this first thorough study of a complete national cohort of
Friedreich ataxia patients, and first nation-wide study of Friedreich ataxia in
Norway, the prevalence of Friedreich ataxia in Norway is lower than in Central
Europe, but higher than in the last Norwegian report, and as expected from
migration studies. A south-north prevalence gradient is present. Based on Hardy
Weinberg's equilibrium, the carrier frequency of 1:196 is consistent with the
observed prevalence. All genotypes, and typical and atypical phenotypes were
present in the Norwegian population. The patients were phenotypically similar to
European cohorts. Frataxin was useful in the diagnostic work-up of heterozygous
symptomatic cases.
DOI: 10.1186/s13023-015-0328-4
PMCID: PMC4559212
PMID: 26338206 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18852343 | 1. Arch Neurol. 2008 Oct;65(10):1296-303. doi: 10.1001/archneur.65.10.1296.
Friedreich ataxia.
Pandolfo M(1).
Author information:
(1)Service de Neurologie, Erasme Hospital, Brussels Free University, Route de
Lennik 808, B-1070, Brussels, Belgium. [email protected]
Friedreich ataxia is an autosomal recessive degenerative disease that primarily
affects the nervous system and the heart. It is named after its original
description as a "degenerative atrophy of the posterior columns of the spinal
cord" by Nicholaus Friedreich, who was a professor of medicine in Heidelberg in
the second half of the 19th century. The full extent of the Friedreich ataxia
phenotype and its genetic epidemiology could only be appreciated after a direct
genetic test became available in 1996. At the same time, the complex
pathogenesis of Friedreich ataxia started to be unraveled. Herein, I review our
current knowledge of the disease and how it is contributing to the development
of therapeutic approaches.
DOI: 10.1001/archneur.65.10.1296
PMID: 18852343 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9448568 | 1. Brain. 1997 Dec;120 ( Pt 12):2131-40. doi: 10.1093/brain/120.12.2131.
Friedreich's ataxia. Revision of the phenotype according to molecular genetics.
Schöls L(1), Amoiridis G, Przuntek H, Frank G, Epplen JT, Epplen C.
Author information:
(1)Department of Neurology, St Josef Hospital, Bochum, Germany.
Friedreich's ataxia is an autosomal recessively inherited neurodegenerative
disorder caused by expansions of an unstable GAA trinucleotide repeat in the
STM7/X25 gene on chromosome 9q. We studied the (GAA)n polymorphism in 178
healthy controls and 102 patients with idiopathic ataxia. The repeat size ranged
from 7 to 29 (GAA)n motifs on normal chromosomes and from 66 to 1360
trinucleotide repetitions in Friedreich's ataxia patients. Meiotic instability
of expanded alleles was observed without significant differences in maternal and
paternal transmissions. Thirty-six of 102 patients were typed homozygous for
expanded (GAA)n alleles. Twenty-seven of these presented with the typical
Friedreich's ataxia symptoms and nine patients with an atypical Friedreich's
ataxia phenotype. Before molecular genetic diagnosis had been performed seven of
these patients had been classified as early onset cerebellar ataxia and two as
idiopathic sporadic cerebellar ataxia of late onset. In contrast, in one family
with typical Friedreich's ataxia phenotype we did not find an expanded allele;
this suggests that there can be either point mutations in the X25 gene on both
chromosomes or locus heterogeneity in Friedreich's ataxia. The phenotypic
spectrum of Friedreich's ataxia is much broader than considered before. Early
onset, areflexia, extensor plantar responses and reduced vibration sense should
no longer be considered essential diagnostic criteria of Friedreich's ataxia. In
comparison with the non-Friedreich's ataxia group hypertrophic cardiomyopathy
seems to be the only symptom specific for Friedreich's ataxia. However, it is
not obligatory. The phenotype is significantly influenced by the number of GAA
repeats with close genotype-phenotype relationships when the smaller of the two
alleles is considered. Repeat length correlated inversely with age at onset,
onset of dysarthria and progression rate. In conclusion, molecular genetic
analysis appears mandatory for the diagnosis and genetic counselling of
Friedreich's ataxia. The molecular genetic test should be applied not only to
patients with typical Friedreich's ataxia phenotype but also in all cases of
idiopathic autosomal recessive or sporadic ataxia.
DOI: 10.1093/brain/120.12.2131
PMID: 9448568 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34920960 | 1. Arch Cardiovasc Dis. 2022 Jan;115(1):17-28. doi: 10.1016/j.acvd.2021.10.010.
Epub 2021 Dec 16.
Characterizing cardiac phenotype in Friedreich's ataxia: The CARFA study.
Legrand L(1), Weinsaft JW(2), Pousset F(1), Ewenczyk C(3), Charles P(3), Hatem
S(4), Heinzmann A(3), Biet M(3), Durr A(3), Redheuil A(5).
Author information:
(1)Cardiology Department, Pitié-Salpêtrière Hospital (AP-HP), Sorbonne
Université, 75013 Paris, France; ICAN Institute of Cardiometabolism and
Nutrition, 75013 Paris, France.
(2)Weill Cornell Medicine, New York 10021, USA.
(3)Paris Brain Institute (ICM), INSERM, CNRS, Pitié-Salpêtrière Hospital
(AP-HP), Sorbonne Université, 75646 Paris cedex 13, France.
(4)Cardiology Department, Pitié-Salpêtrière Hospital (AP-HP), Sorbonne
Université, 75013 Paris, France; ICAN Institute of Cardiometabolism and
Nutrition, 75013 Paris, France; ICT Cardiothoracic Imaging Unit,
Pitié-Salpêtrière Hospital (AP-HP), Laboratoire d'Imagerie Biomédicale, Sorbonne
Université, Inserm, CNRS, 47-83, boulevard de l'hôpital, 75013 Paris, France.
(5)ICAN Institute of Cardiometabolism and Nutrition, 75013 Paris, France; ICT
Cardiothoracic Imaging Unit, Pitié-Salpêtrière Hospital (AP-HP), Laboratoire
d'Imagerie Biomédicale, Sorbonne Université, Inserm, CNRS, 47-83, boulevard de
l'hôpital, 75013 Paris, France. Electronic address: [email protected].
BACKGROUND: Friedreich's ataxia is an autosomal recessive mitochondrial disease
caused by a triplet repeat expansion in the frataxin gene (FXN), exhibiting
cerebellar sensory ataxia, diabetes and cardiomyopathy. Cardiac complications
are the major cause of early death.
AIMS: To characterize the cardiac phenotype associated with Friedreich's ataxia,
and to assess the evolution of the associated cardiopathy over 1 year.
METHODS: This observational single-centre open label study consisted of two
groups: 20 subjects with Friedreich's ataxia and 20 healthy controls studied
over two visits over 1 year. All subjects had transthoracic echocardiography,
cardiac magnetic resonance imaging, cardiopulmonary exercise testing,
quantification of serum cardiac biomarkers and neurological assessment.
RESULTS: Patients with Friedreich's ataxia had left ventricular hypertrophy,
with significantly smaller left ventricular diastolic diameters and volumes and
increased wall thicknesses. Cardiac magnetic resonance imaging demonstrated
significant concentric left ventricular remodelling, according to the
mass/volume ratio, and focal myocardial fibrosis in 50% of patients with
Friedreich's ataxia. Cardiopulmonary exercise testing showed alteration of left
ventricular diastolic filling in patients with Friedreich's ataxia, with an
elevated VE/VCO2 slope (ventilatory flow/exhaled volume of carbon dioxide).
High-sensitivity troponin T plasma concentrations were higher in subjects with
Friedreich's ataxia. None of the previous variables changed at 1 year.
Neurological assessments remained stable for both groups, except for the
nine-hole pegboard test, which was altered over 1 year.
CONCLUSIONS: The multivariable characterization of the cardiac phenotype of
patients with Friedreich's ataxia was significantly different from controls at
baseline. Over 1 year there were no clinically significant changes in patients
with Friedreich's ataxia compared with healthy controls, whereas the
neurological severity score increased modestly.
Copyright © 2021 Elsevier Masson SAS. All rights reserved.
DOI: 10.1016/j.acvd.2021.10.010
PMID: 34920960 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7614092 | 1. Clin Neurosci. 1995;3(1):33-8.
Friedreich ataxia.
Johnson WG(1).
Author information:
(1)Department of Neurology, UMDNJ-Robert Wood Johnson Medical School,
Piscataway, USA.
Friedreich ataxia is an autosomal recessive ataxia with onset usually before
puberty whose characteristic clinical features include progressive ataxia of
gait and limbs, dysarthria, loss of joint position and vibratory sense, absent
knee and ankle jerks, and Babinski signs. Foot deformity, scoliosis, diabetes
mellitus, and cardiac involvement are common and characteristic. Patients
survive until about age 30 years although longer survivals occur. A later onset,
more slowly progressive form seems to be an allelic variant. The basic process
seems to be a dying-back of neuronal processes. Using linkage mapping
techniques, the classical form of Friedreich ataxia has been localized to
9q13-q21, a region on the long arm of chromosome 9. Haplotype analysis, analysis
of recombinants, and physical mapping techniques, including construction of a
YAC contig, have narrowed the interval for the Friedreich ataxia gene, FRDA, to
a few hundred thousand base pairs. Candidate genes in the region are being
studied by techniques of mutation analysis. It is likely that the Freidreich
ataxia gene will be cloned soon. A condition resembling Friedreich ataxia with
decreased vitamin E levels has been localized to chromosome 8 and is discussed
elsewhere.
PMID: 7614092 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12878293 | 1. Pediatr Neurol. 2003 May;28(5):335-41. doi: 10.1016/s0887-8994(03)00004-3.
Friedreich's ataxia.
Alper G(1), Narayanan V.
Author information:
(1)Division of Child Neurology, Department of Pediatrics, Children's Hospital of
Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213, USA.
Friedreich's ataxia, the most common hereditary ataxia, is caused by expansion
of a GAA triplet located within the first intron of the frataxin gene on
chromosome 9q13. There is a clear correlation between size of the expanded
repeat and severity of the phenotype. Frataxin is a mitochondrial protein that
plays a role in iron homeostasis. Deficiency of frataxin results in
mitochondrial iron accumulation, defects in specific mitochondrial enzymes,
enhanced sensitivity to oxidative stress, and eventually free-radical mediated
cell death. Friedreich's ataxia is considered a nuclear encoded mitochondrial
disease. This review discusses the major and rapid progress made in Friedreich's
ataxia from gene mapping and identification of the gene to pathogenesis and
encouraging therapeutic implications.
DOI: 10.1016/s0887-8994(03)00004-3
PMID: 12878293 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29053830 | 1. Br Med Bull. 2017 Dec 1;124(1):19-30. doi: 10.1093/bmb/ldx034.
Friedreich's ataxia: clinical features, pathogenesis and management.
Cook A(1), Giunti P(1).
Author information:
(1)Department of Molecular Neuroscience, Ataxia Centre, UCL Institute of
Neurology, Queen Square, London, UK.
Comment in
Nat Genet. 2019 Apr;51(4):580-581. doi: 10.1038/s41588-019-0387-x.
INTRODUCTION: Friedreich's ataxia is the most common inherited ataxia.
SOURCES OF DATA: Literature search using PubMed with keywords Friedreich's
ataxia together with published papers known to the authors.
AREAS OF AGREEMENT: The last decade has seen important advances in our
understanding of the pathogenesis of disease. In particular, the genetic and
epigenetic mechanisms underlying the disease now offer promising novel
therapeutic targets.
AREAS OF CONTROVERSY: The search for effective disease-modifying agents
continues. It remains to be determined whether the most effective approach to
treatment lies with increasing frataxin protein levels or addressing the
metabolic consequences of the disease, for example with antioxidants.
AREAS TIMELY FOR DEVELOPING RESEARCH: Management of Freidreich's ataxia is
currently focussed on symptomatic management, delivered by the multidisciplinary
team. Phase II clinical trials in agents that address the abberrant silencing of
the frataxin gene need to be translated into large placebo-controlled Phase III
trials to help establish their therapeutic potential.
© The Author 2017. Published by Oxford University Press. All rights reserved.
For permissions, please e-mail: [email protected]
DOI: 10.1093/bmb/ldx034
PMCID: PMC5862303
PMID: 29053830 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30159187 | 1. Case Rep Neurol Med. 2018 Aug 9;2018:8587203. doi: 10.1155/2018/8587203.
eCollection 2018.
Friedreich's Ataxia: Clinical Presentation of a Compound Heterozygote Child with
a Rare Nonsense Mutation and Comparison with Previously Published Cases.
Rao VK(1)(2), DiDonato CJ(2)(3), Larsen PD(4).
Author information:
(1)Division of Neurology, Ann & Robert H. Lurie Children's Hospital of Chicago,
Chicago, IL 60611, USA.
(2)Department of Pediatrics, Feinberg School of Medicine, Northwestern
University, Chicago, IL 60611, USA.
(3)Human Molecular Genetics Program, Ann & Robert H. Lurie Children's Hospital,
Stanley Manne Research Institute, Chicago, IL 60611, USA.
(4)Division of Neurology, Department of Pediatrics, University of Nebraska
Medical Center and Children's Hospital and Medical Center, Omaha, NE, USA.
Friedreich's ataxia is a neurodegenerative disorder associated with a GAA
trinucleotide repeat expansion in intron 1 of the frataxin (FXN) gene. It is the
most common autosomal recessive cerebellar ataxia, with a mean age of onset at
16 years. Nearly 95-98% of patients are homozygous for a 90-1300 GAA repeat
expansion with only 2-5% demonstrating compound heterozygosity. Compound
heterozygous individuals have a repeat expansion in one allele and a point
mutation/deletion/insertion in the other. Compound heterozygosity and point
mutations are very rare causes of Friedreich's ataxia and nonsense mutations are
a further rarity among point mutations. We report a rare compound heterozygous
Friedrich's ataxia patient who was found to have one expanded GAA FXN allele and
a nonsense point mutation in the other. We summarize the four previously
published cases of nonsense mutations and compare the phenotype to that of our
patient. We compared clinical information from our patient with other nonsense
FXN mutations reported in the literature. This nonsense mutation, to our
knowledge, has only been described once previously; interestingly the individual
was also of Cuban ancestry. A comparison with previously published cases of
nonsense mutations demonstrates some common clinical characteristics.
DOI: 10.1155/2018/8587203
PMCID: PMC6106966
PMID: 30159187 |
http://www.ncbi.nlm.nih.gov/pubmed/21985033 | 1. BMC Med. 2011 Oct 11;9:112. doi: 10.1186/1741-7015-9-112.
Friedreich's ataxia: the vicious circle hypothesis revisited.
Bayot A(1), Santos R, Camadro JM, Rustin P.
Author information:
(1)Inserm, U676, Physiopathology and Therapy of Mitochondrial Diseases
Laboratory, CHU - Hôpital Robert Debré, 48, boulevard Sérurier, F-75019 Paris,
France.
Friedreich's ataxia, the most frequent progressive autosomal recessive disorder
involving the central and peripheral nervous systems, is mostly associated with
unstable expansion of GAA trinucleotide repeats in the first intron of the FXN
gene, which encodes the mitochondrial frataxin protein. Since FXN was shown to
be involved in Friedreich's ataxia in the late 1990s, the consequence of
frataxin loss of function has generated vigorous debate. Very early on we
suggested a unifying hypothesis according to which frataxin deficiency leads to
a vicious circle of faulty iron handling, impaired iron-sulphur cluster
synthesis and increased oxygen radical production. However, data from cell and
animal models now indicate that iron accumulation is an inconsistent and late
event and that frataxin deficiency does not always impair the activity of
iron-sulphur cluster-containing proteins. In contrast, frataxin deficiency
appears to be consistently associated with increased sensitivity to reactive
oxygen species as opposed to increased oxygen radical production. By compiling
the findings of fundamental research and clinical observations we defend here
the opinion that the very first consequence of frataxin depletion is indeed an
abnormal oxidative status which initiates the pathogenic mechanism underlying
Friedreich's ataxia.
DOI: 10.1186/1741-7015-9-112
PMCID: PMC3198887
PMID: 21985033 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23936609 | 1. Oxid Med Cell Longev. 2013;2013:487534. doi: 10.1155/2013/487534. Epub 2013
Jul 9.
Neurodegeneration in Friedreich's ataxia: from defective frataxin to oxidative
stress.
Gomes CM(1), Santos R.
Author information:
(1)Instituto Tecnologia Química e Biológica, Universidade Nova de Lisboa,
Avenida da República, 2784-505 Oeiras, Portugal.
Friedreich's ataxia is the most common inherited autosomal recessive ataxia and
is characterized by progressive degeneration of the peripheral and central
nervous systems and cardiomyopathy. This disease is caused by the silencing of
the FXN gene and reduced levels of the encoded protein, frataxin. Frataxin is a
mitochondrial protein that functions primarily in iron-sulfur cluster synthesis.
This small protein with an α / β sandwich fold undergoes complex processing and
imports into the mitochondria, generating isoforms with distinct N-terminal
lengths which may underlie different functionalities, also in respect to
oligomerization. Missense mutations in the FXN coding region, which compromise
protein folding, stability, and function, are found in 4% of FRDA heterozygous
patients and are useful to understand how loss of functional frataxin impacts on
FRDA physiopathology. In cells, frataxin deficiency leads to pleiotropic
phenotypes, including deregulation of iron homeostasis and increased oxidative
stress. Increasing amount of data suggest that oxidative stress contributes to
neurodegeneration in Friedreich's ataxia.
DOI: 10.1155/2013/487534
PMCID: PMC3725840
PMID: 23936609 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33670433 | 1. Int J Mol Sci. 2021 Feb 11;22(4):1815. doi: 10.3390/ijms22041815.
Future Prospects of Gene Therapy for Friedreich's Ataxia.
Ocana-Santero G(1)(2), Díaz-Nido J(1), Herranz-Martín S(1).
Author information:
(1)Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Departamento de
Biología Molecular, Universidad Autónoma de Madrid, Nicolás Cabrera 1, 28049
Madrid, Spain.
(2)Department of Physiology, Anatomy and Genetics, Sherrington Building, Parks
Road, University of Oxford, Oxford OX1 3PT, UK.
Friedreich's ataxia is an autosomal recessive neurogenetic disease that is
mainly associated with atrophy of the spinal cord and progressive
neurodegeneration in the cerebellum. The disease is caused by a GAA-expansion in
the first intron of the frataxin gene leading to a decreased level of frataxin
protein, which results in mitochondrial dysfunction. Currently, there is no
effective treatment to delay neurodegeneration in Friedreich's ataxia. A
plausible therapeutic approach is gene therapy. Indeed, Friedreich's ataxia
mouse models have been treated with viral vectors en-coding for either FXN or
neurotrophins, such as brain-derived neurotrophic factor showing promising
results. Thus, gene therapy is increasingly consolidating as one of the most
promising therapies. However, several hurdles have to be overcome, including
immunotoxicity and pheno-toxicity. We review the state of the art of gene
therapy in Friedreich's ataxia, addressing the main challenges and the most
feasible solutions for them.
