pubmed_id
stringlengths 41
43
| abstract
stringlengths 3
18.8k
|
|---|---|
http://www.ncbi.nlm.nih.gov/pubmed/16280008 | 1. Pigment Cell Res. 2005 Dec;18(6):427-38. doi:
10.1111/j.1600-0749.2005.00275.x.
Pax3 target gene recognition occurs through distinct modes that are
differentially affected by disease-associated mutations.
Corry GN(1), Underhill DA.
Author information:
(1)Department of Medical Genetics, University of Alberta, Edmonton, Alberta,
Canada.
The paired box protein Pax3 is an essential regulator of muscle and neural
crest-derived cell types, including melanocytes. Within this lineage, Pax3 has
been shown to regulate the genes encoding microphthalmia-associated
transcription factor (Mitf) and tyrosinase-related protein-1 (Trp-1), despite
each having dissimilar Pax3 recognition sequences. We have, therefore, examined
the structural requirements for Pax3 binding to the MITF and TRP-1 promoter
elements, focusing on the contribution of the paired domain and homeodomain to
Pax3 target site recognition. Unexpectedly, although the MITF element is
characterized by suboptimal recognition motifs for the paired domain and
homeodomain, it sustains a higher level of Pax3 binding than TRP-1, which
contains a canonical paired domain site. The basis for this difference involves
a context-dependent cooperative binding event requiring both the paired domain
and homeodomain, while the paired domain alone is sufficient for TRP-1
recognition. Significantly, the analysis of Waardenburg syndrome mutations
reveals marked disparity in their effects on MITF and TRP-1 binding that further
underscores mechanistic differences in their interaction with Pax3. Importantly,
these mutations also exert distinct effects on the ability of Pax3 to regulate
reporter genes fused to either the MITF or TRP-1 promoters. Our results,
therefore, establish that Pax3 can regulate target genes through alternate modes
of DNA recognition that are differentially impacted by disease-causing
mutations, which together have important implications for understanding
Pax3-regulated gene networks.
DOI: 10.1111/j.1600-0749.2005.00275.x
PMID: 16280008 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18628967 | 1. PLoS One. 2008 Jul 16;3(7):e2734. doi: 10.1371/journal.pone.0002734.
Oncogenic BRAF regulates melanoma proliferation through the lineage specific
factor MITF.
Wellbrock C(1), Rana S, Paterson H, Pickersgill H, Brummelkamp T, Marais R.
Author information:
(1)Signal Transduction Team, The Institute of Cancer Research, Cancer Research
UK Centre of Cell and Molecular Biology, London, United Kingdom.
The Microphthalmia-associated transcription factor (MITF) is an important
regulator of cell-type specific functions in melanocytic cells. MITF is
essential for the survival of pigmented cells, but whereas high levels of MITF
drive melanocyte differentiation, lower levels are required to permit
proliferation and survival of melanoma cells. MITF is phosphorylated by ERK, and
this stimulates its activation, but also targets it for degradation through the
ubiquitin-proteosome pathway, coupling MITF degradation to its activation. We
have previously shown that because ERK is hyper-activated in melanoma cells in
which BRAF is mutated, the MITF protein is constitutively down-regulated. Here
we describe another intriguing aspect of MITF regulation by oncogenic BRAF in
melanoma cells. We show oncogenic BRAF up-regulates MITF transcription through
ERK and the transcription factor BRN2 (N-Oct3). In contrast, we show that in
melanocytes this pathway does not exist because BRN2 is not expressed,
demonstrating that MITF regulation is a newly acquired function of oncogenic
BRAF that is not performed by the wild-type protein. Critically, in melanoma
cells MITF is required downstream of oncogenic BRAF because it regulates
expression of key cell cycle regulatory proteins such as CDK2 and CDK4.
Wild-type BRAF does not regulate this pathway in melanocytes. Thus, we show that
oncogenic BRAF exerts exquisite control over MITF on two levels. It
downregulates the protein by stimulating its degradation, but then counteracts
this by increasing transcription through BRN2. Our data suggest that oncogenic
BRAF plays a critical role in regulating MITF expression to ensure that its
protein levels are compatible with proliferation and survival of melanoma cells.
We propose that its ability to appropriate the regulation of this critical
factor explains in part why BRAF is such a potent oncogene in melanoma.