DOI: 10.3390/ijms22041815
PMCID: PMC7918362
PMID: 33670433 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/20413654 | 1. Hum Mol Genet. 2010 Apr 15;19(R1):R103-10. doi: 10.1093/hmg/ddq165. Epub 2010
Apr 22.
Understanding the molecular mechanisms of Friedreich's ataxia to develop
therapeutic approaches.
Schmucker S(1), Puccio H.
Author information:
(1)Institut de Genetique et de Biologie Moleculaire et Cellulaire, BP10142,
IllkirchF-67400, France.
Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by reduced
expression of the mitochondrial protein frataxin. The physiopathological
consequences of frataxin deficiency are a severe disruption of iron-sulfur
cluster biosynthesis, mitochondrial iron overload coupled to cellular iron
dysregulation and an increased sensitivity to oxidative stress. Frataxin is a
highly conserved protein, which has been suggested to participate in a variety
of different roles associated with cellular iron homeostasis. The present review
discusses recent advances that have made crucial contributions in understanding
the molecular mechanisms underlying FRDA and in advancements toward potential
novel therapeutic approaches. Owing to space constraints, this review will focus
on the most commonly accepted and solid molecular and biochemical studies
concerning the function of frataxin and the physiopathology of the disease. We
invite the reader to read the following reviews to have a more exhaustive
overview of the field [Pandolfo, M. and Pastore, A. (2009) The pathogenesis of
Friedreich ataxia and the structure and function of frataxin. J. Neurol., 256
(Suppl. 1), 9-17; Gottesfeld, J.M. (2007) Small molecules affecting
transcription in Friedreich ataxia. Pharmacol. Ther., 116, 236-248; Pandolfo, M.
(2008) Drug insight: antioxidant therapy in inherited ataxias. Nat. Clin. Pract.
Neurol., 4, 86-96; Puccio, H. (2009) Multicellular models of Friedreich ataxia.
J. Neurol., 256 (Suppl. 1), 18-24].
DOI: 10.1093/hmg/ddq165
PMID: 20413654 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24848865 | 1. Herz. 2015 Mar;40 Suppl 1:85-90. doi: 10.1007/s00059-014-4097-y. Epub 2014 May
23.
[Heart involvement in Friedreich's ataxia].
[Article in German]
Weidemann F(1), Scholz F, Florescu C, Liu D, Hu K, Herrmann S, Ertl G, Störk S.
Author information:
(1)Medizinische Klinik und Poliklinik I, Deutsches Zentrum für Herzinsuffizienz,
Universität Würzburg, Oberdürrbacherstr. 6, 97080, Würzburg, Deutschland,
[email protected].
Friedreich's ataxia is a rare hereditary disease and although the gene defect
has already been identified as a deficiency of the mitochondrial protein
frataxin, the pathophysiology is still unknown. Although a multisystem disorder
organ involvement is predominantly neurological. Besides the characteristic
features of spinocerebellar ataxia the heart is frequently also affected.
Cardiac involvement typically manifests as hypertrophic cardiomyopathy, which
can progress to heart failure and death. So far most research has focused on the
neurological aspects and cardiac involvement in Friedreich's ataxia has not been
systematically investigated. Thus, a better understanding of the progression of
the cardiomyopathy, cardiac complications and long-term cardiac outcome is
warranted. Although no specific treatment is available general cardiac
therapeutic options for cardiomyopathy should be considered. The current review
focuses on clinical and diagnostic features of cardiomyopathy and discusses
potential therapeutic developments for Friedreich's ataxia.
DOI: 10.1007/s00059-014-4097-y
PMID: 24848865 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21550666 | 1. Brain Res Rev. 2011 Jun 24;67(1-2):311-30. doi:
10.1016/j.brainresrev.2011.04.001. Epub 2011 Apr 17.
Friedreich's ataxia: past, present and future.
Marmolino D(1).
Author information:
(1)Laboratoire de Neurologie experimentale, Universite Libre de Bruxeles, Route
de Lennik 808, Campus Erasme, 1070 Bruxelles, Belgium.
[email protected]
Friedreich's ataxia (FRDA) is an autosomal recessive inherited disorder
characterized by progressive gait and limb ataxia, dysarthria, areflexia, loss
of vibratory and position sense, and a progressive motor weakness of central
origin. Additional features include hypertrophic cardiomyopathy and diabetes.
Large GAA repeat expansions in the first intron of the FXN gene are the most
common mutation underlying FRDA. Patients show severely reduced levels of a
FXN-encoded mitochondrial protein called frataxin. Frataxin deficiency is
associated with abnormalities of iron metabolism: decreased iron-sulfur cluster
(ISC) biogenesis, accumulation of iron in mitochondria and depletion in the
cytosol, enhanced cellular iron uptake. Some models have also shown reduced heme
synthesis. Evidence for oxidative stress has been reported. Respiratory chain
dysfunction aggravates oxidative stress by increasing leakage of electrons and
the formation of superoxide. In vitro studies have demonstrated that Frataxin
deficient cells not only generate more free radicals, but also show a reduced
capacity to mobilize antioxidant defenses. The search for experimental drugs
increasing the amount of frataxin is a very active and timely area of
investigation. In cellular and in animal model systems, the replacement of
frataxin function seems to alleviate the symptoms or even completely reverse the
phenotype. Therefore, drugs increasing the amount of frataxin are attractive
candidates for novel therapies. This review will discuss recent findings on FRDA
pathogenesis, frataxin function, new treatments, as well as recent animal and
cellular models. Controversial aspects are also discussed.
Copyright © 2011 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.brainresrev.2011.04.001
PMID: 21550666 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25554687 | 1. Neurobiol Dis. 2015 Apr;76:1-12. doi: 10.1016/j.nbd.2014.12.017. Epub 2014 Dec
29.
Frataxin knockdown in human astrocytes triggers cell death and the release of
factors that cause neuronal toxicity.
Loría F(1), Díaz-Nido J(2).
Author information:
(1)Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.
(2)Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain;
Departamento de Biología Molecular, Universidad Autónoma de Madrid, Madrid,
Spain; Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
Electronic address: [email protected].
Friedreich's ataxia (FA) is a recessive, predominantly neurodegenerative
disorder caused in most cases by mutations in the first intron of the frataxin
(FXN) gene. This mutation drives the expansion of a homozygous GAA repeat that
results in decreased levels of FXN transcription and frataxin protein. Frataxin
(Fxn) is a ubiquitous mitochondrial protein involved in iron-sulfur cluster
biogenesis, and a decrease in the levels of this protein is responsible for the
symptoms observed in the disease. Although the pathological manifestations of FA
are mainly observed in neurons of both the central and peripheral nervous
system, it is not clear if changes in non-neuronal cells may also contribute to
the pathogenesis of FA, as recently suggested for other neurodegenerative
disorders. Therefore, the aims of this study were to generate and characterize a
cell model of Fxn deficiency in human astrocytes (HAs) and to evaluate the
possible involvement of non-cell autonomous processes in FA. To knockdown
frataxin in vitro, we transduced HAs with a specific shRNA lentivirus (shRNA37),
which produced a decrease in both frataxin mRNA and protein expression, along
with mitochondrial superoxide production, and signs of p53-mediated cell cycle
arrest and apoptotic cell death. To test for non-cell autonomous interactions we
cultured wild-type mouse neurons in the presence of frataxin-deficient astrocyte
conditioned medium, which provoked a delay in the maturation of these neurons, a
decrease in neurite length and enhanced cell death. Our findings confirm a
detrimental effect of frataxin silencing, not only for astrocytes, but also for
neuron-glia interactions, underlining the need to take into account the role of
non-cell autonomous processes in FA.
Copyright © 2014 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.nbd.2014.12.017
PMID: 25554687 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33158039 | 1. Int J Mol Sci. 2020 Nov 4;21(21):8251. doi: 10.3390/ijms21218251.
Effect of Mitochondrial and Cytosolic FXN Isoform Expression on Mitochondrial
Dynamics and Metabolism.
Agrò M(1), Díaz-Nido J(1).
Author information:
(1)Centro de Biología Molecular Severo Ochoa (CSIC-UAM) and Departamento de
Biología Molecular, Universidad Autónoma de Madrid, Nicolás Cabrera, 1, 28049
Madrid, Spain.
Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by recessive
mutations in the frataxin gene that lead to a deficiency of the mitochondrial
frataxin (FXN) protein. Alternative forms of frataxin have been described, with
different cellular localization and tissue distribution, including a
cerebellum-specific cytosolic isoform called FXN II. Here, we explored the
functional roles of FXN II in comparison to the mitochondrial FXN I isoform,
highlighting the existence of potential cross-talk between cellular
compartments. To achieve this, we transduced two human cell lines of patient and
healthy subjects with lentiviral vectors overexpressing the mitochondrial or the
cytosolic FXN isoforms and studied their effect on the mitochondrial network and
metabolism. We confirmed the cytosolic localization of FXN isoform II in our in
vitro models. Interestingly, both cytosolic and mitochondrial isoforms have an
effect on mitochondrial dynamics, affecting different parameters. Accordingly,
increases of mitochondrial respiration were detected after transduction with FXN
I or FXN II in both cellular models. Together, these results point to the
existence of a potential cross-talk mechanism between the cytosol and
mitochondria, mediated by FXN isoforms. A more thorough knowledge of the
mechanisms of action behind the extra-mitochondrial FXN II isoform could prove
useful in unraveling FRDA physiopathology.
DOI: 10.3390/ijms21218251
PMCID: PMC7662637
PMID: 33158039 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/28282710 | 1. Acta Med Iran. 2017 Feb;55(2):128-130.
Early-Onset Friedreich's Ataxia With Oculomotor Apraxia.
Saghazadeh A(1), Hafizi S(2), Hosseini F(2), Ashrafi MR(2), Rezaei N(3).
Author information:
(1)Research Center for Immunodeficiencies, Children's Medical Center, Tehran
University of Medical Sciences, Tehran, Iran. AND Neuroimmunology Research
Association (NIRA), Universal Scientific Education and Research Network (USERN),
Tehran, Iran.
(2)Pediatrics Center of Excellence, Children's Medical Center, Tehran University
of Medical Sciences, Tehran, Iran.
(3)Research Center for Immunodeficiencies, Children's Medical Center, Tehran
University of Medical Sciences, Tehran, Iran. AND Department of Immunology,
School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. AND
Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal
Scientific Education and Research Network (USERN), Tehran, Iran.
Friedreich's ataxia (FRDA) is a rare autosomal recessive spinocerebellar ataxia
which in the majority of cases is associated with a GAA-trinucleotide repeat
expansion in the first intron of Frataxin gene located on chromosome 9. The
clinical features include progressive gait and limb ataxia, cerebellar
dysarthria, neuropathy, optic atrophy, and loss of vibration and proprioception.
Ataxia with ocular motor apraxia type 1 (AOA1) is another autosomal recessive
cerebellar ataxia which is associated with oculomotor apraxia, hypoalbuminaemia,
and hypercholesterolemia. Here we describe two siblings (13- and 10-year-old)
display overlapping clinical features of both early-onset FRDA and AOA1. Almost
all of laboratory test (including urinary analysis/culture, biochemistry,
peripheral blood smear, C-reactive protein level, erythrocyte sedimentation
rate-1h) results were within the normal range for both patients. Due to the
normal laboratory test results; we concluded that the diagnosis was more likely
to be FRDA than AOA1. Therefore, neurologists should bear in mind that clinical
presentations of FRDA may vary widely from the classical phenotype of gait and
limb ataxia to atypical manifestations such as oculomotor apraxia.
PMID: 28282710 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24860428 | 1. Front Cell Neurosci. 2014 May 13;8:124. doi: 10.3389/fncel.2014.00124.
eCollection 2014.
Mitochondrial dysfunction induced by frataxin deficiency is associated with
cellular senescence and abnormal calcium metabolism.
Bolinches-Amorós A(1), Mollá B(1), Pla-Martín D(1), Palau F(2), González-Cabo
P(1).
Author information:
(1)Program in Rare and Genetic Diseases, Centro de Investigación Príncipe Felipe
Valencia, Spain ; IBV/CSIC Associated Unit, Centro de Investigación Príncipe
Felipe Valencia, Spain ; CIBER de Enfermedades Raras Valencia, Spain.
(2)Program in Rare and Genetic Diseases, Centro de Investigación Príncipe Felipe
Valencia, Spain ; IBV/CSIC Associated Unit, Centro de Investigación Príncipe
Felipe Valencia, Spain ; CIBER de Enfermedades Raras Valencia, Spain ; Facultad
de Medicina de Ciudad Real, Universidad de Castilla-La Mancha Ciudad Real,
Spain.
Friedreich ataxia is considered a neurodegenerative disorder involving both the
peripheral and central nervous systems. Dorsal root ganglia (DRG) are the major
target tissue structures. This neuropathy is caused by mutations in the FXN gene
that encodes frataxin. Here, we investigated the mitochondrial and cell
consequences of frataxin depletion in a cellular model based on frataxin
silencing in SH-SY5Y human neuroblastoma cells, a cell line that has been used
widely as in vitro models for studies on neurological diseases. We showed that
the reduction of frataxin induced mitochondrial dysfunction due to a
bioenergetic deficit and abnormal Ca(2+) homeostasis in the mitochondria that
were associated with oxidative and endoplasmic reticulum stresses. The depletion
of frataxin did not cause cell death but increased autophagy, which may have a
cytoprotective effect against cellular insults such as oxidative stress.
Frataxin silencing provoked slow cell growth associated with cellular
senescence, as demonstrated by increased SA-βgal activity and cell cycle arrest
at the G1 phase. We postulate that cellular senescence might be related to a
hypoplastic defect in the DRG during neurodevelopment, as suggested by necropsy
studies.
DOI: 10.3389/fncel.2014.00124
PMCID: PMC4026758
PMID: 24860428 |
http://www.ncbi.nlm.nih.gov/pubmed/21782979 | 1. Mitochondrion. 2012 Jan;12(1):156-61. doi: 10.1016/j.mito.2011.07.001. Epub
2011 Jul 18.
Rapamycin reduces oxidative stress in frataxin-deficient yeast cells.
Marobbio CM(1), Pisano I, Porcelli V, Lasorsa FM, Palmieri L.
Author information:
(1)Laboratory of Biochemistry and Molecular Biology, Department of
Pharmaco-Biology, University of Bari, Via E. Orabona 4, 70125 Bari, Italy.
Friedreich ataxia (FRDA) is a common form of ataxia caused by decreased
expression of the mitochondrial protein frataxin. Oxidative damage of
mitochondria is thought to play a key role in the pathogenesis of the disease.
Therefore, a possible therapeutic strategy should be directed to an antioxidant
protection against mitochondrial damage. Indeed, treatment of FRDA patients with
the antioxidant idebenone has been shown to improve neurological functions. The
yeast frataxin knock-out model of the disease shows mitochondrial iron
accumulation, iron-sulfur cluster defects and high sensitivity to oxidative
stress. By flow cytometry analysis we studied reactive oxygen species (ROS)
production of yeast frataxin mutant cells treated with two antioxidants,
N-acetyl-L-cysteine and a mitochondrially-targeted analog of vitamin E,
confirming that mitochondria are the main site of ROS production in this model.
Furthermore we found a significant reduction of ROS production and a decrease in
the mitochondrial mass in mutant cells treated with rapamycin, an inhibitor of
TOR kinases, most likely due to autophagy of damaged mitochondria.
Copyright © 2011 Elsevier B.V. and Mitochondria Research Society. All rights
reserved.
DOI: 10.1016/j.mito.2011.07.001
PMID: 21782979 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20073435 | 1. Gac Med Mex. 2009 Jul-Aug;145(4):343-6.
[Two case studies of hypertrophic cardiomyopathy in Friedreich's ataxia].
[Article in Spanish]
Cervantes-Arriaga A(1), Rodríguez-Violante M, Villar-Velarde A, Vargas-Cañas S.
Author information:
(1)Instituto Nacional de Neurología y Neurocirugía, Manuel Velasco Suárez,
México DF, México. [email protected]
BACKGROUND: Friedreich's ataxia is the most common hereditary ataxia and its
clinical spectrum includes cardiac disease, mainly hypertrophic cardiomyopathy.
METHODS: We present two cases with molecular diagnosis of Friedreich's ataxia
and cardiac disease shown on electrocardiogram and echocardiogram.
RESULTS: Neurological symptoms which lead to the diagnosis are described
together with cardiac comorbidities.
CONCLUSIONS: The cases here described highlight the importance of early
screening and identification of systemic complications, specifically cardiac
disease, in patients with this neurological disease.
PMID: 20073435 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18710357 | 1. Expert Opin Pharmacother. 2008 Sep;9(13):2327-37. doi:
10.1517/14656566.9.13.2327.
Idebenone in Friedreich's ataxia.
Tonon C(1), Lodi R.
Author information:
(1)Università di Bologna, Dipartimento di Medicina Interna, dell'Invecchiamento
e Malattie Nefrologiche, Azienda Ospedaliero-Universitaria di Bologna, Via
Massarenti 9, 40138 Bologna, Italy.
BACKGROUND: Friedreich's ataxia is an autosomal recessive neurodegenerative
disease where impaired mitochondrial function and excessive production of free
radicals play a central pathogenetic role. Idebenone, a synthetic analogue of
coenzyme Q, is a powerful antioxidant that was first administrated to
Friedreich's ataxia patients less than 10 years ago.
OBJECTIVE: The aim of this study was to evaluate the efficacy of idebenone
administration and define the optimal dosage.
METHODS: A critical evaluation of all open and double-blinded idebenone trials
in Friedreich's ataxia patients was undertaken.
RESULTS/CONCLUSIONS: Idebenone is well tolerated in paediatric and adult
patients. Most trials demonstrated a positive effect on cardiac hypertrophy. The
neurological function is in general not modified in adult patients, but a
dose-dependent effect was demonstrated in young Friedreich's ataxia patients.
Further double-blinded high-dose trials should evaluate idebenone in
Friedreich's ataxia early in the disease course.
DOI: 10.1517/14656566.9.13.2327
PMID: 18710357 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33609476 | 1. Lancet Neurol. 2021 Mar;20(3):182-192. doi: 10.1016/S1474-4422(20)30489-0.