DOI: 10.1371/journal.pone.0002734
PMCID: PMC2444043
PMID: 18628967 [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/25818589 | 1. Pigment Cell Melanoma Res. 2015 Jul;28(4):390-406. doi: 10.1111/pcmr.12370.
Epub 2015 Apr 17.
Microphthalmia-associated transcription factor in melanoma development and
MAP-kinase pathway targeted therapy.
Wellbrock C(1), Arozarena I(1).
Author information:
(1)Manchester Cancer Research Centre, Wellcome Trust Centre for Cell Matrix
Research, Faculty of Life Sciences, The University of Manchester, Manchester,
UK.
Malignant melanoma is a neoplasm of melanocytes, and the
microphthalmia-associated transcription factor (MITF) is essential for the
existence of melanocytes. MITF's relevance for this cell lineage is maintained
in melanoma, where it is an important regulator of survival and balances
melanoma cell proliferation with terminal differentiation (pigmentation). The
MITF gene is amplified in ~20% of melanomas and MITF mutation can predispose to
melanoma development. Furthermore, the regulation of MITF expression and
function is strongly linked to the BRAF/MEK/ERK/MAP-kinase (MAPK) pathway, which
is deregulated in >90% of melanomas and central target of current therapies.
MITF expression in melanoma is heterogeneous, and recent findings highlight the
relevance of this heterogeneity for the response of melanoma to MAPK pathway
targeting drugs, as well as for MITF's role in melanoma progression. This review
aims to provide an updated overview on the regulation of MITF function and
plasticity in melanoma with a focus on its link to MAPK signaling.
© 2015 The Authors. Pigment Cell & Melanoma Research Published by John Wiley &
Sons Ltd.
DOI: 10.1111/pcmr.12370
PMCID: PMC4692100
PMID: 25818589 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14660543 | 1. Development. 2003 Dec;130(26):6545-53. doi: 10.1242/dev.00872.
Mitf expression is sufficient to direct differentiation of medaka blastula
derived stem cells to melanocytes.
Béjar J(1), Hong Y, Schartl M.
Author information:
(1)Physiological Chemistry I, Biocenter of the University Würzburg, D-97074
Würzburg, Germany.
Embryonic stem (ES) cell lines have provided very useful models to analyse
differentiation processes. We present here the development of a differentiation
system using ES-like cell lines from medaka. These cells were transfected with
the melanocyte specific isoform of the microphtalmia-related transcription
factor (Mitf). Mitf is a basic helix-loop-helix-leucine zipper transcription
factor whose M isoform is restricted to neural crest derived melanocytes and is
essential for the development of these cells in vertebrates from mammals to
fish. What is not clear yet is whether Mitf is a downstream factor or a master
regulator of melanocyte commitment and differentiation. Expression of Mitf in
the ES-like cells from medaka led to the induction of cells that, by morphology,
physiology and gene expression pattern, were confirmed to be fully
differentiated pigment cells. Mitf expression is therefore sufficient for the
proper differentiation of medaka pluripotent stem cells into melanocytes.
DOI: 10.1242/dev.00872
PMID: 14660543 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36040798 | 1. JCI Insight. 2022 Oct 10;7(19):e156577. doi: 10.1172/jci.insight.156577.
DNA promoter hypermethylation of melanocyte lineage genes determines melanoma
phenotype.
Sanna A(1), Phung B(1), Mitra S(1), Lauss M(1), Choi J(2), Zhang T(2), Njauw
CN(3), Cordero E(4), Harbst K(1), Rosengren F(1), Cabrita R(1), Johansson I(5),
Isaksson K(6)(7), Ingvar C(6), Carneiro A(1)(8), Brown K(2), Tsao H(3),
Andersson M(9), Pietras K(4), Jönsson G(1).
Author information:
(1)Division of Oncology, Department of Clinical Sciences, Lund University, Lund,
Sweden.
(2)Laboratory of Translational Genomics, Division of Cancer Epidemiology and
Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA.
(3)Department of Dermatology, Harvard Medical School, Boston, Massachusetts,
USA.
(4)Division of Translational Cancer Research, Department of Laboratory Medicine.
(5)Department of Clinical Pathology, Skåne University Hospital; and.
(6)Division of Surgery, Department of Clinical Sciences, Lund University, Lund,
Sweden.
(7)Department of Surgery, Kristianstad Hospital, Kristianstad, Sweden.
(8)Department of Oncology, Skåne University Hospital, and.