Safety and efficacy of tilavonemab in progressive supranuclear palsy: a phase 2,
randomised, placebo-controlled trial.
Höglinger GU(1), Litvan I(2), Mendonca N(3), Wang D(4), Zheng H(4),
Rendenbach-Mueller B(5), Lon HK(6), Jin Z(4), Fisseha N(3), Budur K(3), Gold
M(3), Ryman D(3), Florian H(3); Arise Investigators.
Collaborators: Ahmed A, Aiba I, Albanese A, Bertram K, Bordelon Y, Bower J,
Brosch J, Claassen D, Colosimo C, Corvol JC, Cudia P, Daniele A, Defebvre L,
Driver-Dunckley E, Duquette A, Eleopra R, Eusebio A, Fung V, Geldmacher D, Golbe
L, Grandas F, Hall D, Hatano T, Höglinger GU, Honig L, Hui J, Kerwin D, Kikuchi
A, Kimber T, Kimura T, Kumar R, Litvan I, Ljubenkov P, Lorenzl S, Ludolph A,
Mari Z, McFarland N, Meissner W, Mir Rivera P, Mochizuki H, Morgan J, Munhoz R,
Nishikawa N, O Sullivan J, Oeda T, Oizumi H, Onodera O, Ory-Magne F, Peckham E,
Postuma R, Quattrone A, Quinn J, Ruggieri S, Sarna J, Schulz PE, Slevin J,
Tagliati M, Wile D, Wszolek Z, Xie T, Zesiewicz T.
Author information:
(1)German Center for Neurodegenerative Diseases, Munich, Germany; Department of
Neurology, Technische Universität München, Munich, Germany; Department of
Neurology, Hannover Medical School, Hannover, Germany. Electronic address:
[email protected].
(2)Parkinson and Other Movement Disorders Center, University of California San
Diego, La Jolla, CA, USA.
(3)Neuroscience, AbbVie Inc, North Chicago, IL, USA.
(4)Data and Statistical Sciences, AbbVie Inc, North Chicago, IL, USA.
(5)Neuroscience, AbbVie Deutschland GmbH & Co KG, Ludwigshafen, Germany.
(6)Clinical Pharmacology and Pharmacometrics, AbbVie Inc, North Chicago, IL,
USA.
Comment in
Lancet Neurol. 2021 Mar;20(3):162-163. doi: 10.1016/S1474-4422(21)00035-1.
Nat Med. 2021 Aug;27(8):1341-1342. doi: 10.1038/s41591-021-01465-9.
Lancet Neurol. 2021 Oct;20(10):786-787. doi: 10.1016/S1474-4422(21)00283-0.
Lancet Neurol. 2021 Oct;20(10):787-788. doi: 10.1016/S1474-4422(21)00284-2.
BACKGROUND: Progressive supranuclear palsy is a neurodegenerative disorder
associated with tau protein aggregation. Tilavonemab (ABBV-8E12) is a monoclonal
antibody that binds to the N-terminus of human tau. We assessed the safety and
efficacy of tilavonemab for the treatment of progressive supranuclear palsy.
METHODS: We did a phase 2, multicentre, randomised, placebo-controlled,
double-blind study at 66 hospitals and clinics in Australia, Canada, France,
Germany, Italy, Japan, Spain, and the USA. Participants (aged ≥40 years)
diagnosed with possible or probable progressive supranuclear palsy who were
symptomatic for less than 5 years, had a reliable study partner, and were able
to walk five steps with minimal assistance, were randomly assigned (1:1:1) by
interactive response technology to tilavonemab 2000 mg, tilavonemab 4000 mg, or
matching placebo administered intravenously on days 1, 15, and 29, then every 28
days through to the end of the 52-week treatment period. Randomisation was done
by the randomisation specialist of the study sponsor, who did not otherwise
participate in the study. The sponsor, investigators, and participants were
unaware of treatment allocations. The primary endpoint was the change from
baseline to week 52 in the Progressive Supranuclear Palsy Rating Scale (PSPRS)
total score in the intention-to-treat population. Adverse events were monitored
in participants who received at least one dose of study drug. Prespecified
interim futility criteria were based on a model-based effect size of 0 or lower
when 60 participants had completed the 52-week treatment period and 0·12 or
lower when 120 participants had completed the 52-week treatment period. This
study is registered at ClinicalTrials.gov, number NCT02985879.
FINDINGS: Between Dec 12, 2016, and Dec 31, 2018, 466 participants were
screened, 378 were randomised. The study was terminated on July 3, 2019, after
prespecified futility criteria were met at the second interim analysis. A total
of 377 participants received at least one dose of study drug and were included
in the efficacy and safety analyses (2000 mg, n=126; 4000 mg, n=125; placebo,
n=126). Least squares mean change from baseline to week 52 in PSPRS was similar
in all groups (between-group difference vs placebo: 2000 mg, 0·0 [95% CI -2·6 to
2·6], effect size 0·000, p>0·99; 4000 mg, 1·0 [-1·6 to 3·6], -0·105, p=0·46).
Most participants reported at least one adverse event (2000 mg, 111 [88%]; 4000
mg, 111 [89%]; placebo, 108 [86%]). Fall was the most common adverse event (2000
mg, 42 [33%]; 4000 mg, 54 [43%]; placebo, 49 [39%]). Proportions of patients
with serious adverse events were similar among groups (2000 mg, 29 [23%]; 4000
mg, 34 [27%]; placebo, 33 [26%]). Fall was the most common treatment-emergent
serious adverse event (2000 mg, five [4%]; 4000 mg, six [5%]; placebo, six
[5%]). 26 deaths occurred during the study (2000 mg, nine [7%]; 4000 mg, nine
[7%]; placebo, eight [6%]) but none was drug related.
INTERPRETATION: A similar safety profile was seen in all treatment groups. No
beneficial treatment effects were recorded. Although this study did not provide
evidence of efficacy in progressive supranuclear palsy, the findings provide
potentially useful information for future investigations of passive immunisation
using tau antibodies for progressive supranuclear palsy.
FUNDING: AbbVie Inc.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1474-4422(20)30489-0
PMID: 33609476 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7909957 | 1. Science. 1994 May 13;264(5161):968-71. doi: 10.1126/science.7909957.
Enhancer point mutation results in a homeotic transformation in Drosophila.
Shimell MJ(1), Simon J, Bender W, O'Connor MB.
Author information:
(1)Department of Molecular Biology and Biochemistry, University of California,
Irvine 92717.
In Drosophila, the misexpression or altered activity of genes from the bithorax
complex results in homeotic transformations. One of these genes, abd-A, normally
specifies the identity of the second through fourth abdominal segments (A2 to
A4). In the dominant Hyperabdominal mutations (Hab), portions of the third
thoracic segment (T3) are transformed toward A2 as the result of ectopic abd-A
expression. Sequence analysis and deoxyribonuclease I footprinting demonstrate
that the misexpression of abd-A in two independent Hab mutations results from
the same single base change in a binding site for the gap gene Krüppel protein.
These results establish that the spatial limits of the homeotic genes are
directly regulated by gap gene products.
DOI: 10.1126/science.7909957
PMID: 7909957 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26596987 | 1. Chromosoma. 2016 Jun;125(3):535-51. doi: 10.1007/s00412-015-0553-6. Epub 2015
Nov 23.
Hox genes, evo-devo, and the case of the ftz gene.
Pick L(1).
Author information:
(1)Department of Entomology and Program in Molecular and Cell Biology,
University of Maryland, College Park, MD, 20742, USA. [email protected].
The discovery of the broad conservation of embryonic regulatory genes across
animal phyla, launched by the cloning of homeotic genes in the 1980s, was a
founding event in the field of evolutionary developmental biology (evo-devo).
While it had long been known that fundamental cellular processes, commonly
referred to as housekeeping functions, are shared by animals and plants across
the planet-processes such as the storage of information in genomic DNA,
transcription, translation and the machinery for these processes, universal
codon usage, and metabolic enzymes-Hox genes were different: mutations in these
genes caused "bizarre" homeotic transformations of insect body parts that were
certainly interesting but were expected to be idiosyncratic. The isolation of
the genes responsible for these bizarre phenotypes turned out to be highly
conserved Hox genes that play roles in embryonic patterning throughout Metazoa.
How Hox genes have changed to promote the development of diverse body plans
remains a central issue of the field of evo-devo today. For this Memorial
article series, I review events around the discovery of the broad evolutionary
conservation of Hox genes and the impact of this discovery on the field of
developmental biology. I highlight studies carried out in Walter Gehring's lab
and by former lab members that have continued to push the field forward, raising
new questions and forging new approaches to understand the evolution of
developmental mechanisms.
DOI: 10.1007/s00412-015-0553-6
PMCID: PMC4877300
PMID: 26596987 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23022097 | 1. Am J Hum Genet. 2012 Oct 5;91(4):629-35. doi: 10.1016/j.ajhg.2012.08.014. Epub
2012 Sep 27.
Homeotic arm-to-leg transformation associated with genomic rearrangements at the
PITX1 locus.
Spielmann M(1), Brancati F, Krawitz PM, Robinson PN, Ibrahim DM, Franke M, Hecht
J, Lohan S, Dathe K, Nardone AM, Ferrari P, Landi A, Wittler L, Timmermann B,
Chan D, Mennen U, Klopocki E, Mundlos S.
Author information:
(1)Institute for Medical Genetics and Human Genetics,
Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.
The study of homeotic-transformation mutants in model organisms such as
Drosophila revolutionized the field of developmental biology, but how these
mutants relate to human developmental defects remains to be elucidated. Here, we
show that Liebenberg syndrome, an autosomal-dominant upper-limb malformation,
shows features of a homeotic limb transformation in which the arms have acquired
morphological characteristics of a leg. Using high-resolution array comparative
genomic hybridization and paired-end whole-genome sequencing, we identified two
deletions and a translocation 5' of PITX1. The structural changes are likely to
remove active PITX1 forelimb suppressor and/or insulator elements and thereby
move active enhancer elements in the vicinity of the PITX1 regulatory landscape.
We generated transgenic mice in which PITX1 was misexpressed under the control
of a nearby enhancer and were able to recapitulate the Liebenberg phenotype.
Copyright © 2012 The American Society of Human Genetics. Published by Elsevier
Inc. All rights reserved.
DOI: 10.1016/j.ajhg.2012.08.014
PMCID: PMC3484647
PMID: 23022097 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26596501 | 1. Trends Neurosci. 2015 Dec;38(12):751-762. doi: 10.1016/j.tins.2015.10.005.
Homeotic Transformations of Neuronal Cell Identities.
Arlotta P(1), Hobert O(2).
Author information:
(1)Department of Stem Cell and Regenerative Biology, Harvard University,
Cambridge, MA 02138, USA. Electronic address: [email protected].
(2)Department of Biology and Department of Biochemistry and Molecular
Biophysics, Howard Hughes Medical Institute, Columbia University, New York, NY,
USA. Electronic address: [email protected].
Homeosis is classically defined as the transformation of one body part into
something that resembles another body part. We propose here to broaden the
concept of homeosis to the many neuronal cell identity transformations that have
been uncovered over the past few years upon removal of specific regulatory
factors in organisms from Caenorhabditis elegans to Drosophila, zebrafish, and
mice. The concept of homeosis provides a framework for the evolution of cell
type diversity in the brain.
Copyright © 2015. Published by Elsevier Ltd.
DOI: 10.1016/j.tins.2015.10.005
PMID: 26596501 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29761492 | 1. J Anat. 2018 Aug;233(2):255-265. doi: 10.1111/joa.12822. Epub 2018 May 14.
C7 vertebra homeotic transformation in domestic dogs - are Pug dogs breaking
mammalian evolutionary constraints?
Brocal J(1), De Decker S(2), José-López R(1), Manzanilla EG(3), Penderis J(4),
Stalin C(1), Bertram S(2), Schoenebeck JJ(5), Rusbridge C(6)(7), Fitzpatrick
N(6), Gutierrez-Quintana R(1).
Author information:
(1)School of Veterinary Medicine, College of Medical, Veterinary and Life
Sciences, University of Glasgow, Glasgow, UK.
(2)Department of Veterinary Clinical Science and Services, The Royal Veterinary
College, University of London, North Mymms, Hertfordshire, UK.
(3)Teagasc Animal and Grassland Research and Innovation Centre, Moorepark,
Fermoy, Co. Cork, Ireland.
(4)Vet-Extra Neurology, Broadleys Veterinary Hospital, Stirling, UK.
(5)Royal (Dick) School of Veterinary Studies and Roslin Institute, University of
Edinburgh, Easter Bush, Midlothian, UK.
(6)Fitzpatrick Referrals, Eashing, Surrey, UK.
(7)School of Veterinary Medicine, Faculty of Health & Medical Sciences,
University of Surrey, Guildford, Surrey, UK.
The number of cervical vertebrae in mammals is almost constant at seven,
regardless of their neck length, implying that there is selection against
variation in this number. Homebox (Hox) genes are involved in this evolutionary
mammalian conservation, and homeotic transformation of cervical into thoracic
vertebrae (cervical ribs) is a common phenotypic abnormality when Hox gene
expression is altered. This relatively benign phenotypic change can be
associated with fatal traits in humans. Mutations in genes upstream of Hox,
inbreeding and stressors during organogenesis can also cause cervical ribs. The
aim of this study was to describe the prevalence of cervical ribs in a large
group of domestic dogs of different breeds, and explore a possible relation with
other congenital vertebral malformations (CVMs) in the breed with the highest
prevalence of cervical ribs. By phenotyping we hoped to give clues as to the
underlying genetic causes. Twenty computed tomography studies from at least two
breeds belonging to each of the nine groups recognized by the Federation
Cynologique Internationale, including all the brachycephalic 'screw-tailed'
breeds that are known to be overrepresented for CVMs, were reviewed. The Pug dog
was more affected by cervical ribs than any other breed (46%; P < 0.001), and
was selected for further analysis. No association was found between the presence
of cervical ribs and vertebral body formation defect, bifid spinous process,
caudal articular process hypoplasia/aplasia and an abnormal sacrum, which may
infer they have a different aetiopathogenesis. However, Pug dogs with cervical
ribs were more likely to have a transitional thoraco-lumbar vertebra (P = 0.041)
and a pre-sacral vertebral count of 26 (P < 0.001). Higher C7/T1 dorsal spinous
processes ratios were associated with the presence of cervical ribs (P < 0.001),
supporting this is a true homeotic transformation. Relaxation of the stabilizing
selection has likely occurred, and the Pug dog appears to be a good naturally
occurring model to further investigate the aetiology of cervical ribs, other
congenital vertebral anomalies and numerical alterations.
© 2018 Anatomical Society.
DOI: 10.1111/joa.12822
PMCID: PMC6036932
PMID: 29761492 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29227708 | 1. Biol Bull. 1996 Jun;190(3):313-321. doi: 10.2307/1543023.
Homeotic Transformation of Crab Walking Leg into Claw by Autotransplantation of
Claw Tissue.
Kao HW, Chang ES.
Homeotic transformation is defined as transformation of one body part into the
likeness of something else. By autotransplantation of crab claw tissue into the
autotomized stump of the fourth walking leg, the stump can regenerate a complete
claw. Frozen claw tissue, sham operation, or walking leg tissue had no such
activity. Contralateral autotransplantation of claw tissue into the autotomized
stump of the fourth walking leg can induce the regeneration of a claw with
normal handedness. Most of the transformed claws combined features of the claw
and the walking leg, suggesting that both host and donor tissues play a role in
regeneration. Three possible mechanisms that might account for limb
transformation are discussed. Simple intercalary regeneration does not explain
all of the observations, but some regulatory events might be taking place during
regeneration. Two other processes--secretion of some morphogen by the claw
tissue and alteration in the expression of Hox genes--offer alternatives that
might explain the results of this study.
DOI: 10.2307/1543023
PMID: 29227708 |
http://www.ncbi.nlm.nih.gov/pubmed/1359423 | 1. Nature. 1992 Oct 29;359(6398):835-41. doi: 10.1038/359835a0.
Homeotic transformation of the occipital bones of the skull by ectopic
expression of a homeobox gene.
Lufkin T(1), Mark M, Hart CP, Dollé P, LeMeur M, Chambon P.
Author information:
(1)Laboratoire de Génétique Moléculaire des Eucaryotes du CNRS, Institut de
Chimie Biologique, Faculté de Medecine, Strasbourg, France.
Murine Hox genes have been postulated to play a role in patterning of the
embryonic body plan. Gene disruption studies have suggested that for a given Hox
complex, patterning of cell identity along the antero-posterior axis is directed
by the more 'posterior' (having a more posterior rostral boundary of expression)
Hox proteins expressed in a given cell. This supports the 'posterior prevalence'
model, which also predicts that ectopic expression of a given Hox gene would
result in altered structure only in regions anterior to its normal domain of
expression. To test this model further, we have expressed the Hox-4.2 gene more
rostrally than its normal mesoderm anterior boundary of expression, which is at
the level of the first cervical somites. This ectopic expression results in a
homeotic transformation of the occipital bones towards a more posterior
phenotype into structures that resemble cervical vertebrae, whereas it has no
effect in regions that normally express Hox-4.2. These results are similar to
the homeotic posteriorization phenomenon generated in Drosophila by ectopic
expression of genes of the homeotic complex HOM-C (refs 7-10; reviewed in ref.
3).
DOI: 10.1038/359835a0
PMID: 1359423 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1346973 | 1. New Biol. 1992 Jan;4(1):5-15.
Downstream of the homeotic genes.
Andrew DJ(1), Scott MP.
Author information:
(1)Department of Developmental Biology, Stanford University School of Medicine,
California 94305-5427.
The homeotic genes of Drosophila melanogaster determine which structures form in
each of the body segments. Disrupting the function of the homeotic genes causes
body parts found in one domain of the animal to be replaced by body parts
normally found elsewhere. Each of the homeotic genes encodes a protein, or a
closely related family of proteins, which is capable of binding DNA and
controlling the transcriptional activities of downstream genes. The homeotic
genes are in the middle of a complex regulatory network, and many of the genes
that control homeotic expression have been well characterized. However, very
little is known about what comes after the homeotic genes, the downstream genes
whose activities are regulated by the homeotic genes. Here, we review the known
relationships between the homeotic proteins and the few identified target genes.
The details of these interactions may be characteristic and may thus guide the
search for additional targets.
PMID: 1346973 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22560091 | 1. Am J Hum Genet. 2012 May 4;90(5):907-14. doi: 10.1016/j.ajhg.2012.04.002.
A human homeotic transformation resulting from mutations in PLCB4 and GNAI3
causes auriculocondylar syndrome.