(9)Department of Neurology, Epilepsy Center, Lund University, Lund, Sweden.
Cellular stress contributes to the capacity of melanoma cells to undergo
phenotype switching into highly migratory and drug-tolerant dedifferentiated
states. Such dedifferentiated melanoma cell states are marked by loss of
melanocyte-specific gene expression and increase of mesenchymal markers. Two
crucial transcription factors, microphthalmia-associated transcription factor
(MITF) and SRY-box transcription factor 10 (SOX10), important in melanoma
development and progression, have been implicated in this process. In this study
we describe that loss of MITF is associated with a distinct transcriptional
program, MITF promoter hypermethylation, and poor patient survival in metastatic
melanoma. From a comprehensive collection of melanoma cell lines, we observed
that MITF-methylated cultures were subdivided in 2 distinct subtypes. Examining
mRNA levels of neural crest-associated genes, we found that 1 subtype had lost
the expression of several lineage genes, including SOX10. Intriguingly, SOX10
loss was associated with SOX10 gene promoter hypermethylation and distinct
phenotypic and metastatic properties. Depletion of SOX10 in MITF-methylated
melanoma cells using CRISPR/Cas9 supported these findings. In conclusion, this
study describes the significance of melanoma state and the underlying functional
properties explaining the aggressiveness of such states.
DOI: 10.1172/jci.insight.156577
PMCID: PMC9675437
PMID: 36040798 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12235125 | 1. J Cell Biol. 2002 Sep 16;158(6):1079-87. doi: 10.1083/jcb.200202049. Epub 2002
Sep 16.
Beta-catenin-induced melanoma growth requires the downstream target
Microphthalmia-associated transcription factor.
Widlund HR(1), Horstmann MA, Price ER, Cui J, Lessnick SL, Wu M, He X, Fisher
DE.
Author information:
(1)Department of Pediatric Oncology, Dana-Farber Cancer Institute, Dana 630, 44
Binney Street, Boston, MA 02115, USA.
The transcription factor Microphthalmia-associated transcription factor (MITF)
is a lineage-determination factor, which modulates melanocyte differentiation
and pigmentation. MITF was recently shown to reside downstream of the canonical
Wnt pathway during melanocyte differentiation from pluripotent neural crest
cells in zebrafish as well as in mammalian melanocyte lineage cells. Although
expression of many melanocytic/pigmentation markers is lost in human melanoma,
MITF expression remains intact, even in unpigmented tumors, suggesting a role
for MITF beyond its role in differentiation. A significant fraction of primary
human melanomas exhibit deregulation (via aberrant nuclear accumulation) of
beta-catenin, leading us to examine its role in melanoma growth and survival.
Here, we show that beta-catenin is a potent mediator of growth for melanoma
cells in a manner dependent on its downstream target MITF. Moreover, suppression
of melanoma clonogenic growth by disruption of beta-catenin-T-cell transcription
factor/LEF is rescued by constitutive MITF. This rescue occurs largely through a
prosurvival mechanism. Thus, beta-catenin regulation of MITF expression
represents a tissue-restricted pathway that significantly influences the growth
and survival behavior of this notoriously treatment-resistant neoplasm.
DOI: 10.1083/jcb.200202049
PMCID: PMC2173224
PMID: 12235125 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21326905 | 1. Transcription. 2011 Jan-Feb;2(1):19-22. doi: 10.4161/trns.2.1.13650.
Dual roles of lineage restricted transcription factors: the case of MITF in
melanocytes.
Levy C(1), Fisher DE.
Author information:
(1)Cutaneous Biology Research Center, Department of Dermatology, Massachusetts
General Hospital, Harvard Medical School, Boston, USA.
Microphthalmia-associated Transcription Factor, MITF, is a master regulator of
melanocyte development, differentiation, migration, and survival.(1) A broad
collection of studies have indicated that MITF directly regulates the
transcription of genes involved in pigmentation, which are selective to the
melanocyte lineage. In addition, MITF controls expression of genes which are
expressed in multiple cell lineages, and may also play differential roles in
activating vs. maintaining gene expression patterns. In this Point of View
article, we discuss lineage restricted transcription factor activation of both
tissue-specific and ubiquitously expressed genes using melanocytes and MITF as a
model system that may eventually provide insights into such processes in
multiple cell lineages.