Rieder MJ(1), Green GE, Park SS, Stamper BD, Gordon CT, Johnson JM, Cunniff CM,
Smith JD, Emery SB, Lyonnet S, Amiel J, Holder M, Heggie AA, Bamshad MJ,
Nickerson DA, Cox TC, Hing AV, Horst JA, Cunningham ML.
Author information:
(1)Department of Genome Sciences, University of Washington, Seattle, WA 98195,
USA.
Erratum in
Am J Hum Genet. 2012 Aug 10;91(2):397.
Am J Hum Genet. 2012 Jun 8;90(6):1116.
Auriculocondylar syndrome (ACS) is a rare, autosomal-dominant craniofacial
malformation syndrome characterized by variable micrognathia, temporomandibular
joint ankylosis, cleft palate, and a characteristic "question-mark" ear
malformation. Careful phenotypic characterization of severely affected probands
in our cohort suggested the presence of a mandibular patterning defect resulting
in a maxillary phenotype (i.e., homeotic transformation). We used exome
sequencing of five probands and identified two novel (exclusive to the patient
and/or family studied) missense mutations in PLCB4 and a shared mutation in
GNAI3 in two unrelated probands. In confirmatory studies, three additional novel
PLCB4 mutations were found in multigenerational ACS pedigrees. All mutations
were confirmed by Sanger sequencing, were not present in more than 10,000
control chromosomes, and resulted in amino-acid substitutions located in highly
conserved protein domains. Additionally, protein-structure modeling demonstrated
that all ACS substitutions disrupt the catalytic sites of PLCB4 and GNAI3. We
suggest that PLCB4 and GNAI3 are core signaling molecules of the
endothelin-1-distal-less homeobox 5 and 6 (EDN1-DLX5/DLX6) pathway. Functional
studies demonstrated a significant reduction in downstream DLX5 and DLX6
expression in ACS cases in assays using cultured osteoblasts from probands and
controls. These results support the role of the previously implicated
EDN1-DLX5/6 pathway in regulating mandibular specification in other species,
which, when disrupted, results in a maxillary phenotype. This work defines the
molecular basis of ACS as a homeotic transformation (mandible to maxilla) in
humans.
Copyright © 2012 The American Society of Human Genetics. Published by Elsevier
Inc. All rights reserved.
DOI: 10.1016/j.ajhg.2012.04.002
PMCID: PMC3376493
PMID: 22560091 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29879896 | 1. BMC Evol Biol. 2018 Jun 7;18(1):84. doi: 10.1186/s12862-018-1202-5.
Homeotic transformations reflect departure from the mammalian 'rule of seven'
cervical vertebrae in sloths: inferences on the Hox code and morphological
modularity of the mammalian neck.
Böhmer C(1), Amson E(2)(3)(4), Arnold P(5)(6), van Heteren AH(7)(8)(9),
Nyakatura JA(2)(3).
Author information:
(1)UMR 7179 CNRS/MNHN, Muséum National d'Histoire Naturelle, 57 rue Cuvier,
CP-55, Paris, France. [email protected].
(2)AG Morphologie und Formengeschichte, Institut für Biologie, Humboldt
Universität zu Berlin, Philippstraße 13, 10115, Berlin, Germany.
(3)Image Knowledge Gestaltung: An Interdisciplinary Laboratory, Humboldt
University, Philippstraße 13, 10115, Berlin, Germany.
(4)Museum für Naturkunde, Leibniz-Institut für Evolutions- und
Biodiversitätsforschung, Invalidenstraße 43, 10115, Berlin, Germany.
(5)Institut für Zoologie und Evolutionsforschung mit Phyletischem Museum,
Ernst-Haeckel-Haus und Biologiedidaktik, Friedrich-Schiller-Universität Jena,
Erbertstraße 1, 07743, Jena, Germany.
(6)Department of Human Evolution, Max Planck Institute for Evolutionary
Anthropology, Deutscher Platz 6, 04103, Leipzig, Germany.
(7)Sektion Mammalogie, SNSB - Zoologische Staatssammlung, Münchhausenstraße 21,
81247, München, Germany.
(8)GeoBio-Center, Ludwig-Maximilians-Universität München, Richard-Wagner-Straße
10, 80333, Munich, Germany.
(9)Department Biologie II, Ludwig-Maximilians-Universität München, Großhaderner
Straße 2, 82152, Planegg-Martinsried, Germany.
BACKGROUND: Sloths are one of only two exceptions to the mammalian 'rule of
seven' vertebrae in the neck. As a striking case of breaking the evolutionary
constraint, the explanation for the exceptional number of cervical vertebrae in
sloths is still under debate. Two diverging hypotheses, both ultimately linked
to the low metabolic rate of sloths, have been proposed: hypothesis 1 involves
morphological transformation of vertebrae due to changes in the Hox gene
expression pattern and hypothesis 2 assumes that the Hox gene expression pattern
is not altered and the identity of the vertebrae is not changed. Direct evidence
supporting either hypothesis would involve knowledge of the vertebral Hox code
in sloths, but the realization of such studies is extremely limited. Here, on
the basis of the previously established correlation between anterior Hox gene
expression and the quantifiable vertebral shape, we present the morphological
regionalization of the neck in three different species of sloths with aberrant
cervical count providing indirect insight into the vertebral Hox code.
RESULTS: Shape differences within the cervical vertebral column suggest a
mouse-like Hox code in the neck of sloths. We infer an anterior shift of HoxC-6
expression in association with the first thoracic vertebra in short-necked
sloths with decreased cervical count, and a posterior shift of HoxC-5 and HoxC-6
expression in long-necked sloths with increased cervical count.
CONCLUSION: Although only future developmental analyses in non-model organisms,
such as sloths, will yield direct evidence for the evolutionary mechanism
responsible for the aberrant number of cervical vertebrae, our observations lend
support to hypothesis 1 indicating that the number of modules is retained but
their boundaries are displaced. Our approach based on quantified morphological
differences also provides a reliable basis for further research including fossil
taxa such as extinct 'ground sloths' in order to trace the pattern and the
underlying genetic mechanisms in the evolution of the vertebral column in
mammals.
DOI: 10.1186/s12862-018-1202-5
PMCID: PMC5992679
PMID: 29879896 [Indexed for MEDLINE]
Conflict of interest statement: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: Not
applicable. COMPETING INTERESTS: The authors declare that they have no competing
interests. PUBLISHER’S NOTE: Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations. |
http://www.ncbi.nlm.nih.gov/pubmed/20795330 | 1. Adv Exp Med Biol. 2010;689:155-65. doi: 10.1007/978-1-4419-6673-5_12.
Homeosis and beyond. What is the function of the Hox genes?
Deutsch JS(1).
Author information:
(1)Developmental Biology, Pierre and Marie Curie University, Paris, France.
[email protected]
What is the function of the Hox genes? At first glance, it is a curious
question. Indeed, the answer seems so obvious that several authors have spoken
of 'the Hox function' about some of the Hox genes, namely Hox3/zen and Hox6/ftz
that seem to have lost it during the evolution of Arthropods. What these authors
meant is that these genes have lost their 'homeotic' function. Indeed,
'homeotic' refers to a functional property that is so often associated with the
Hox genes. However, the word 'Hox' should not be used to refer to a function,
but to a group of genes. The above examples of Hox3/zen (see Schmitt-Ott's
chapter, this book) and Hox6/ftz show that the homeotic function may be not so
tightly linked to the Hox genes. Reversely, many genes, not belonging to the Hox
group, do present a homeotic function. In the present chapter, I will first give
a definition of the Hox genes. I will then ask what is the 'function' of a gene,
examining its various meanings at different levels of biological organization. I
will review and revisit the relation between the Hox genes and homeosis. I will
suggest that their morphological homeotic function has been secondarily derived
during the evolution of the Bilateria.
DOI: 10.1007/978-1-4419-6673-5_12
PMID: 20795330 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35316106 | 1. Expert Opin Investig Drugs. 2022 May;31(5):451-461. doi:
10.1080/13543784.2022.2056836. Epub 2022 Apr 11.
Risdiplam: an investigational survival motor neuron 2 (SMN2) splicing modifier
for spinal muscular atrophy (SMA).
Markati T(1)(2), Fisher G(1)(2), Ramdas S(1)(2), Servais L(1)(2)(3).
Author information:
(1)MDUK Oxford Neuromuscular Centre, Department of Paediatrics, University of
Oxford, Oxford, UK.
(2)Department of Paediatric Neurology, Oxford University Hospitals NHS
Foundation Trust, Oxford, UK.
(3)Division of Child Neurology, Centre de Références des Maladies
Neuromusculaires, Department of Pediatrics, University Hospital Liège &
University of Liège, Liege, Belgium.
INTRODUCTION: Spinal muscular atrophy (SMA) is a rare autosomal recessive
neuromuscular disease which is characterised by muscle atrophy and early death
in most patients. Risdiplam is the third overall and first oral drug approved
for SMA with disease-modifying potential. Risdiplam acts as a survival motor
neuron 2 (SMN2) pre-mRNA splicing modifier with satisfactory safety and efficacy
profile. This review aims to critically appraise the place of risdiplam in the
map of SMA therapeutics.
AREAS COVERED: This review gives an overview of the current market for SMA and
presents the mechanism of action and the pharmacological properties of
risdiplam. It also outlines the development of risdiplam from early preclinical
stages through to the most recently published results from phase 2/3 clinical
trials. Risdiplam has proved its efficacy in pivotal trials for SMA Types 1, 2,
and 3 with a satisfactory safety profile.
EXPERT OPINION: In the absence of comparative data with the other two approved
drugs, the role of risdiplam in the treatment algorithm of affected individuals
is examined in three different patient populations based on the age and
diagnosis method (newborn screening or clinical, symptom-driven diagnosis).
Long-term data and real-world data will play a fundamental role in its future.
DOI: 10.1080/13543784.2022.2056836
PMID: 35316106 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22196485 | 1. Pediatr Neurol. 2012 Jan;46(1):1-12. doi: 10.1016/j.pediatrneurol.2011.09.001.
Spinal muscular atrophy: a clinical and research update.
Markowitz JA(1), Singh P, Darras BT.
Author information:
(1)Department of Neurology, Children's Hospital Boston, Boston, Massachusetts
02115, USA.
Spinal muscular atrophy, a hereditary degenerative disorder of lower motor
neurons associated with progressive muscle weakness and atrophy, is the most
common genetic cause of infant mortality. It is caused by decreased levels of
the "survival of motor neuron" (SMN) protein. Its inheritance pattern is
autosomal recessive, resulting from mutations involving the SMN1 gene on
chromosome 5q13. However, unlike many other autosomal recessive diseases, the
SMN gene involves a unique structure (an inverted duplication) that presents
potential therapeutic targets. Although no effective treatment for spinal
muscular atrophy exists, the field of translational research in spinal muscular
atrophy is active, and clinical trials are ongoing. Advances in the
multidisciplinary supportive care of children with spinal muscular atrophy also
offer hope for improved life expectancy and quality of life.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.pediatrneurol.2011.09.001
PMID: 22196485 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34032944 | 1. Neurol Sci. 2022 Jan;43(1):399-410. doi: 10.1007/s10072-021-05291-2. Epub 2021
May 25.
An open-label phase 1 clinical trial of the allogeneic side population
adipose-derived mesenchymal stem cells in SMA type 1 patients.
Mohseni R(1)(2), Hamidieh AA(3)(4), Shoae-Hassani A(5), Ghahvechi-Akbari M(6),
Majma A(7), Mohammadi M(8), Nikougoftar M(9), Shervin-Badv R(8), Ai J(2),
Montazerlotfelahi H(10), Ashrafi MR(11)(12).
Author information:
(1)Pediatric Cell and Gene Therapy Research Center (PCGTRC), Tehran University
of Medical Sciences, Tehran, Iran.
(2)Applied Cell Sciences and Tissue Engineering department, School of Advanced
Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
(3)Pediatric Cell and Gene Therapy Research Center (PCGTRC), Tehran University
of Medical Sciences, Tehran, Iran. [email protected].
(4)Pediatric Hematology, Oncology and Stem Cell Transplantation Department,
Children's Medical Center, Pediatrics Center of Excellence, Tehran University of
Medical Sciences, Tehran, Iran. [email protected].
(5)Stem Cell and Regenerative Medicine Research Center, Iran University of
Medical Sciences, Tehran, Iran.
(6)Department of Physical Medicine and Rehabilitation, Pediatrics Center of
Excellence, Children's Medical Center, Tehran University of Medical Sciences,
Tehran, Iran.
(7)Department of Pediatric Intensive Care Unit, Pediatrics Center of Excellence,
Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
(8)Department of Pediatric Neurology, Growth and Development Research Center,
Children's Medical Center, Pediatrics Center of Excellence, Tehran University of
Medical Sciences, Tehran, Iran.
(9)Blood Transfusion Research Center, High Institute for Research and Education
in Transfusion Medicine, Iranian Blood Transfusion Organization (IBTO), Tehran,
Iran.
(10)Department of Pediatric Neurology, Farhikhtegan Teaching Hospital, Islamic
Azad, Tehran Medical Sciences, Tehran, Iran.
(11)Pediatric Cell and Gene Therapy Research Center (PCGTRC), Tehran University
of Medical Sciences, Tehran, Iran. [email protected].
(12)Department of Pediatric Neurology, Growth and Development Research Center,
Children's Medical Center, Pediatrics Center of Excellence, Tehran University of
Medical Sciences, Tehran, Iran. [email protected].
INTRODUCTION: Spinal muscular atrophy (SMA), an autosomal recessive
neurodegenerative disorder of alpha motor neurons of spinal cord associated with
progressive muscle weakness and hypotonia, is the most common genetic cause of
infant mortality. Although there is few promising treatment for SMA, but the
field of translational research is active in it, and stem cell-based therapy
clinical trials or case studies are ongoing. Combination of different
therapeutic approaches for noncurative treatments may increase their
effectiveness and compliance of patients. We present a phase 1 clinical trial in
patients with SMA1 who received side population adipose-derived mesenchymal stem
cells (SPADMSCs).
METHODS: The intervention group received three intrathecal administrations of
escalating doses of SPADMSCs and followed until 24 months or the survival time.
The safety analysis was assessed by controlling the side effects and efficacy
evaluations performed by the Hammersmith Infant Neurological Examination (HINE),
Ballard score, and electrodiagnostic (EDX) evaluation. These evaluations were
performed before intervention and at the end of the follow-up.
RESULTS: The treatment was safe and well tolerated, without any adverse event
related to the stem cell administration. One of the patients in the intervention
group was alive after 24 months of study follow-up. He is a non-sitter
62-month-old boy with appropriate weight gain and need for noninvasive
ventilation (NIV) for about 8 h per day. Clinical scores, need for supportive
ventilation, and number of hospitalizations were not meaningful parameters in
the response of patients in the intervention and control groups. All five
patients in the intervention group showed significant improvement in the motor
amplitude response of the tibial nerve (0.56mV; p: 0.029).
CONCLUSION: This study showed that SPADMSCs therapy is tolerable and safe with
promising efficacy in SMA I. Probably same as other treatment strategies, early
intervention will increase its efficacy and prepare time for more injections. We
suggest EDX evaluation for the follow-up of treatment efficacy.
© 2021. Fondazione Società Italiana di Neurologia.
DOI: 10.1007/s10072-021-05291-2
PMID: 34032944 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35866733 | 1. Biomedica. 2022 May 1;42(Sp. 1):89-99. doi: 10.7705/biomedica.6178.
Clinical-functional characterization of patients with spinal muscular atrophy in
Central-Western Colombia.
[Article in English, Spanish; Abstract available in Spanish from the publisher]
Cardona N(1), Ocampo SJ(2), Estrada JM(3), Mojica MI(4), Porras GL(5).
Author information:
(1)Centro de Enfermedades Huérfanas - ComSentido, Salud Comfamiliar, Comfamiliar
Risaralda, Pereira, Colombia; Grupo de Investigación Salud Comfamiliar,
Comfamiliar Risaralda, Pereira, Colombia. [email protected].
(2)Maestría en Genética Humana, Universidad Nacional de Colombia, Bogotá, D.C.,
Colombia. [email protected].
(3)Grupo de Investigación Salud Comfamiliar, Comfamiliar Risaralda, Pereira,
Colombia. [email protected].
(4)Grupo de Investigación Salud Comfamiliar, Comfamiliar Risaralda, Pereira,
Colombia. [email protected].
(5)Centro de Enfermedades Huérfanas - ComSentido, Salud Comfamiliar, Comfamiliar
Risaralda, Pereira, Colombia; Grupo de Investigación Salud Comfamiliar,
Comfamiliar Risaralda, Pereira, Colombia. [email protected].
Introduction: Spinal muscular atrophy is a rare genetic neurodegenerative
disorder affecting the motor neurons of the anterior horn of the spinal cord,
which results in muscle atrophy and weakness. In Colombia, few studies have been
published on the pathology and none with functional analysis. Objective: To
characterize clinically and functionally some cases of spinal muscular atrophy
patients from Central-Western Colombia. Materials and methods: We conducted a
cross-sectional descriptive study between 2007 and 2020 with patients clinically
and molecularly diagnosed with spinal muscular atrophy who attended a care
center. For the functional assessment we used the Hammersmith and Chop-Intend
scales and the data were systematized with the Epi-Info, version 7.0 software.
Results: We analyzed 14 patients (42.8 % men). The most prevalent spinal
muscular atrophy was type II with 71.4 %. We found phenotypic variability in
terms of functionality in some patients with type II spinal muscular atrophy,
37.5 % of whom reached gait. Survival was estimated at 28.6 years. Conclusions:
The findings in the group of patients analyzed revealed that the scores of the
revised and expanded Hammersmith scales correlated with the severity of SMA.
Publisher: Introducción. La atrofia muscular espinal es una enfermedad
neurodegenerativa huérfana de origen genético que afecta las neuronas motoras
del asta anterior de la médula espinal, y produce atrofia y debilidad muscular.
En Colombia, son pocos los estudios publicados sobre la enfermedad y no hay
ninguno con análisis funcional. Objetivo. Caracterizar clínica y funcionalmente
una serie de casos de atrofia muscular espinal del centro-occidente colombiano.
Materiales y métodos. Se hizo un estudio descriptivo transversal, entre el 2007
y el 2020, de pacientes con diagnóstico clínico y molecular de atrofia muscular
espinal que consultaron en el centro de atención. La evaluación funcional se
realizó con las escalas Hammersmith y Chop Intend. En la sistematización de los
datos, se empleó el programa Epi-Info, versión 7.0. Resultados. Se analizaron 14
pacientes: 8 mujeres y 6 hombres. La atrofia muscular espinal más prevalente fue
la de tipo II, la cual se presentó en 10 casos. Se encontró variabilidad
fenotípica en términos de funcionalidad en algunos pacientes con atrofia
muscular espinal de tipo II, cinco de los cuales lograron alcanzar la marcha. La
estimación de la supervivencia fue de 28,6 años. Conclusiones. Los hallazgos en
el grupo de pacientes analizados evidenciaron que los puntajes de la escala de
Hammersmith revisada y expandida, concordaron con la gravedad de la enfermedad.
INTRODUCTION: Spinal muscular atrophy is a rare genetic neurodegenerative
disorder affecting the motor neurons of the anterior horn of the spinal cord,
which results in muscle atrophy and weakness. In Colombia, few studies have been
published on the pathology and none with functional analysis.
OBJECTIVE: To characterize clinically and functionally some cases of spinal
muscular atrophy patients from Central-Western Colombia.
MATERIALS AND METHODS: We conducted a cross-sectional descriptive study between
2007 and 2020 with patients clinically and molecularly diagnosed with spinal
muscular atrophy who attended a care center. For the functional assessment we
used the Hammersmith and Chop-Intend scales and the data were systematized with
the Epi-Info, version 7.0 software.
RESULTS: We analyzed 14 patients (42.8 % men). The most prevalent spinal
muscular atrophy was type II with 71.4 %. We found phenotypic variability in
terms of functionality in some patients with type II spinal muscular atrophy,
37.5 % of whom reached gait. Survival was estimated at 28.6 years.
CONCLUSIONS: The findings in the group of patients analyzed revealed that the
scores of the revised and expanded Hammersmith scales correlated with the
severity of SMA.
DOI: 10.7705/biomedica.6178
PMCID: PMC9410705
PMID: 35866733 [Indexed for MEDLINE]
Conflict of interest statement: Conflicto de intereses: Los autores declaramos
no tener conflicto de intereses. |
http://www.ncbi.nlm.nih.gov/pubmed/36376972 | 1. J Med Case Rep. 2022 Nov 15;16(1):435. doi: 10.1186/s13256-022-03633-y.
Clinical characterizations of three adults with genetically confirmed spinal
muscular atrophy: a case series.
Setyaningrum CTS(1), Harahap ISK(2), Nurputra DK(3), Ar Rochmah M(2), Sadewa
AH(4), Alkarani GH(2), Harahap NIF(5).
Author information:
(1)Department of Neurology, Faculty of Medicine, Public Health and Nursing,
Universitas Gadjah Mada, Yogyakarta, Indonesia. [email protected].
(2)Department of Neurology, Faculty of Medicine, Public Health and Nursing,
Universitas Gadjah Mada, Yogyakarta, Indonesia.
(3)Department of Pediatrics, Faculty of Medicine, Public Health and Nursing,
Universitas Gadjah Mada, Yogyakarta, Indonesia.
(4)Department of Biochemistry, Faculty of Medicine, Public Health and Nursing,
Universitas Gadjah Mada, Yogyakarta, Indonesia.
(5)Department of Clinical Pathology, Faculty of Medicine, Public Health and
Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia.
BACKGROUND: Spinal muscular atrophy is a recessively inherited autosomal
neuromuscular disorder, with characteristic progressive muscle weakness. Most
spinal muscular atrophy cases clinically manifest during infancy or childhood,
although it may first manifest in adulthood. Although spinal muscular atrophy
has come to the era of newborn screening and promising treatments, genetically
confirmed spinal muscular atrophy patients are still rare in third world
countries, including Indonesia.
CASE PRESENTATIONS: We presented three Indonesian patients with spinal muscular
atrophy genetically confirmed during adulthood. The first case was a 40-year-old
male who presented with weakness in his lower limbs that started when he was
9 years old. At the age of 16 years, he could no longer walk and started using a
wheelchair. He first came to our clinic at the age of 38 years, and was
diagnosed with spinal muscular atrophy 2 years later. The second patient was a
58-year-old male who presented with lower limb weakness since he was 12 years
old. Owing to the geographical distance and financial problems, he was referred
to our clinic at the age of 56 years, when he already used a walker to walk.
Lastly, the third patient was a 28-year-old woman, who was in the first semester
of her second pregnancy, and who presented with slowly progressing lower limb
weakness. Her limb weakness began at the age of 8 years, and slowly progressed
until she became dependent on her wheelchair 8 years later until now. She had
successfully given birth to a healthy daughter 3 years before her first visit to
our clinic. All three patients were diagnosed with neuromuscular disorder
diseases, with the differential diagnoses of Duchenne muscular dystrophy, spinal
muscular atrophy, and Becker muscular dystrophy. These patients were finally
confirmed to have spinal muscular atrophy due to SMN1 deletion by polymerase
chain reaction and restriction fragment length polymorphism.
CONCLUSIONS: Many genetic diseases are often neglected in developing countries
owing to the difficulty in diagnosis and unavailable treatment. Our case series
focused on the disease courses, diagnosis difficulties, and clinical
presentations of three patients that finally lead to diagnoses of spinal
muscular atrophy.
© 2022. The Author(s).
DOI: 10.1186/s13256-022-03633-y
PMCID: PMC9664805
PMID: 36376972 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no competing
interests. |
http://www.ncbi.nlm.nih.gov/pubmed/24124019 | 1. Am J Med Genet A. 2013 Nov;161A(11):2836-45. doi: 10.1002/ajmg.a.36251. Epub
2013 Oct 3.
Solving the puzzle of spinal muscular atrophy: what are the missing pieces?
Tiziano FD(1), Melki J, Simard LR.
Author information:
(1)Istituto di Genetica Medica, Università Cattolica del Sacro Cuore, Roma,
Italy.
Spinal muscular atrophy (SMA) is an autosomal recessive, lower motor neuron
disease. Clinical heterogeneity is pervasive: three infantile (type I-III) and
one adult-onset (type IV) forms are recognized. Type I SMA is the most common
genetic cause of death in infancy and accounts for about 50% of all patients
with SMA. Most forms of SMA are caused by mutations of the survival motor neuron
(SMN1) gene. A second gene that is 99% identical to SMN1 (SMN2) is located in
the same region. The only functionally relevant difference between the two genes
identified to date is a C → T transition in exon 7 of SMN2, which determines an
alternative spliced isoform that predominantly excludes exon 7. Thus, SMN2 genes
do not produce sufficient full length SMN protein to prevent the onset of the
disease. Since the identification of the causative mutation, biomedical research
of SMA has progressed by leaps and bounds: from clues on the function of SMN
protein, to the development of different models of the disease, to the
identification of potential treatments, some of which are currently in human
trials. The aim of this review is to elucidate the current state of knowledge,
emphasizing how close we are to the solution of the puzzle that is SMA, and,
more importantly, to highlight the missing pieces of this puzzle. Filling in
these gaps in our knowledge will likely accelerate the development and delivery
of efficient treatments for SMA patients and be a prerequisite towards achieving
our final goal, the cure of SMA.
© 2013 Wiley Periodicals, Inc.
DOI: 10.1002/ajmg.a.36251
PMID: 24124019 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10695894 | 1. J Child Neurol. 2000 Feb;15(2):97-101. doi: 10.1177/088307380001500207.
Prospective analysis of strength in spinal muscular atrophy. DCN/Spinal Muscular
Atrophy Group.
Iannaccone ST(1), Russman BS, Browne RH, Buncher CR, White M, Samaha FJ.
Author information:
(1)Department of Neurology, University of Texas Southwestern Medical Center and
Texas Scottish Rite Hospital for Children, Dallas, USA. [email protected]
Spinal muscular atrophy is a genetic disorder of the motor neurons that causes
profound hypotonia, severe weakness, and often fatal restrictive lung disease.
Patients with spinal muscular atrophy present a spectrum of disease from the
most severe infantile-onset type, called Werdnig-Hoffmann disease (type 1),
associated with a mortality rate of up to 90%, to a late-onset mild form (type
3), wherein patients remain independently ambulatory throughout adult life.
Although many clinicians agree that patients with spinal muscular atrophy lose
motor abilities with age, it is unknown whether progressive weakness occurs in
all patients with spinal muscular atrophy. We present here results of the first
prospective study of muscle strength in patients with spinal muscular atrophy.
There was no loss in muscle strength as determined by a quantitative muscle test
during the observation period. However, motor function diminished dramatically
in some patients with spinal muscular atrophy. Explanations for this loss of
function could not be determined from our data. Decrease in motor function could
be caused by factors other than loss of strength. Therefore, it is not clear
from our results whether spinal muscular atrophy is a neurodegenerative disease.
We conclude that treatment trials in spinal muscular atrophy should be designed
with consideration of the natural history of strength and motor function in this
disorder.
DOI: 10.1177/088307380001500207
PMID: 10695894 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15794183 | 1. J Child Neurol. 2005 Feb;20(2):147-50. doi: 10.1177/08830738050200022101.
Type I spinal muscular atrophy can mimic sensory-motor axonal neuropathy.
Anagnostou E(1), Miller SP, Guiot MC, Karpati G, Simard L, Dilenge ME, Shevell
MI.
Author information:
(1)Division of Pediatric Neurology, Montreal Children's Hospital, Department of
Neurology, McGill University, Montreal, Quebec.
Spinal muscular atrophy is a group of allelic autosomal recessive disorders
characterized by progressive motoneuron loss, symmetric weakness, and skeletal
muscle atrophy. It is traditionally considered a pure lower motoneuron disorder,
for which a current definitive diagnosis is now possible by molecular genetic
testing. We report two newborns with a clinical phenotype consistent with that
of spinal muscular atrophy type I and nerve conduction studies and
electromyography suggesting more extensive sensory involvement than classically
described with spinal muscular atrophy. Molecular testing confirmed spinal
muscular atrophy in patient 1 but not in patient 2. Thus, in the setting of a
suspected congenital axonal neuropathy, molecular testing might be necessary to
distinguish spinal muscular atrophy type I from infantile polyneuropathy.
DOI: 10.1177/08830738050200022101
PMID: 15794183 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34445199 | 1. Int J Mol Sci. 2021 Aug 6;22(16):8494. doi: 10.3390/ijms22168494.
What Genetics Has Told Us and How It Can Inform Future Experiments for Spinal
Muscular Atrophy, a Perspective.
Blatnik AJ 3rd(1), McGovern VL(1), Burghes AHM(1).
Author information:
(1)Department of Biological Chemistry & Pharmacology, The Ohio State University
Wexner Medical Center, Rightmire Hall, Room 168, 1060 Carmack Road, Columbus, OH
43210, USA.
Proximal spinal muscular atrophy (SMA) is an autosomal recessive
neurodegenerative disorder characterized by motor neuron loss and subsequent
atrophy of skeletal muscle. SMA is caused by deficiency of the essential
survival motor neuron (SMN) protein, canonically responsible for the assembly of
the spliceosomal small nuclear ribonucleoproteins (snRNPs). Therapeutics aimed
at increasing SMN protein levels are efficacious in treating SMA. However, it
remains unknown how deficiency of SMN results in motor neuron loss, resulting in
many reported cellular functions of SMN and pathways affected in SMA. Herein is
a perspective detailing what genetics and biochemistry have told us about SMA
and SMN, from identifying the SMA determinant region of the genome, to the
development of therapeutics. Furthermore, we will discuss how genetics and
biochemistry have been used to understand SMN function and how we can determine
which of these are critical to SMA moving forward.
DOI: 10.3390/ijms22168494
PMCID: PMC8395208
PMID: 34445199 [Indexed for MEDLINE]
Conflict of interest statement: A.H.M.B. consults for Novartis. |
http://www.ncbi.nlm.nih.gov/pubmed/34560767 | 1. Clin Obstet Gynecol. 2021 Dec 1;64(4):917-925. doi:
10.1097/GRF.0000000000000654.
Spinal Muscular Atrophy: A Potential Target for In Utero Therapy.
Baptiste C(1), De Vivo DC.
Author information:
(1)Columbia University Irving Medical Center, New York, New York.
Spinal muscular atrophy (SMA) is a life-threatening autosomal recessive disease
that leads to progressive muscle weakness and atrophy, respiratory insufficiency
and scoliosis. SMA is currently the most common monogenic cause of infant
mortality. Amazing advancements have been made in the therapeutic options
available for these children since 2016. What has also become clear is that the
earlier the treatment is administered, the better the clinical outcome. For
several reasons, which we will review in this chapter, SMA may be an excellent
disease candidate for in utero therapy.
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/GRF.0000000000000654
PMID: 34560767 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25497877 | 1. Brain. 2015 Feb;138(Pt 2):293-310. doi: 10.1093/brain/awu356. Epub 2014 Dec
14.
Phenotypic and molecular insights into spinal muscular atrophy due to mutations
in BICD2.
Rossor AM(1), Oates EC(2), Salter HK(3), Liu Y(3), Murphy SM(4), Schule R(5),
Gonzalez MA(6), Scoto M(7), Phadke R(1), Sewry CA(7), Houlden H(1), Jordanova
A(8), Tournev I(9), Chamova T(10), Litvinenko I(11), Zuchner S(6), Herrmann
DN(12), Blake J(13), Sowden JE(14), Acsadi G(15), Rodriguez ML(16), Menezes
MP(2), Clarke NF(2), Auer Grumbach M(17), Bullock SL(3), Muntoni F(18), Reilly
MM(19), North KN(20).
Author information:
(1)1 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London,
WC1N 3BG, UK.
(2)2 Institute for Neuroscience and Muscle Research, Children's Hospital at
Westmead, New South Wales, 2145, Australia 3 Discipline of Paediatrics and Child
Health, Faculty of Medicine, The University of Sydney, Sydney, New South Wales,
2006, Australia.
(3)4 Cell Biology Division, MRC Laboratory of Molecular Biology, Cambridge, CB2
0QH, UK.
(4)5 Department of Neurology, Adelaide and Meath Hospitals Incorporating the
National Children's Hospital, Tallaght, Dublin, Ireland 6 Academic Unit of
Neurology, Trinity College Dublin, Ireland.
(5)7 Hertie Institute for Clinical Brain Research and Centre for Neurology,
Department of Neurodegenerative Disease, University of Tübingen and the German
Research Centre for Neurodegenerative Diseases (DZNE), Tübingen, Germany 8 Dr.
John T. Macdonald Foundation Department of Human Genetics and John P. Hussman
Institute for Human Genomics, University of Miami Miller School of Medicine,
Miami, Florida, 33136, USA.
(6)8 Dr. John T. Macdonald Foundation Department of Human Genetics and John P.
Hussman Institute for Human Genomics, University of Miami Miller School of
Medicine, Miami, Florida, 33136, USA.
(7)9 Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, WC1N
1EH, UK.
(8)10 Molecular Neurogenomics Group, Department of Molecular Genetics, VIB,
Antwerp 2610, Belgium 11 Neurogenetics Laboratory, Institute Born-Bunge,
University of Antwerp, Antwerp 2610, Belgium 12 Department of Medical Chemistry
and Biochemistry, Molecular Medicine Centre, Medical University-Sofia, Sofia
1431, Bulgaria.
(9)13 Department of Neurology, Medical University-Sofia, Sofia 1000, Bulgaria 14
Department of Cognitive Science and Psychology, New Bulgarian University, Sofia.
(10)13 Department of Neurology, Medical University-Sofia, Sofia 1000, Bulgaria.
(11)15 Clinic of Child Neurology, Department of Paediatrics, Medical
University-Sofia, Sofia 1000, Bulgaria.
(12)16 University of Rochester Medical Centre, Departments of Neurology and
Pathology, Rochester, NY, 14642, USA.
(13)17 Department of Clinical Neurophysiology, The National Hospital for
Neurology and Neurosurgery and Department of Molecular Neuroscience, UCL
Institute of Neurology, London, UK 18 Department of Clinical Neurophysiology,
Norfolk and Norwich University Hospital, UK.
(14)19 University of Rochester Medical Centre, Department of Neurology,
Rochester, NY, 14642, USA.
(15)20 Connecticut Children's Medical Centre, Department of Neurology, Hartford
Connecticut, 06106, USA.
(16)21 Department of Forensic Medicine, Sydney Local Health District, New South
Wales, 2037, Australia 22 Discipline of Pathology, Sydney Medical School, The
University of Sydney, Sydney, New South Wales, 2006, Australia.
(17)23 Division of Orthopaedics, Medical University of Vienna, Währinger Gürtel
18-20, A-1090 Vienna, Austria.
(18)1 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London,
WC1N 3BG, UK 9 Dubowitz Neuromuscular Centre, UCL Institute of Child Health,
London, WC1N 1EH, UK.
(19)1 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London,
WC1N 3BG, UK [email protected].
(20)2 Institute for Neuroscience and Muscle Research, Children's Hospital at
Westmead, New South Wales, 2145, Australia 3 Discipline of Paediatrics and Child
Health, Faculty of Medicine, The University of Sydney, Sydney, New South Wales,
2006, Australia 24 Murdoch Children's Research Institute. The Royal Children's
Hospital, Parkville Victoria 3052 Australia 25 Department of Paediatrics,
University of Melbourne Parkville Victoria 3010 Australia.
Comment in
Brain. 2015 Nov;138(Pt 11):e391. doi: 10.1093/brain/awv159.
Brain. 2015 Nov;138(Pt 11):e392. doi: 10.1093/brain/awv160.
Spinal muscular atrophy is a disorder of lower motor neurons, most commonly
caused by recessive mutations in SMN1 on chromosome 5q. Cases without SMN1
mutations are subclassified according to phenotype. Spinal muscular atrophy,
lower extremity-predominant, is characterized by lower limb muscle weakness and
wasting, associated with reduced numbers of lumbar motor neurons and is caused
by mutations in DYNC1H1, which encodes a microtubule motor protein in the
dynein-dynactin complex and one of its cargo adaptors, BICD2. We have now
identified 32 patients with BICD2 mutations from nine different families,
providing detailed insights into the clinical phenotype and natural history of
BICD2 disease. BICD2 spinal muscular atrophy, lower extremity predominant most
commonly presents with delayed motor milestones and ankle contractures.
Additional features at presentation include arthrogryposis and congenital
dislocation of the hips. In all affected individuals, weakness and wasting is
lower-limb predominant, and typically involves both proximal and distal muscle
groups. There is no evidence of sensory nerve involvement. Upper motor neuron
signs are a prominent feature in a subset of individuals, including one family
with exclusively adult-onset upper motor neuron features, consistent with a
diagnosis of hereditary spastic paraplegia. In all cohort members, lower motor
neuron features were static or only slowly progressive, and the majority
remained ambulant throughout life. Muscle MRI in six individuals showed a common
pattern of muscle involvement with fat deposition in most thigh muscles, but
sparing of the adductors and semitendinosus. Muscle pathology findings were
highly variable and included pseudomyopathic features, neuropathic features, and
minimal change. The six causative mutations, including one not previously
reported, result in amino acid changes within all three coiled-coil domains of
the BICD2 protein, and include a possible 'hot spot' mutation, p.Ser107Leu
present in four families. We used the recently solved crystal structure of a
highly conserved region of the Drosophila orthologue of BICD2 to further-explore
how the p.Glu774Gly substitution inhibits the binding of BICD2 to Rab6. Overall,
the features of BICD2 spinal muscular atrophy, lower extremity predominant are
consistent with a pathological process that preferentially affects lumbar lower
motor neurons, with or without additional upper motor neuron involvement.