DOI: 10.4161/trns.2.1.13650
PMCID: PMC3023642
PMID: 21326905 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18983540 | 1. Pigment Cell Melanoma Res. 2008 Dec;21(6):627-45. doi:
10.1111/j.1755-148X.2008.00514.x.
Pigmentation PAX-ways: the role of Pax3 in melanogenesis, melanocyte stem cell
maintenance, and disease.
Kubic JD(1), Young KP, Plummer RS, Ludvik AE, Lang D.
Author information:
(1)Section of Dermatology, Department of Medicine, University of Chicago,
Chicago, IL, USA.
Transcription factors initiate programs of gene expression and are catalysts in
downstream molecular cascades that modulate a variety of cellular processes.
Pax3 is a transcription factor that is important in the melanocyte and
influences melanocytic proliferation, resistance to apoptosis, migration,
lineage specificity and differentiation. In this review, we focus on Pax3 and
the molecular pathways that Pax3 is a part of during melanogenesis and in the
melanocyte stem cell. These roles of Pax3 are emphasized during the development
of diseases and syndromes resulting from either too much or too little Pax3
function. Due to its key task in melanocyte stem cells and tumors, the Pax3
pathway may provide an ideal target for either stem cell or cancer therapies.
DOI: 10.1111/j.1755-148X.2008.00514.x
PMCID: PMC2979299
PMID: 18983540 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23913827 | 1. Cancer Res. 2013 Sep 15;73(18):5709-18. doi: 10.1158/0008-5472.CAN-12-4620.
Epub 2013 Aug 1.
SOX10 ablation arrests cell cycle, induces senescence, and suppresses
melanomagenesis.
Cronin JC(1), Watkins-Chow DE, Incao A, Hasskamp JH, Schönewolf N, Aoude LG,
Hayward NK, Bastian BC, Dummer R, Loftus SK, Pavan WJ.
Author information:
(1)Authors' Affiliations: Genetic Disease Research Branch, National Human Genome
Research Institute, Bethesda, Maryland; Maryland Melanoma Center at Medstar
Franklin Square Medical Center, Baltimore, Maryland; Department of Dermatology,
University Hospital of Zurich, Zurich, Switzerland; Queensland Institute of
Medical Research, Oncogenomics Laboratory, Brisbane, Australia; and Helen Diller
Family Comprehensive Cancer Center, UCSF, San Francisco, CA.
The transcription factor SOX10 is essential for survival and proper
differentiation of neural crest cell lineages, where it plays an important role
in the generation and maintenance of melanocytes. SOX10 is also highly expressed
in melanoma tumors, but a role in disease progression has not been established.
Here, we report that melanoma tumor cell lines require wild-type SOX10
expression for proliferation and SOX10 haploinsufficiency reduces melanoma
initiation in the metabotropic glutamate receptor 1 (Grm1(Tg)) transgenic mouse
model. Stable SOX10 knockdown in human melanoma cells arrested cell growth,
altered cellular morphology, and induced senescence. Melanoma cells with stable
loss of SOX10 were arrested in the G1 phase of the cell cycle, with reduced
expression of the melanocyte determining factor microphthalmia-associated
transcription factor, elevated expression of p21WAF1 and p27KIP2,
hypophosphorylated RB, and reduced levels of its binding partner E2F1. As
cell-cycle dysregulation is a core event in neoplastic transformation, the role
for SOX10 in maintaining cell-cycle control in melanocytes suggests a rational
new direction for targeted treatment or prevention of melanoma.
©2013 AACR.
DOI: 10.1158/0008-5472.CAN-12-4620
PMCID: PMC3803156
PMID: 23913827 [Indexed for MEDLINE]
Conflict of interest statement: “The authors disclose no potential conflicts of
interest” |
http://www.ncbi.nlm.nih.gov/pubmed/22290434 | 1. Mol Cell Biol. 2012 Apr;32(7):1237-47. doi: 10.1128/MCB.06257-11. Epub 2012
Jan 30.
Phosphorylation of BRN2 modulates its interaction with the Pax3 promoter to
control melanocyte migration and proliferation.
Berlin I(1), Denat L, Steunou AL, Puig I, Champeval D, Colombo S, Roberts K,
Bonvin E, Bourgeois Y, Davidson I, Delmas V, Nieto L, Goding CR, Larue L.
Author information:
(1)Institut Curie, Developmental Genetics of Melanocytes, Orsay, France.