Defining the phenotypic features in this, the largest BICD2 disease cohort
reported to date, will facilitate focused genetic testing and filtering of next
generation sequencing-derived variants in cases with similar features.
© The Author (2014). Published by Oxford University Press on behalf of the
Guarantors of Brain. All rights reserved. For Permissions, please email:
[email protected].
DOI: 10.1093/brain/awu356
PMCID: PMC4306822
PMID: 25497877 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18572081 | 1. Lancet. 2008 Jun 21;371(9630):2120-33. doi: 10.1016/S0140-6736(08)60921-6.
Spinal muscular atrophy.
Lunn MR(1), Wang CH.
Author information:
(1)Department of Medicine, Stanford University School of Medicine, Stanford, CA,
USA.
Comment in
Lancet. 2008 Nov 1;372(9649):1542; author reply 1542. doi:
10.1016/S0140-6736(08)61645-1.
Spinal muscular atrophy is an autosomal recessive neurodegenerative disease
characterised by degeneration of spinal cord motor neurons, atrophy of skeletal
muscles, and generalised weakness. It is caused by homozygous disruption of the
survival motor neuron 1 (SMN1) gene by deletion, conversion, or mutation.
Although no medical treatment is available, investigations have elucidated
possible mechanisms underlying the molecular pathogenesis of the disease.
Treatment strategies have been developed to use the unique genomic structure of
the SMN1 gene region. Several candidate treatment agents have been identified
and are in various stages of development. These and other advances in medical
technology have changed the standard of care for patients with spinal muscular
atrophy. In this Seminar, we provide a comprehensive review that integrates
clinical manifestations, molecular pathogenesis, diagnostic strategy,
therapeutic development, and evidence from clinical trials.
DOI: 10.1016/S0140-6736(08)60921-6
PMID: 18572081 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10226744 | 1. Curr Opin Neurol. 1999 Apr;12(2):137-42. doi:
10.1097/00019052-199904000-00002.
Spinal muscular atrophy: molecular pathophysiology.
Gendron NH(1), MacKenzie AE.
Author information:
(1)Children's Hospital of Eastern Ontario Research Institute, Solange Gauthier
Karsh Laboratory, Ottawa, Canada. [email protected]
Spinal muscular atrophy is an autosomal recessive disease characterized by motor
neurone loss, muscle atrophy and weakness. Deletion or mutation of the SMN1 gene
reduces intracellular survival motor neurone protein levels causes spinal
muscular atrophy, most likely by interfering with spliceosome assembly. A range
of clinical severity and corresponding survival motor neurone levels is seen
because of the presence of copies of the transcriptionally inefficient SMN2 gene
and possibly other modifying genes. The delineation of SMN1 as the gene that
causes spinal muscular atrophy and the identification of genes that modify
spinal muscular atrophy raise the prospect of gene therapy or in-vivo gene
activation treatment for this frequently fatal disorder.
DOI: 10.1097/00019052-199904000-00002
PMID: 10226744 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/13129800 | 1. Amyotroph Lateral Scler Other Motor Neuron Disord. 2003 Sep;4(3):144-9. doi:
10.1080/14660820310011296.
Molecular and cellular basis of spinal muscular atrophy.
Jablonka S(1), Sendtner M.
Author information:
(1)Institute for Clinical Neurobiology, University of Wuerzburg, Wuerzburg,
Germany.
Autosomal recessive spinal muscular atrophy (SMA) is a neuromuscular disorder
characterized by muscle atrophy combined with motor neuron degeneration. SMA is
caused by homozygous mutation or loss of the telomeric copy of the survival of
motor neuron gene (SMN). The SMN gene is localized as an inverted repeat on
chromosome 5q13. Both gene copies (SMN1 and SMN2) are expressed, but they differ
in the expression of full-length protein. SMN2 gene preferentially gives rise to
a truncated and less stable version of the SMN protein and thus can not
compensate for SMN1 loss or mutations unless it is not present in multiple
copies. The SMN protein is part of multiprotein complexes in the cytoplasm and
the nucleus of all cell types. These complexes are involved in assembly of
spliceosomal snRNPs. SMN interacts with RNA polymerase II and other binding
proteins, indicating that the SMN protein is involved in messenger and ribosomal
RNA transcription and processing. The analysis of animal models for SMA could
help to identify the pathophysiological changes that are responsible for spinal
muscular atrophy.
DOI: 10.1080/14660820310011296
PMID: 13129800 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30221755 | 1. Dev Med Child Neurol. 2019 Jan;61(1):19-24. doi: 10.1111/dmcn.14027. Epub 2018
Sep 17.
Nusinersen treatment of spinal muscular atrophy: current knowledge and existing
gaps.
Gidaro T(1)(2), Servais L(1)(2)(3).
Author information:
(1)I-Motion - Pediatric Clinical Trials Department, Trousseau Hospital, Paris,
France.
(2)Institute of Myology, Pitié-Salpêtrière Hospital, Paris, France.
(3)CHU de Liège, Centre de référence des maladies Neuromusculaires, Liège,
Belgium.
Spinal muscular atrophy (SMA) is a recessive disorder caused by a mutation in
the survival motor neuron 1 gene (SMN1); it affects 1 in 11 000 newborn infants.
The most severe and most common form, type 1 SMA, is associated with early
mortality in most cases and severe disability in survivors. Nusinersen, an
antisense oligonucleotide, promotes production of full-length protein from the
pseudogene SMN2. Nusinersen treatment prolongs survival of patients with type 1
SMA and allows motor milestone acquisition. Patients with type 2 SMA also show
progress on different motor scales after nusinersen treatment. Nusinersen was
recently approved by the European Medicines Agency and the US Food and Drug
Administration; it is now reimbursed in several European countries and in the
USA. In Australia, the transition from expanded access programme to commercial
availability is coming soon. In New Zealand, an expanded access programme is
opened, and in Canada price negotiation for the treatment is in progress. In
this review we exemplify the clinical benefit of nusinersen in subgroups of
patients with SMA. Nusinersen represents the first efficacious marked approved
drug in type 1 and type 2 SMA. Different knowledge gaps, such as results in
older patients, in patients with permanent ventilation, in patients with
neonatal forms, or in patients after spinal fusion, still need to be addressed.
WHAT THIS PAPER ADDS: Identifies gaps in knowledge about the efficacy of
nusinersen in broader populations of patients with spinal muscular atrophy.
Identifies open questions in populations of patients where proof of efficacy is
available.
© 2018 Mac Keith Press.
DOI: 10.1111/dmcn.14027
PMID: 30221755 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24334346 | 1. J Child Neurol. 2014 Feb;29(2):254-9. doi: 10.1177/0883073813511858. Epub 2013
Dec 11.
A paucisymptomatic neuromuscular disease mimicking type III 5q-SMA with complex
rearrangements in the SMN gene.
Lohkamp LN(1), von Au K, Goebel HH, Kress W, Grieben U, Drossel K, Garbes L,
Wirth B, Heppner FL, Stenzel W.
Author information:
(1)1Department of Neuropathology, Charité-Universitätsmedizin Berlin, Berlin,
Germany.
Spinal muscular atrophy is an autosomal-recessive neuromuscular disorder,
causing progressive proximal weakness and atrophy of the voluntary muscles. More
than 96% of the spinal muscular atrophy patients show a homozygous absence of
exons 7 and 8, or exon 7 only, in SMN1, the telomeric copy of the SMN gene. We
report a young male patient with neurogenic symptoms and sparse muscle fiber
atrophy, suggestive of a mild form of type III spinal muscular atrophy. He was
found to be a carrier of intragenic mutations in both copies of the SMN gene,
exhibiting a homozygous duplication of exons 7 and 8 in SMN1 and a homozygous
deletion of exon 8 as well as a heterozygous deletion of exon 7 in SMN2.
However, an intact full-length SMN1 complementary deoxyribonucleic acid was
identified, and SMN protein levels in a muscle specimen were identical to that
of a healthy control, formally excluding the diagnosis of spinal muscular
atrophy III.
DOI: 10.1177/0883073813511858
PMID: 24334346 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31371124 | 1. Pediatr Neurol. 2019 Nov;100:3-11. doi: 10.1016/j.pediatrneurol.2019.06.007.
Epub 2019 Jun 13.
From Clinical Trials to Clinical Practice: Practical Considerations for Gene
Replacement Therapy in SMA Type 1.
Al-Zaidy SA(1), Mendell JR(2).
Author information:
(1)Department of Pediatrics, Ohio State University, Columbus, Ohio; Center for
Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio.
(2)Department of Pediatrics, Ohio State University, Columbus, Ohio; Center for
Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio; Department of
Neurology, Ohio State University, Columbus, Ohio. Electronic address:
[email protected].
Spinal muscular atrophy is a devastating neurodegenerative autosomal recessive
disease that results from survival of motor neuron 1 (SMN1) gene mutation or
deletion. Patients with spinal muscular atrophy type 1 utilizing supportive
care, which focuses on symptom management, never sit unassisted, and 75% die or
require permanent ventilation by age 13.6 months. Onasemnogene abeparvovec
(Zolgensma, formerly AVXS-101) is a gene replacement therapy comprising an
adeno-associated viral vector containing the human SMN gene under control of the
chicken beta-actin promoter. This therapy addresses the genetic root cause of
the disease by increasing functional SMN protein in motor neurons and preventing
neuronal cell death, resulting in improved neuronal and muscular function as
previously demonstrated in transgenic animal models. In an open-label, one-arm,
dose-escalation phase 1 trial, systemic administration of onasemnogene
abeparvovec via a one-time infusion over one hour demonstrated improved motor
function and survival in all infants symptomatic for spinal muscular atrophy
type 1. Of the 12 patients who received the proposed therapeutic dose, 11
achieved independent sitting, two achieved independent standing, and two are
able to walk. Most of these 12 patients remained free of respiratory supportive
care. The only treatment-related adverse event observed was transient
asymptomatic transaminasemia that resolved with a short course of prednisolone
treatment. This review discusses the biological rationale underlying gene
replacement therapy for spinal muscular atrophy, describes the onasemnogene
abeparvovec clinical trial experience, and provides expert recommendations as a
reference for the real-world use of onasemnogene abeparvovec in clinical
practice. As of May 24, 2019, the Food and Drug Administration approved
onasemnogene abeparvovec, the first gene therapy approved to treat children
younger than two years with spinal muscular atrophy.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.pediatrneurol.2019.06.007
PMID: 31371124 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26515624 | 1. Neurol Clin. 2015 Nov;33(4):831-46. doi: 10.1016/j.ncl.2015.07.004.
Spinal Muscular Atrophy.
Kolb SJ(1), Kissel JT(2).
Author information:
(1)Department of Neurology, The Ohio State University Wexner Medical Center,
Columbus, OH, USA; Department of Biological Chemistry and Pharmacology, The Ohio
State University Wexner Medical Center, Columbus, OH 43210-1228, USA. Electronic
address: [email protected].
(2)Department of Neurology, The Ohio State University Wexner Medical Center,
Columbus, OH, USA.
Spinal muscular atrophy is an autosomal-recessive disorder characterized by
degeneration of motor neurons in the spinal cord and caused by mutations in the
survival motor neuron 1 gene, SMN1. The severity of SMA is variable. The SMN2
gene produces a fraction of the SMN messenger RNA (mRNA) transcript produced by
the SMN1 gene. There is an inverse correlation between SMN2 gene copy number and
clinical severity. Clinical management focuses on multidisciplinary care.
Preclinical models of SMA have led to an explosion of SMA clinical trials that
hold great promise of effective therapy in the future.
Copyright © 2015 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ncl.2015.07.004
PMCID: PMC4628728
PMID: 26515624 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28229309 | 1. Drugs. 2017 Mar;77(4):473-479. doi: 10.1007/s40265-017-0711-7.
Nusinersen: First Global Approval.
Hoy SM(1).
Author information:
(1)Springer, Private Bag 65901, Mairangi Bay, 0754, Auckland, New Zealand.
[email protected].
Spinal muscular atrophy (SMA) is a rare autosomal recessive disorder
characterized by muscle atrophy and weakness resulting from motor neuron
degeneration in the spinal cord and brainstem. It is most commonly caused by
insufficient levels of survival motor neuron (SMN) protein (which is critical
for motor neuron maintenance) secondary to deletions or mutations in the SMN1
gene. Nusinersen (SPINRAZA™) is a modified antisense oligonucleotide that binds
to a specific sequence in the intron, downstream of exon 7 on the pre-messenger
ribonucleic acid (pre-mRNA) of the SMN2 gene. This modulates the splicing of the
SMN2 mRNA transcript to include exon 7, thereby increasing the production of
full-length SMN protein. Nusinersen is approved in the USA for intrathecal use
in paediatric and adult patients with SMA. Regulatory assessments for nusinersen
as a treatment for SMA are underway in the EU and several other countries. This
article summarizes the milestones in the development of nusinersen leading to
this first approval for SMA in paediatric and adult patients.
DOI: 10.1007/s40265-017-0711-7
PMID: 28229309 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18990310 | 1. Curr Treat Options Neurol. 2008 Nov;10(6):420-8. doi:
10.1007/s11940-008-0044-7.
Spinal muscular atrophy: advances in research and consensus on care of patients.
Wang CH(1), Lunn MR.
Author information:
(1)Ching H. Wang, MD, PhD Department of Neurology and Neurological Sciences,
Stanford University Medical Center, 300 Pasteur Drive, Room A343, Stanford, CA
94305-5235, USA. [email protected].
Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by
degeneration of spinal cord motor neurons and muscular atrophy. Advances in
recent research have led to understanding of the molecular genetics of SMA.
Therapeutic strategies have been developed according to the unique genomic
structure of the SMN genes. Three groups of compounds have been identified as
therapeutic candidates. One group was identified before the molecular genetics
of SMA was understood, chosen on the basis of their effectiveness in similar
neurologic disorders. The second group was identified based on their ability to
modify SMN2 gene expression. Several of these agents are currently in clinical
trials. A third group, identified by large-scale drug screening, is still under
preclinical investigation. In addition, other advances in medical technology
have led to the publication of a consensus statement regarding the care of SMA
patients.
DOI: 10.1007/s11940-008-0044-7
PMID: 18990310 |
http://www.ncbi.nlm.nih.gov/pubmed/18651653 | 1. Dev Dyn. 2008 Aug;237(8):2268-78. doi: 10.1002/dvdy.21642.
Identification and characterization of the porcine (Sus scrofa) survival motor
neuron (SMN1) gene: an animal model for therapeutic studies.
Lorson MA(1), Spate LD, Prather RS, Lorson CL.
Author information:
(1)University of Missouri, Department of Veterinary Pathobiology, Life Sciences
Center, Columbia, Missouri 65211-7310, USA. [email protected]
Spinal muscular atrophy (SMA) is an autosomal recessive disorder that is
characterized by the degeneration of the motor neurons of the spinal cord
leading to muscle atrophy. SMA is a result of a loss-of-function of the gene
survival motor neuron-1 (SMN1). We have chosen to generate a transgenic swine
model of SMA for the development and testing of therapeutics and evaluation of
toxicology. To this end, we report the first cloning and identification of the
swine SMN1 gene and show that there is significant sequence homology between
swine and human SMN throughout the coding region. Reverse
transcriptase-polymerase chain reaction results demonstrated slight changes in
SMN RNA expression during development and in different tissues. In contrast,
protein expression profiles were dramatically different based upon different
tissues and developmental stages, consistent with human SMN expression. Porcine
SMN localization is consistent with human SMN, localizing diffusely within the
cytoplasm and in punctate nuclear structures characteristic of nuclear gems.
Importantly, transient transfection of porcine SMN1 in 3813 SMA type 1
fibroblasts demonstrate that porcine SMN1 can rescue the deficiency of SMN
protein and gem formation in these cells. These studies provide the first
characterization of the porcine SMN1 gene and SMN protein and suggest that a
transgenic swine SMA model is feasible.
Copyright (c) 2008 Wiley-Liss, Inc.
DOI: 10.1002/dvdy.21642
PMCID: PMC2556073
PMID: 18651653 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33979606 | 1. Cell Rep. 2021 May 11;35(6):109125. doi: 10.1016/j.celrep.2021.109125.
A high-throughput genome-wide RNAi screen identifies modifiers of survival motor
neuron protein.
McCormack NM(1), Abera MB(1), Arnold ES(2), Gibbs RM(2), Martin SE(3), Buehler
E(3), Chen YC(3), Chen L(3), Fischbeck KH(2), Burnett BG(4).
Author information:
(1)Department of Anatomy, Physiology and Genetics, Uniformed Services University
of the Health Sciences, F. Edward Hébert School of Medicine, Bethesda, MD 20814,
USA.
(2)Neurogenetics Branch, National Institute of Neurological Disorders and
Stroke, Bethesda, MD 20892, USA.
(3)Functional Genomics Lab, National Center for Advancing Translational
Sciences, National Institutes of Health, Bethesda, MD 20850, USA.
(4)Department of Anatomy, Physiology and Genetics, Uniformed Services University
of the Health Sciences, F. Edward Hébert School of Medicine, Bethesda, MD 20814,
USA. Electronic address: [email protected].
Spinal muscular atrophy (SMA) is a debilitating neurological disorder marked by
degeneration of spinal motor neurons and muscle atrophy. SMA results from
mutations in survival motor neuron 1 (SMN1), leading to deficiency of survival
motor neuron (SMN) protein. Current therapies increase SMN protein and improve
patient survival but have variable improvements in motor function, making it
necessary to identify complementary strategies to further improve disease
outcomes. Here, we perform a genome-wide RNAi screen using a luciferase-based
activity reporter and identify genes involved in regulating SMN gene expression,
RNA processing, and protein stability. We show that reduced expression of
Transcription Export complex components increases SMN levels through the
regulation of nuclear/cytoplasmic RNA transport. We also show that the E3
ligase, Neurl2, works cooperatively with Mib1 to ubiquitinate and promote SMN
degradation. Together, our screen uncovers pathways through which SMN expression
is regulated, potentially revealing additional strategies to treat SMA.
Published by Elsevier Inc.
DOI: 10.1016/j.celrep.2021.109125
PMCID: PMC8679797
PMID: 33979606 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests The authors declare no
competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/23876144 | 1. J Anat. 2014 Jan;224(1):15-28. doi: 10.1111/joa.12083. Epub 2013 Jul 22.
Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease?
Shababi M(1), Lorson CL, Rudnik-Schöneborn SS.
Author information:
(1)Department of Veterinary Pathobiology, Life Sciences Center, University of
Missouri, Columbia, MO, USA; Department of Molecular Microbiology and
Immunology, School of Medicine, University of Missouri, Columbia, MO, USA.
Spinal muscular atrophy (SMA) is an autosomal recessive disorder that is the
leading genetic cause of infantile death. SMA is characterized by loss of motor
neurons in the ventral horn of the spinal cord, leading to weakness and muscle
atrophy. SMA occurs as a result of homozygous deletion or mutations in Survival
Motor Neuron-1 (SMN1). Loss of SMN1 leads to a dramatic reduction in SMN
protein, which is essential for motor neuron survival. SMA disease severity
ranges from extremely severe to a relatively mild adult onset form of proximal
muscle atrophy. Severe SMA patients typically die mostly within months or a few
years as a consequence of respiratory insufficiency and bulbar paralysis. SMA is
widely known as a motor neuron disease; however, there are numerous clinical
reports indicating the involvement of additional peripheral organs contributing
to the complete picture of the disease in severe cases. In this review, we have
compiled clinical and experimental reports that demonstrate the association
between the loss of SMN and peripheral organ deficiency and malfunction. Whether
defective peripheral organs are a consequence of neuronal damage/muscle atrophy
or a direct result of SMN loss will be discussed.
© 2013 Anatomical Society.
DOI: 10.1111/joa.12083
PMCID: PMC3867883
PMID: 23876144 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34329347 | 1. PLoS One. 2021 Jul 30;16(7):e0255544. doi: 10.1371/journal.pone.0255544.
eCollection 2021.
Risk factors for severity of COVID-19 in hospital patients age 18-29 years.
Sandoval M(1)(2), Nguyen DT(1), Vahidy FS(3), Graviss EA(1)(4).
Author information:
(1)Department of Pathology and Genomic Medicine, Houston Methodist Research
Institute, Houston, TX, United States of America.
(2)Department of Epidemiology, Human Genetics & Environmental Sciences, The
University of Texas Health Science Center School of Public Health, Houston, TX,
United States of America.
(3)Center for Outcomes Research, Houston Methodist Research Institute, Houston,
TX, United States of America.
(4)Department of Surgery, Houston Methodist Hospital, Houston, TX, United States
of America.
BACKGROUND: Since February 2020, over 2.5 million Texans have been diagnosed
with COVID-19, and 20% are young adults at risk for SARS-CoV-2 exposure at work,
academic, and social settings. This study investigated demographic and clinical
risk factors for severe disease and readmission among young adults 18-29 years
old, who were diagnosed at a hospital encounter in Houston, Texas, USA.
METHODS AND FINDINGS: A retrospective registry-based chart review was conducted
investigating demographic and clinical risk factors for severe COVID-19 among
patients aged 18-29 with positive SARS-CoV-2 tests within a large metropolitan
healthcare system in Houston, Texas, USA. In the cohort of 1,853 young adult
patients diagnosed with COVID-19 infection at a hospital encounter, including
226 pregnant women, 1,438 (78%) scored 0 on the Charlson Comorbidity Index, and
833 (45%) were obese (≥30 kg/m2). Within 30 days of their diagnostic encounter,
316 (17%) patients were diagnosed with pneumonia, 148 (8%) received other severe
disease diagnoses, and 268 (14%) returned to the hospital after being discharged
home. In multivariable logistic regression analyses, increasing age (adjusted
odds ratio [aOR] 1.1, 95% confidence interval [CI] 1.1-1.2, p<0.001), male
gender (aOR 1.8, 95% CI 1.2-2.7, p = 0.002), Hispanic ethnicity (aOR 1.9, 95% CI
1.2-3.1, p = 0.01), obesity (3.1, 95% CI 1.9-5.1, p<0.001), asthma history (aOR
2.3, 95% CI 1.3-4.0, p = 0.003), congestive heart failure (aOR 6.0, 95% CI
1.5-25.1, p = 0.01), cerebrovascular disease (aOR 4.9, 95% CI 1.7-14.7, p =
0.004), and diabetes (aOR 3.4, 95% CI 1.9-6.2, p<0.001) were predictive of
severe disease diagnoses within 30 days. Non-Hispanic Black race (aOR 1.6, 95%
CI 1.0-2.4, p = 0.04), obesity (aOR 1.7, 95% CI 1.0-2.9, p = 0.046), asthma
history (aOR 1.7, 95% CI 1.0-2.7, p = 0.03), myocardial infarction history (aOR
6.2, 95% CI 1.7-23.3, p = 0.01), and household exposure (aOR 1.5, 95% CI
1.1-2.2, p = 0.02) were predictive of 30-day readmission.
CONCLUSIONS: This investigation demonstrated the significant risk of severe
disease and readmission among young adult populations, especially marginalized
communities and people with comorbidities, including obesity, asthma,
cardiovascular disease, and diabetes. Health authorities must emphasize COVID-19
awareness and prevention in young adults and continue investigating risk factors
for severe disease, readmission and long-term sequalae.
DOI: 10.1371/journal.pone.0255544
PMCID: PMC8323903
PMID: 34329347 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/22047105 | 1. Orphanet J Rare Dis. 2011 Nov 2;6:71. doi: 10.1186/1750-1172-6-71.
Spinal muscular atrophy.
D'Amico A(1), Mercuri E, Tiziano FD, Bertini E.
Author information:
(1)Department of Neurosciences, Unit of Molecular Medicine for Neuromuscular and
Neurodegenerative Disorders, Bambino Gesu' Children's Research Hospital, P.za S.
Onofrio, 4, Rome (00165), Italy.
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease
characterized by degeneration of alpha motor neurons in the spinal cord,
resulting in progressive proximal muscle weakness and paralysis. Estimated
incidence is 1 in 6,000 to 1 in 10,000 live births and carrier frequency of
1/40-1/60. This disease is characterized by generalized muscle weakness and
atrophy predominating in proximal limb muscles, and phenotype is classified into
four grades of severity (SMA I, SMAII, SMAIII, SMA IV) based on age of onset and
motor function achieved. This disease is caused by homozygous mutations of the
survival motor neuron 1 (SMN1) gene, and the diagnostic test demonstrates in
most patients the homozygous deletion of the SMN1 gene, generally showing the
absence of SMN1 exon 7. The test achieves up to 95% sensitivity and nearly 100%
specificity. Differential diagnosis should be considered with other
neuromuscular disorders which are not associated with increased CK manifesting
as infantile hypotonia or as limb girdle weakness starting later in life.
Considering the high carrier frequency, carrier testing is requested by siblings
of patients or of parents of SMA children and are aimed at gaining information
that may help with reproductive planning. Individuals at risk should be tested
first and, in case of testing positive, the partner should be then analyzed. It
is recommended that in case of a request on carrier testing on siblings of an
affected SMA infant, a detailed neurological examination should be done and
consideration given doing the direct test to exclude SMA. Prenatal diagnosis
should be offered to couples who have previously had a child affected with SMA
(recurrence risk 25%). The role of follow-up coordination has to be managed by
an expert in neuromuscular disorders and in SMA who is able to plan a
multidisciplinary intervention that includes pulmonary,
gastroenterology/nutrition, and orthopedic care. Prognosis depends on the
phenotypic severity going from high mortality within the first year for SMA type
1 to no mortality for the chronic and later onset forms.
DOI: 10.1186/1750-1172-6-71
PMCID: PMC3231874
PMID: 22047105 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33741488 | 1. Int J Infect Dis. 2021 Apr;105:776-783. doi: 10.1016/j.ijid.2021.03.037. Epub
2021 Mar 16.
Clinical features and risk factors associated with morbidity and mortality among
patients with COVID-19 in northern Ethiopia.
Abraha HE(1), Gessesse Z(1), Gebrecherkos T(1), Kebede Y(1), Weldegiargis AW(2),
Tequare MH(1), Welderufael AL(1), Zenebe D(1), Gebremariam AG(1), Dawit TC(1),
Gebremedhin DW(1), de Wit TR(3), Wolday D(4).
Author information:
(1)Mekelle University College of Health Sciences, Mekelle, Ethiopia.
(2)Deutsche Gesellschaft fϋr Internationale Zusammenarbeit, GMBH, Nutrition
Sensitive Agriculture Project in Mekelle, Ethiopia.
(3)Amsterdam Institute for Global Health and Development, Academic Medical
Centre, University of Amsterdam, The Netherlands.
(4)Mekelle University College of Health Sciences, Mekelle, Ethiopia. Electronic
address: [email protected].
OBJECTIVE: To describe the clinical features and assess the determinants of
severity and in-hospital mortality of patients with coronavirus disease 2019
(COVID-19) from a unique setting in Ethiopia.
METHODS: Consecutive patients admitted to a COVID-19 isolation and treatment
centre were included in this study. The overall clinical spectrum of COVID-19,
and factors associated with risk of severe COVID-19 and in-hospital mortality
were analysed.
RESULTS: Of 2617 quarantined patients, three-quarters (n = 1935, 74%) were
asymptomatic and only 114 (4.4%) presented with severe COVID-19. Common
characteristics among the 682 symptomatic patients were cough (n = 354, 50.6%),
myalgia (n = 212, 31.1%), headache (n = 196, 28.7%), fever (n = 161, 23.6%),
dyspnoea (n = 111, 16.3%), anosmia and/or dysgeusia (n = 90, 13.2%), sore throat
(n = 87, 12.8%) and chest pain (n = 77, 11.3%). Factors associated with severe
COVID-19 were older age [adjusted relative risk (aRR) 1.78, 95% confidence
interval (CI) 1.61-1.97; P < 0.0001], diabetes (aRR 2.00, 95% CI 1.20-3.32; P =
0.007), cardiovascular disease (aRR 2.53, 95% CI 1.53-4.17; P < 0.0001),
malignancy (aRR 4.57, 95% CI 1.62-12.87; P = 0.004), surgery/trauma (aRR 23.98,
95% CI 10.35-55.57; P < 0.0001) and human immunodeficiency virus infection (aRR
4.24, 95% CI 1.55-11.61; P = 005). Factors associated with risk of in-hospital
mortality included older age (aRR 2.37, 95% CI 1.90-2.95; P < 0.001), malignancy
(aRR 6.73, 95% CI 1.50-30.16; P = 0.013) and surgery/trauma (aRR 59.52, 95% CI
12.90-274.68; P < 0.0001).
CONCLUSIONS: A significant proportion of cases of COVID-19 were asymptomatic,
and key comorbid conditions increased the risk of severe COVID-19 and
in-hospital mortality. These findings could help in the design of appropriate
management strategies for patients.
Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/j.ijid.2021.03.037
PMCID: PMC7962557
PMID: 33741488 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33713486 | 1. Hepatology. 2021 Jun;73(6):2099-2109. doi: 10.1002/hep.31797.
Outcome of COVID-19 in Patients With Autoimmune Hepatitis: An International
Multicenter Study.
Efe C(1), Dhanasekaran R(2), Lammert C(3), Ebik B(4), Higuera-de la Tijera F(5),
Aloman C(6), Rıza Calışkan A(7), Peralta M(8)(9), Gerussi A(10)(11), Massoumi
H(12), Catana AM(13), Torgutalp M(14), Purnak T(15), Rigamonti C(16)(17), Gomez
Aldana AJ(18), Khakoo N(19), Kacmaz H(7), Nazal L(20), Frager S(12), Demir
N(21), Irak K(22), Ellik ZM(23), Balaban Y(24), Atay K(25), Eren F(26),
Cristoferi L(10)(11), Batıbay E(1), Urzua Á(27), Snijders R(28)(29), Kıyıcı
M(30), Akyıldız M(31), Ekin N(4), Carr RM(32), Harputluoğlu M(33), Hatemi I(34),
Mendizabal M(9)(35), Silva M(9)(35), Idilman R(23), Silveira M(36), Drenth
JPH(28)(29), Assis DN(36), Björnsson E(37)(38), Boyer JL(36), Invernizzi
P(10)(11), Levy C(19), Schiano TD(39), Ridruejo E(9)(34)(40), Wahlin S(41).
Author information:
(1)Department of Gastroenterology, Harran University Hospital, Şanlıurfa,
Turkey.
(2)Division of Gastroenterology and Hepatology, Department of Medicine, Stanford
University, Stanford, CA, USA.
(3)Department of Medicine Indiana, University School of Medicine, Indianapolis,
IN, USA.
(4)Department of Gastroenterology, Gazi Yaşargil Education and Research
Hospital, Diyarbakir, Turkey.
(5)Gastroenterology and Hepatology Unit, Hospital General de México, Mexico
City, Mexico.
(6)Section of Hepatology, Rush University Medical Center, Chicago, IL, USA.
(7)Department of Gastroenterology, Adıyaman University, Adıyaman, Turkey.
(8)Hepatology Section, Hospital Francisco J Muñiz, Buenos Aires, Argentina.
(9)Latin American Liver Research Educational and Awareness Network, Pilar,
Argentina.
(10)Division of Gastroenterology, Center for Autoimmune Liver Diseases,
Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
(11)European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San
Gerardo Hospital, Monza, Italy.
(12)Department of Medicine, Montefiore Medical Center, Bronx, NY, USA.
(13)Division of Gastroenterology/Hepatology, Department of Medicine, Beth Israel
Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
(14)Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus
Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin, Germany.
(15)Division of Gastroenterology, Hepatology and Nutrition, McGovern Medical
School, Houston, TX, USA.
(16)Department of Translational Medicine, Università del Piemonte Orientale UPO,
Novara, Italy.
(17)Division of Internal Medicine, "AOU Maggiore della Carità", Novara, Italy.
(18)Gastroenterology and Hepatology Unit, Fundación Santa Fe de Bogotá y
universidad de Los Andes, Bogotá, Colombia.
(19)Division of Hepatology, University of Miami Miller School of Medicine,
Miami, FL, USA.
(20)Gastroenterology and Hepatology Unit, Clínica Las Condes, Santiago de Chile,
Chile.
(21)Department of Gastroenterology, Haseki Training and Research Hospital,
Istanbul, Turkey.
(22)Department of Gastroenterology, SBU Kanuni Sultan Süleyman Training and
Research Hospital, Istanbul, Turkey.
(23)Department of Gastroenterology, Ankara University Medical Faculty, Ankara,
Turkey.
(24)Department of Gastroenterology, Faculty of Medicine, Hacettepe University,
Ankara, Turkey.
(25)Department of Gastroenterology, Mardin State Hospital, Mardin, Turkey.
(26)Department of Gastroenterology, Ordu State Hospital, Ordu, Turkey.
(27)Gastroenterology and Hepatology Unit, Hospital Clínico Universidad de Chile,
Santiago de Chile, Chile.
(28)Department of Gastroenterology and Hepatology, Radboud University Medical
Center, Nijmegen, The Netherlands.
(29)European Reference Network on Hepatological Diseases (ERN RARE-LIVER).
(30)Department of Gastroenterology, Medical Faculty, Uludag University, Bursa,
Turkey.
(31)Department of Gastroenterology, Koc University School of Medicine, Istanbul,
Turkey.
(32)Division of Gastroenterology,, University of Pennsylvania, Philadelphia, PA,
USA.
(33)Department of Gastroenterology, Inönü University School of Medicine,
Malatya, Turkey.
(34)Department of Gastroenterology, Cerrahpaşa School of Medicine, İstanbul,
Turkey.
(35)Hepatology and Liver Transplant Unit, Hospital Universitario Austral, Pilar,
Argentina.
(36)Department of Medicine, Section of Digestive Diseases, Yale School of
Medicine, New Haven, CT, USA.
(37)Department of Internal Medicine, Section of Gastroenterology, Landspitali
University Hospital, Reykjavik, Iceland.
(38)Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
(39)Division of Liver Diseases, Mount Sinai Medical Center, New York, NY, USA.
(40)Hepatology Section, Department of Medicine, Centro de Educación Médica e
Investigaciones Clínicas, Buenos Aires, Argentina.
(41)Hepatology Division, Department of Upper GI, Karolinska Institutet,
Karolinska University Hospital, Stockholm, Sweden.
Erratum in
Hepatology. 2022 Mar;75(3):774. doi: 10.1002/hep.32263.
Comment in
Hepatol Commun. 2021 Oct;5(10):1801-1802. doi: 10.1002/hep4.1750.
Hepatol Commun. 2022 Nov;6(11):3272. doi: 10.1002/hep4.1798.
BACKGROUND AND AIMS: Data regarding outcome of COVID-19 in patients with
autoimmune hepatitis (AIH) are lacking.
APPROACH AND RESULTS: We performed a retrospective study on patients with AIH
and COVID-19 from 34 centers in Europe and the Americas. We analyzed factors
associated with severe COVID-19 outcomes, defined as the need for mechanical
ventilation, intensive care admission, and/or death. The outcomes of patients
with AIH were compared to a propensity score-matched cohort of patients without
AIH but with chronic liver diseases (CLD) and COVID-19. The frequency and
clinical significance of new-onset liver injury (alanine aminotransferase > 2 ×
the upper limit of normal) during COVID-19 was also evaluated. We included 110
patients with AIH (80% female) with a median age of 49 (range, 18-85) years at
COVID-19 diagnosis. New-onset liver injury was observed in 37.1% (33/89) of the
patients. Use of antivirals was associated with liver injury (P = 0.041; OR,
3.36; 95% CI, 1.05-10.78), while continued immunosuppression during COVID-19 was
associated with a lower rate of liver injury (P = 0.009; OR, 0.26; 95% CI,
0.09-0.71). The rates of severe COVID-19 (15.5% versus 20.2%, P = 0.231) and
all-cause mortality (10% versus 11.5%, P = 0.852) were not different between AIH
and non-AIH CLD. Cirrhosis was an independent predictor of severe COVID-19 in
patients with AIH (P < 0.001; OR, 17.46; 95% CI, 4.22-72.13). Continuation of
immunosuppression or presence of liver injury during COVID-19 was not associated
with severe COVID-19.
CONCLUSIONS: This international, multicenter study reveals that patients with
AIH were not at risk for worse outcomes with COVID-19 than other causes of CLD.
Cirrhosis was the strongest predictor for severe COVID-19 in patients with AIH.
Maintenance of immunosuppression during COVID-19 was not associated with
increased risk for severe COVID-19 but did lower the risk for new-onset liver
injury during COVID-19.