MITF-M and PAX3 are proteins central to the establishment and transformation of
the melanocyte lineage. They control various cellular mechanisms, including
migration and proliferation. BRN2 is a POU domain transcription factor expressed
in melanoma cell lines and is involved in proliferation and invasion, at least
in part by regulating the expression of MITF-M and PAX3. The T361 and S362
residues of BRN2, both in the POU domain, are conserved throughout the POU
protein family and are targets for phosphorylation, but their roles in vivo
remain unknown. To examine the role of this phosphorylation, we generated mutant
BRN2 in which these two residues were replaced with alanines (BRN2TS→BRN2AA).
When expressed in melanocytes in vitro or in the melanocyte lineage in
transgenic mice, BRN2TS induced proliferation and repressed migration, whereas
BRN2AA repressed both proliferation and migration. BRN2TS and BRN2AA bound and
repressed the MITF-M promoter, whereas PAX3 transcription was induced by BRN2TS
but repressed by BRN2AA. Expression of the BRN2AA transgene in a Mitf
heterozygous background and in a Pax3 mutant background enhanced the coat color
phenotype. Our findings show that melanocyte migration and proliferation are
controlled both through the regulation of PAX3 by nonphosphorylated BRN2 and
through the regulation of MITF-M by the overall BRN2 level.
DOI: 10.1128/MCB.06257-11
PMCID: PMC3302439
PMID: 22290434 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32796736 | 1. Cancers (Basel). 2020 Aug 11;12(8):2248. doi: 10.3390/cancers12082248.
Intrinsic Balance between ZEB Family Members Is Important for Melanocyte
Homeostasis and Melanoma Progression.
Bruneel K(1)(2), Verstappe J(1)(2), Vandamme N(1)(2)(3), Berx G(1)(2).
Author information:
(1)Molecular and Cellular Oncology Laboratory, Department of Biomedical
Molecular Biology, Ghent University, Technologiepark-Zwijnaarde 71, 9052 Ghent,
Belgium.
(2)Cancer Research Institute Ghent (CRIG), Ghent University, 9000 Ghent,
Belgium.
(3)VIB-UGent Center for Inflammation Research, Ghent University,
Technologiepark-Zwijnaarde 71, 9052 Ghent, Belgium.
It has become clear that cellular plasticity is a main driver of cancer therapy
resistance. Consequently, there is a need to mechanistically identify the
factors driving this process. The transcription factors of the zinc-finger
E-box-binding homeobox family, consisting of ZEB1 and ZEB2, are notorious for
their roles in epithelial-to-mesenchymal transition (EMT). However, in melanoma,
an intrinsic balance between ZEB1 and ZEB2 seems to determine the cellular state
by modulating the expression of the master regulator of melanocyte homeostasis,
microphthalmia-associated transcription factor (MITF). ZEB2 drives MITF
expression and is associated with a differentiated/proliferative melanoma cell
state. On the other hand, ZEB1 is correlated with low MITF expression and a more
invasive, stem cell-like and therapy-resistant cell state. This intrinsic
balance between ZEB1 and ZEB2 could prove to be a promising therapeutic target
for melanoma patients. In this review, we will summarise what is known on the
functional mechanisms of these transcription factors. Moreover, we will look
specifically at their roles during melanocyte-lineage development and
homeostasis. Finally, we will overview the current literature on ZEB1 and ZEB2
in the melanoma context and link this to the 'phenotype-switching' model of
melanoma cellular plasticity.
DOI: 10.3390/cancers12082248
PMCID: PMC7465899
PMID: 32796736
Conflict of interest statement: The authors declare no conflict of interest. The
funders had no role in study design; data collection, analyses, interpretation;
manuscript writing, or the decision to publish the results. |
http://www.ncbi.nlm.nih.gov/pubmed/35021087 | 1. Cell Rep. 2022 Jan 11;38(2):110234. doi: 10.1016/j.celrep.2021.110234.
Tfap2b specifies an embryonic melanocyte stem cell that retains adult multifate
potential.
Brombin A(1), Simpson DJ(2), Travnickova J(1), Brunsdon H(1), Zeng Z(1), Lu
Y(1), Young AIJ(1), Chandra T(3), Patton EE(4).
Author information:
(1)MRC Human Genetics Unit, Institute of Genetics and Cancer, University of
Edinburgh, Edinburgh EH4 2XU, UK; CRUK Edinburgh Centre, Institute of Genetics
and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK.
(2)MRC Human Genetics Unit, Institute of Genetics and Cancer, University of
Edinburgh, Edinburgh EH4 2XU, UK.
(3)MRC Human Genetics Unit, Institute of Genetics and Cancer, University of
Edinburgh, Edinburgh EH4 2XU, UK. Electronic address: [email protected].
(4)MRC Human Genetics Unit, Institute of Genetics and Cancer, University of
Edinburgh, Edinburgh EH4 2XU, UK; CRUK Edinburgh Centre, Institute of Genetics
and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK. Electronic address:
[email protected].
Melanocytes, the pigment-producing cells, are replenished from multiple stem
cell niches in adult tissue. Although pigmentation traits are known risk factors
for melanoma, we know little about melanocyte stem cell (McSC) populations other
than hair follicle McSCs and lack key lineage markers with which to identify
McSCs and study their function. Here we find that Tfap2b and a select set of
target genes specify an McSC population at the dorsal root ganglia in zebrafish.
Functionally, Tfap2b is required for only a few late-stage embryonic
melanocytes, and is essential for McSC-dependent melanocyte regeneration. Fate
mapping data reveal that tfap2b+ McSCs have multifate potential, and are the
cells of origin for large patches of adult melanocytes, two other pigment cell
types (iridophores and xanthophores), and nerve-associated cells. Hence, Tfap2b
confers McSC identity in early development, distinguishing McSCs from other
neural crest and pigment cell lineages, and retains multifate potential in the
adult zebrafish.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.celrep.2021.110234
PMCID: PMC8764619
PMID: 35021087 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests The authors declare no
competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/21997191 | 1. Cell Death Differ. 2012 Apr;19(4):616-22. doi: 10.1038/cdd.2011.132. Epub 2011
Oct 14.
FGF2 regulates melanocytes viability through the STAT3-transactivated PAX3
transcription.
Dong L(1), Li Y, Cao J, Liu F, Pier E, Chen J, Xu Z, Chen C, Wang RA, Cui R.
Author information:
(1)Department of Dermatology, Boston University School of Medicine, 609 Albany
Street, Boston, MA 02118, USA.
PAX3 (paired box 3) is known to have an important role in melanocyte development
through modulation of microphthalmia-associated transcription factor
transcription. Here we found that PAX3 transcriptional activity could be
regulated through FGF2 (basic fibroblast growth factor)-STAT3 (signal transducer
and activator of transcription 3) signaling in the pigment cells. To study its
function in vivo, we have generated a transgenic mouse model expressing PAX3
driven by tyrosinase promoter in a tissue-specific fashion. These animals
exhibit hyperpigmentation in the epidermis, evident in the skin color of their
ears and tails. We showed that the darker skin color results from both increased
melanocyte numbers and melanin synthesis. Together, our study delineated a novel
pathway in the melanocyte lineage, linking FGF2-STAT3 signaling to increased
PAX3 transcription. Moreover, our results suggest that this pathway might
contribute to the regulation of melanocyte numbers and melanin levels, and
thereby provide an alternative strategy to induce pigmentation.
DOI: 10.1038/cdd.2011.132
PMCID: PMC3307977
PMID: 21997191 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19464596 | 1. Hematol Oncol Clin North Am. 2009 Jun;23(3):447-65, viii. doi:
10.1016/j.hoc.2009.03.003.
Transcriptional regulation in melanoma.
Mitra D(1), Fisher DE.
Author information:
(1)Biology and Biomedical Sciences Program, Cutaneous Biology Research Center,
Massachusetts General Hospital, Harvard Medical School, Building 149, 13th
Street, Charlestown, MA 02129, USA.
Transcriptional regulation in melanoma is a complex process that tends to hijack
the normal melanocyte signaling pathways involved in melanocyte development,
pigmentation, and survival. At the center of these often overlapping networks of
transcriptional activation and repression is microphthalmia-associated
transcription factor (MITF), a melanocyte lineage marker that increases pigment
production and exhibits diverse effects on cell survival, proliferation, and
cell cycle arrest. The particular conditions that allow MITF to produce these
potentially contradictory roles have not yet been fully elucidated, but analysis
of the pathways involved provides opportunities to learn about new therapeutic
strategies.
DOI: 10.1016/j.hoc.2009.03.003
PMID: 19464596 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23874858 | 1. PLoS One. 2013 Jul 16;8(7):e69037. doi: 10.1371/journal.pone.0069037. Print
2013.