© 2021 by the American Association for the Study of Liver Diseases.
DOI: 10.1002/hep.31797
PMCID: PMC8250536
PMID: 33713486 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33353564 | 1. Acta Neuropathol Commun. 2020 Dec 22;8(1):223. doi:
10.1186/s40478-020-01101-6.
Mitochondrial defects in the respiratory complex I contribute to impaired
translational initiation via ROS and energy homeostasis in SMA motor neurons.
Thelen MP(1)(2), Wirth B(1)(2)(3), Kye MJ(4)(5).
Author information:
(1)Institute of Human Genetics, University of Cologne, Kerpener Str. 34, 50931,
Cologne, Germany.
(2)Center for Molecular Medicine, Cologne, University of Cologne, 50931,
Cologne, Germany.
(3)Center for Rare Diseases Cologne, University Hospital Cologne, University of
Cologne, 50931, Cologne, Germany.
(4)Institute of Human Genetics, University of Cologne, Kerpener Str. 34, 50931,
Cologne, Germany. [email protected].
(5)Center for Molecular Medicine, Cologne, University of Cologne, 50931,
Cologne, Germany. [email protected].
Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by loss
of lower motor neurons, which leads to proximal muscle weakness and atrophy. SMA
is caused by reduced survival motor neuron (SMN) protein levels due to biallelic
deletions or mutations in the SMN1 gene. When SMN levels fall under a certain
threshold, a plethora of cellular pathways are disturbed, including RNA
processing, protein synthesis, metabolic defects, and mitochondrial function.
Dysfunctional mitochondria can harm cells by decreased ATP production and
increased oxidative stress due to elevated cellular levels of reactive oxygen
species (ROS). Since neurons mainly produce energy via mitochondrial oxidative
phosphorylation, restoring metabolic/oxidative homeostasis might rescue SMA
pathology. Here, we report, based on proteome analysis, that SMA motor neurons
show disturbed energy homeostasis due to dysfunction of mitochondrial complex I.
This results in a lower basal ATP concentration and higher ROS production that
causes an increase of protein carbonylation and impaired protein synthesis in
SMA motor neurons. Counteracting these cellular impairments with pyruvate
reduces elevated ROS levels, increases ATP and SMN protein levels in SMA motor
neurons. Furthermore, we found that pyruvate-mediated SMN protein synthesis is
mTOR-dependent. Most importantly, we showed that ROS regulates protein synthesis
at the translational initiation step, which is impaired in SMA. As many
neuropathies share pathological phenotypes such as dysfunctional mitochondria,
excessive ROS, and impaired protein synthesis, our findings suggest new
molecular interactions among these pathways. Additionally, counteracting these
impairments by reducing ROS and increasing ATP might be beneficial for motor
neuron survival in SMA patients.
DOI: 10.1186/s40478-020-01101-6
PMCID: PMC7754598
PMID: 33353564 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflict
of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/36264571 | 1. JAMA Netw Open. 2022 Oct 3;5(10):e2240037. doi:
10.1001/jamanetworkopen.2022.40037.
Factors Associated With Severe COVID-19 Among Vaccinated Adults Treated in US
Veterans Affairs Hospitals.
Vo AD(1), La J(1), Wu JT(2)(3), Strymish JM(4)(5), Ronan M(4), Brophy
M(1)(4)(6), Do NV(1)(4)(6), Branch-Elliman W(1)(4)(5)(7), Fillmore
NR(1)(4)(5)(8), Monach PA(1)(4)(5).
Author information:
(1)VA Boston Cooperative Studies Program, Boston, Massachusetts.
(2)VA Palo Alto Healthcare System, Palo Alto, California.
(3)Stanford University School of Medicine, Stanford, California.
(4)Department of Medicine, VA Boston Healthcare System, Boston, Massachusetts.
(5)Harvard Medical School, Boston, Massachusetts.
(6)Boston University School of Medicine, Boston, Massachusetts.
(7)VA Boston Center for Healthcare Organization and Implementation Research,
Boston, Massachusetts.
(8)Dana Farber Cancer Institute, Boston, Massachusetts.
Erratum in
JAMA Netw Open. 2023 Feb 1;6(2):e231692. doi:
10.1001/jamanetworkopen.2023.1692.
IMPORTANCE: With a large proportion of the US adult population vaccinated
against SARS-CoV-2, it is important to identify who remains at risk of severe
infection despite vaccination.
OBJECTIVE: To characterize risk factors for severe COVID-19 disease in a
vaccinated population.
DESIGN, SETTING, AND PARTICIPANTS: This nationwide, retrospective cohort study
included US veterans who received a SARS-CoV-2 vaccination series and later
developed laboratory-confirmed SARS-CoV-2 infection and were treated at US
Department of Veterans Affairs (VA) hospitals. Data were collected from December
15, 2020, through February 28, 2022.
EXPOSURES: Demographic characteristics, comorbidities, immunocompromised status,
and vaccination-related variables.
MAIN OUTCOMES AND MEASURES: Development of severe vs nonsevere SARS-CoV-2
infection. Severe disease was defined as hospitalization within 14 days of a
positive SARS-CoV-2 diagnostic test and either blood oxygen level of less than
94%, receipt of supplemental oxygen or dexamethasone, mechanical ventilation, or
death within 28 days. Association between severe disease and exposures was
estimated using logistic regression models.
RESULTS: Among 110 760 patients with infections following vaccination (97 614
[88.1%] men, mean [SD] age at vaccination, 60.8 [15.3] years; 26 953 [24.3%]
Black, 11 259 [10.2%] Hispanic, and 71 665 [64.7%] White), 10 612 (9.6%) had
severe COVID-19. The strongest association with risk of severe disease after
vaccination was age, which increased among patients aged 50 years or older with
an adjusted odds ratio (aOR) of 1.42 (CI, 1.40-1.44) per 5-year increase in age,
such that patients aged 80 years or older had an aOR of 16.58 (CI, 13.49-20.37)
relative to patients aged 45 to 50 years. Immunocompromising conditions,
including receipt of different classes of immunosuppressive medications (eg,
leukocyte inhibitor: aOR, 2.80; 95% CI, 2.39-3.28) or cytotoxic chemotherapy
(aOR, 2.71; CI, 2.27-3.24) prior to breakthrough infection, or leukemias or
lymphomas (aOR, 1.87; CI, 1.61-2.17) and chronic conditions associated with
end-organ disease, such as heart failure (aOR, 1.74; CI, 1.61-1.88), dementia
(aOR, 2.01; CI, 1.83-2.20), and chronic kidney disease (aOR, 1.59; CI,
1.49-1.69), were also associated with increased risk. Receipt of an additional
(ie, booster) dose of vaccine was associated with reduced odds of severe disease
(aOR, 0.50; CI, 0.44-0.57).
CONCLUSIONS AND RELEVANCE: In this nationwide, retrospective cohort of
predominantly male US Veterans, we identified risk factors associated with
severe disease despite vaccination. Findings could be used to inform outreach
efforts for booster vaccinations and to inform clinical decision-making about
patients most likely to benefit from preexposure prophylaxis and antiviral
therapy.
DOI: 10.1001/jamanetworkopen.2022.40037
PMCID: PMC9585432
PMID: 36264571 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of Interest Disclosures: Dr
Branch-Elliman reported receiving grants from Gilead Sciences and funds to their
institution during the conduct of the study. Dr Fillmore reported receiving
grants from American Heart Association and grants from Veterans Affairs (VA)
Cooperative Studies Program during the conduct of the study. No other
disclosures were reported. |
http://www.ncbi.nlm.nih.gov/pubmed/33986052 | 1. BMJ Open. 2021 May 13;11(5):e044684. doi: 10.1136/bmjopen-2020-044684.
Risk factors for severity of COVID-19: a rapid review to inform vaccine
prioritisation in Canada.
Wingert A(1), Pillay J(2), Gates M(2), Guitard S(2), Rahman S(2), Beck A(2),
Vandermeer B(2), Hartling L(2).
Author information:
(1)Alberta Research Centre for Health Evidence, Department of Pediatrics,
University of Alberta Faculty of Medicine and Dentistry, Edmonton, Alberta,
Canada [email protected].
(2)Alberta Research Centre for Health Evidence, Department of Pediatrics,
University of Alberta Faculty of Medicine and Dentistry, Edmonton, Alberta,
Canada.
OBJECTIVES: Rapid review to determine the magnitude of association between
potential risk factors and severity of COVID-19, to inform vaccine
prioritisation in Canada.
SETTING: Ovid MEDLINE(R) ALL, Epistemonikos COVID-19 in L·OVE Platform, McMaster
COVID-19 Evidence Alerts and websites were searched to 15 June 2020. Eligible
studies were conducted in high-income countries and used multivariate analyses.
PARTICIPANTS: After piloting, screening, data extraction and quality appraisal
were performed by a single experienced reviewer. Of 3740 unique records
identified, 34 were included that reported on median 596 (range 44-418 794)
participants, aged 42-84 years. 19/34 (56%) were good quality.
OUTCOMES: Hospitalisation, intensive care unit admission, length of stay in
hospital or intensive care unit, mechanical ventilation, severe disease,
mortality.
RESULTS: Authors synthesised findings narratively and appraised the certainty of
the evidence for each risk factor-outcome association. There was low or moderate
certainty evidence for a large (≥2-fold) magnitude of association between
hospitalisation in people with COVID-19, and: obesity class III, heart failure,
diabetes, chronic kidney disease, dementia, age >45 years, male gender, black
race/ethnicity (vs non-Hispanic white), homelessness and low income. Age >60 and
>70 years may be associated with large increases in mechanical ventilation and
severe disease, respectively. For mortality, a large magnitude of association
may exist with liver disease, Bangladeshi ethnicity (vs British white), age >45
years, age >80 years (vs 65-69 years) and male gender among 20-64 years (but not
older). Associations with hospitalisation and mortality may be very large
(≥5-fold) for those aged ≥60 years.
CONCLUSIONS: Increasing age (especially >60 years) may be the most important
risk factor for severe outcomes. High-quality primary research accounting for
multiple confounders is needed to better understand the magnitude of
associations for severity of COVID-19 with several other factors.
PROSPERO REGISTRATION NUMBER: CRD42020198001.
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No
commercial re-use. See rights and permissions. Published by BMJ.
DOI: 10.1136/bmjopen-2020-044684
PMCID: PMC8126435
PMID: 33986052 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: All authors have completed
the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and
declare: grants from the National Advisory Committee for Immunisation during the
conduct of the study; no other relationships or activities that could appear to
have influenced the submitted work. LH is supported by a Canada Research Chair
in Knowledge Synthesis and Translation. |
http://www.ncbi.nlm.nih.gov/pubmed/34538426 | 1. Mayo Clin Proc. 2021 Oct;96(10):2528-2539. doi: 10.1016/j.mayocp.2021.06.023.
Epub 2021 Jul 5.
Factors Associated With Severe COVID-19 Infection Among Persons of Different
Ages Living in a Defined Midwestern US Population.
St Sauver JL(1), Lopes GS(2), Rocca WA(3), Prasad K(4), Majerus MR(5), Limper
AH(6), Jacobson DJ(7), Fan C(7), Jacobson RM(8), Rutten LJ(9), Norman AD(7),
Vachon CM(2).
Author information:
(1)Division of Epidemiology, Department of Quantitative Health Sciences, Mayo
Clinic, Rochester, MN; Robert D. and Patricia E. Kern Center for the Science of
Health Care Delivery, Mayo Clinic, Rochester, MN. Electronic address:
[email protected].
(2)Division of Epidemiology, Department of Quantitative Health Sciences, Mayo
Clinic, Rochester, MN.
(3)Division of Epidemiology, Department of Quantitative Health Sciences, Mayo
Clinic, Rochester, MN; Department of Neurology, Mayo Clinic, Rochester, MN.
(4)Zumbro Valley Health Center, Rochester, MN.
(5)Olmsted Medical Center, Rochester, MN.
(6)Robert D. and Patricia E. Kern Center for the Science of Health Care
Delivery, Mayo Clinic, Rochester, MN; Department of Pulmonary and Critical Care
Medicine, Mayo Clinic, Rochester, MN.
(7)Division of Clinical Trials and Biostatistics, Department of Quantitative
Health Sciences, Mayo Clinic, Rochester, MN.
(8)Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN.
(9)Robert D. and Patricia E. Kern Center for the Science of Health Care
Delivery, Mayo Clinic, Rochester, MN.
Dataset use reported in
Mayo Clin Proc. 2021 Oct;96(10):2508-2510. doi:
10.1016/j.mayocp.2021.08.016.
OBJECTIVE: To identify risk factors associated with severe COVID-19 infection in
a defined Midwestern US population overall and within different age groups.
PATIENTS AND METHODS: We used the Rochester Epidemiology Project research
infrastructure to identify persons residing in a defined 27-county Midwestern
region who had positive results on polymerase chain reaction tests for COVID-19
between March 1, 2020, and September 30, 2020 (N=9928). Age, sex, race,
ethnicity, body mass index, smoking status, and 44 chronic disease categories
were considered as possible risk factors for severe infection. Severe infection
was defined as hospitalization or death caused by COVID-19. Associations between
risk factors and severe infection were estimated using Cox proportional hazard
models overall and within 3 age groups (0 to 44, 45 to 64, and 65+ years).
RESULTS: Overall, 474 (4.8%) persons developed severe COVID-19 infection. Older
age, male sex, non-White race, Hispanic ethnicity, obesity, and a higher number
of chronic conditions were associated with increased risk of severe infection.
After adjustment, 36 chronic disease categories were significantly associated
with severe infection. The risk of severe infection varied significantly across
age groups. In particular, persons 0 to 44 years of age with cancer, chronic
neurologic disorders, hematologic disorders, ischemic heart disease, and other
endocrine disorders had a greater than 3-fold increased risk of severe infection
compared with persons of the same age without those conditions. Associations
were attenuated in older age groups.
CONCLUSION: Older persons are more likely to experience severe infections;
however, severe cases occur in younger persons as well. Our data provide insight
regarding younger persons at especially high risk of severe COVID-19 infection.
Copyright © 2021 Mayo Foundation for Medical Education and Research. Published
by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.mayocp.2021.06.023
PMCID: PMC8255113
PMID: 34538426 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33050972 | 1. Epidemiol Infect. 2020 Oct 14;148:e255. doi: 10.1017/S0950268820002502.
Predictive indicators of severe COVID-19 independent of comorbidities and
advanced age: a nested case-control study.
Li X(1), Marmar T(1), Xu Q(1), Tu J(1), Yin Y(1), Tao Q(1), Chen H(2), Shen
T(1), Xu D(2).
Author information:
(1)Department of Microbiology and Infectious Disease Center, School of Basic
Medical Sciences, Peking University, Beijing100191, China.
(2)Department and Institute of Infectious Disease, Tongji Hospital, Tongji
Medical College, Huazhong University of Science and Technology, Wuhan430030,
China.
To determine what exacerbate severity of the COVID-19 among patients without
comorbidities and advanced age and investigate potential clinical indicators for
early surveillance, we adopted a nested case-control study, design in which
severe cases (case group, n = 67) and moderate cases (control group, n = 67) of
patients diagnosed with COVID-19 without comorbidities, with ages ranging from
18 to 50 years who admitted to Wuhan Tongji Hospital were matched based on age,
sex and BMI. Demographic and clinical characteristics, and risk factors
associated with severe symptoms were analysed. Percutaneous oxygen saturation
(SpO2), lymphocyte counts, C-reactive protein (CRP) and IL-10 were found closely
associated with severe COVID-19. The adjusted multivariable logistic regression
analyses revealed that the independent risk factors associated with severe
COVID-19 were CRP (OR 2.037, 95% CI 1.078-3.847, P = 0.028), SpO2 (OR 1.639, 95%
CI 0.943-2.850, P = 0.080) and lymphocyte (OR 1.530, 95% CI 0.850-2.723, P =
0.148), whereas the changes exhibited by indicators influenced incidence of
disease severity. Males exhibited higher levels of indicators associated with
inflammation, myocardial injury and kidney injury than the females. This study
reveals that increased CRP levels and decreased SpO2 and lymphocyte counts could
serve as potential indicators of severe COVID-19, independent of comorbidities,
advanced age and sex. Males could at higher risk of developing severe symptoms
of COVID-19 than females.
DOI: 10.1017/S0950268820002502
PMCID: PMC7642916
PMID: 33050972 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interest exists. |
http://www.ncbi.nlm.nih.gov/pubmed/32607513 | 1. medRxiv [Preprint]. 2020 Jun 27:2020.06.25.20137323. doi:
10.1101/2020.06.25.20137323.
Factors Associated with Hospitalization and Disease Severity in a Racially and
Ethnically Diverse Population of COVID-19 Patients.
Mendy A, Apewokin S, Wells AA, Morrow AL.
BACKGROUND: The coronavirus disease (COVID-19) first identified in Wuhan in
December 2019 became a pandemic within a few months of its discovery. The impact
of COVID-19 is due to both its rapid spread and its severity, but the
determinants of severity have not been fully delineated.
OBJECTIVE: Identify factors associated with hospitalization and disease severity
in a racially and ethnically diverse cohort of COVID-19 patients.
METHODS: We analyzed data from COVID-19 patients diagnosed at the University of
Cincinnati health system from March 13, 2020 to May 31, 2020. Severe COVID-19
was defined as admission to intensive care unit or death. Logistic regression
modeling adjusted for covariates was used to identify the factors associated
with hospitalization and severe COVID-19.
RESULTS: Among the 689 COVID-19 patients included in our study, 29.2% were
non-Hispanic White, 25.5% were non-Hispanic Black, 32.5% were Hispanic, and
12.8% were of other race/ethnicity. About 31.3% of patients were hospitalized
and 13.2% had severe disease. In adjusted analyses, the sociodemographic factors
associated with hospitalization and/or disease severity included older age,
non-Hispanic Black or Hispanic race/ethnicity (compared to non-Hispanic White),
and smoking. The following comorbidities: diabetes, hypercholesterolemia,
asthma, COPD, chronic kidney disease, cardiovascular diseases, osteoarthritis,
and vitamin D deficiency were associated with hospitalization and/or disease
severity. Hematological disorders such as anemia, coagulation disorders, and
thrombocytopenia were associated with both hospitalization and disease severity.
CONCLUSION: This study confirms race and ethnicity as predictors of severe
COVID-19. It also finds clinical risk factors for hospitalization and severe
COVID-19 not previously identified such a vitamin D deficiency,
hypercholesterolemia, osteoarthritis, and anemia.
DOI: 10.1101/2020.06.25.20137323
PMCID: PMC7325178
PMID: 32607513 |
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