SWI/SNF enzymes promote SOX10- mediated activation of myelin gene expression.
Marathe HG(1), Mehta G, Zhang X, Datar I, Mehrotra A, Yeung KC, de la Serna IL.
Author information:
(1)Department of Biochemistry and Cancer Biology, University of Toledo College
of Medicine and Life Sciences, Toledo, Ohio, United States of America.
SOX10 is a Sry-related high mobility (HMG)-box transcriptional regulator that
promotes differentiation of neural crest precursors into Schwann cells,
oligodendrocytes, and melanocytes. Myelin, formed by Schwann cells in the
peripheral nervous system, is essential for propagation of nerve impulses.
SWI/SNF complexes are ATP dependent chromatin remodeling enzymes that are
critical for cellular differentiation. It was recently demonstrated that the
BRG1 subunit of SWI/SNF complexes activates SOX10 expression and also interacts
with SOX10 to activate expression of OCT6 and KROX20, two transcriptional
regulators of Schwann cell differentiation. To determine the requirement for
SWI/SNF enzymes in the regulation of genes that encode components of myelin,
which are downstream of these transcriptional regulators, we introduced SOX10
into fibroblasts that inducibly express dominant negative versions of the
SWI/SNF ATPases, BRM or BRG1. Dominant negative BRM and BRG1 have mutations in
the ATP binding site and inhibit gene activation events that require SWI/SNF
function. Ectopic expression of SOX10 in cells derived from NIH 3T3 fibroblasts
led to the activation of the endogenous Schwann cell specific gene, myelin
protein zero (MPZ) and the gene that encodes myelin basic protein (MBP). Thus,
SOX10 reprogrammed these cells into myelin gene expressing cells. Ectopic
expression of KROX20 was not sufficient for activation of these myelin genes.
However, KROX20 together with SOX10 synergistically activated MPZ and MBP
expression. Dominant negative BRM and BRG1 abrogated SOX10 mediated activation
of MPZ and MBP and synergistic activation of these genes by SOX10 and KROX20.
SOX10 was required to recruit BRG1 to the MPZ locus. Similarly, in immortalized
Schwann cells, BRG1 recruitment to SOX10 binding sites at the MPZ locus was
dependent on SOX10 and expression of dominant negative BRG1 inhibited expression
of MPZ and MBP in these cells. Thus, SWI/SNF enzymes cooperate with SOX10 to
directly activate genes that encode components of peripheral myelin.
DOI: 10.1371/journal.pone.0069037
PMCID: PMC3712992
PMID: 23874858 [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/11231058 | 1. Mech Dev. 2001 Mar;101(1-2):47-59. doi: 10.1016/s0925-4773(00)00569-4.
Transcription factors in melanocyte development: distinct roles for Pax-3 and
Mitf.
Hornyak TJ(1), Hayes DJ, Chiu LY, Ziff EB.
Author information:
(1)The Ronald O. Perelman Department of Dermatology, New York University Medical
Center, NY 10016, New York, USA. [email protected]
A transgenic mouse model was used to examine the roles of the murine
transcription factors Pax-3 and Mitf in melanocyte development. Transgenic mice
expressing beta-galactosidase from the dopachrome tautomerase (Dct) promoter
were generated and found to express the transgene in developing melanoblasts as
early as embryonic day (E) 9.5. These mice express the transgene in a pattern
characteristic of endogenous Dct expression. Transgenic mice were intercrossed
with two murine coat color mutants, Splotch (Sp), containing a mutation in the
murine Pax3 gene, and Mitf(mi), with a mutation in the
basic-helix-loop-helix-leucine zipper gene Mitf. Transgenic heterozygous mutant
animals were crossed to generate transgenic embryos for analysis. Examination of
beta-galactosidase-expressing melanoblasts in mutant embryos reveals that Mitf
is required in vivo for survival of melanoblasts up to the migration staging
area in neural crest development. Examination of Mitf(mi)/+ embryos shows that
there are diminished numbers of melanoblasts in the heterozygous state early in
melanocyte development, consistent with a gene dosage-dependent effect upon cell
survival. However, quantification and analysis of melanoblast growth during the
migratory phase suggests that melanoblasts then increase in number more rapidly
in the heterozygous embryo. In contrast to Mitf(mi)/Mitf(mi) embryos, Sp/Sp
embryos exhibit melanoblasts that have migrated to characteristic locations
along the melanoblast migratory pathway, but are greatly reduced in number
compared to control littermates. Together, these results support a model for
melanocyte development whereby Pax3 is required to expand a pool of committed
melanoblasts or restricted progenitor cells early in development, whereas Mitf
facilitates survival of the melanoblast in a gene dosage-dependent manner within
and immediately after emigration from the dorsal neural tube, and may also
directly or indirectly affect the rate at which melanoblast number increases
during dorsolateral pathway migration.
DOI: 10.1016/s0925-4773(00)00569-4
PMID: 11231058 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15760336 | 1. Pigment Cell Res. 2005 Apr;18(2):74-85. doi: 10.1111/j.1600-0749.2005.00218.x.
Secrets to a healthy Sox life: lessons for melanocytes.
Wegner M(1).
Author information:
(1)Institut für Biochemie, Universität Erlangen-Nürnberg, D-91054 Erlangen,
Germany. [email protected]
Comment in
Pigment Cell Res. 2005 Apr;18(2):63. doi: 10.1111/j.1600-0749.2005.00224.x.
Sox proteins are transcriptional regulators with a high-mobility-group domain as
sequence-specific DNA-binding domain. For function, they generally require other
transcription factors as partner proteins. Sox proteins furthermore affect DNA
topology and may shape the conformation of enhancer-bound multiprotein complexes
as architectural proteins. Recent studies suggest that Sox proteins are tightly
regulated in their expression by many signalling pathways, and that their
transcriptional activity is subject to post-translational modification and
sequestration mechanisms. Sox proteins are thus ideally suited to perform their
many different functions as transcriptional regulators throughout mammalian
development. Their unique properties also cause Sox proteins to escape detection
in many standard transcription assays. In melanocytes, studies have so far
focused on the Sox10 protein which functions both during melanocyte
specification and at later times in the melanocyte lineage. During
specification, Sox10 activates the Mitf gene as the key regulator of melanocyte
development. At later stages, it ensures cell-type specific expression of
melanocyte genes such as Dopachrome tautomerase. Both activities require
cooperation with transcriptional partner proteins such as Pax-3, CREB and
eventually Mitf. If predictions can be made from other cell lineages, further
functions of Sox proteins in melanocytes may still lie ahead.
DOI: 10.1111/j.1600-0749.2005.00218.x
PMID: 15760336 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30871534 | 1. BMC Med Genomics. 2019 Mar 13;12(Suppl 2):43. doi: 10.1186/s12920-019-0488-5.
Genotype-phenotype correlations in FSHD.
Zernov N(1), Skoblov M(2)(3).
Author information:
(1)Research Center for Medical Genetics, Moscow, Russia. [email protected].
(2)Research Center for Medical Genetics, Moscow, Russia.
(3)School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia.
BACKGROUND: Facial-scapular-humeral myodystrophy Landouzy-Dejerine (FSHD) is an
autosomal dominant disease, the basis of its pathogenesis is ectopic expression
of the transcription factor DUX4 in skeletal muscle. There are two types of the
disease: FSHD1 (MIM:158900) and FSHD2 (MIM: 158901), which have different
genetic causes but are phenotypically indistinguishable. In FSHD1, partial
deletion of the D4Z4 repeats on the 4th chromosome affects the expression of
DUX4, whereas FSHD2 is caused by the mutations in the protein regulating the
methylation status of chromatin - SMCHD1. High variability of clinical picture,
both intra - and inter-family indicates a large number of factors influencing
clinical picture. There are key genetic, epigenetic and gender factors that
influence the expressivity and penetrance of the disease. Using only one of
these factors allows just a rough prediction of the course of the disease, which
indicates the combined effect of all of the factors on the DUX4 expression and
on the clinical picture.
RESULTS: In this paper, we analyzed the impact of genetic, epigenetic and gender
differences on phenotype and the possibility of using them for disease prognosis
and family counselling.
CONCLUSIONS: Key pathogenesis factors have been identified for FSHD. However,
the pronounced intra - and inter-family polymorphism of manifestations indicates
a large number of modifiers of the pathological process, many of which remain
unknown.
DOI: 10.1186/s12920-019-0488-5
PMCID: PMC6416831
PMID: 30871534 [Indexed for MEDLINE]
Conflict of interest statement: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: Not
applicable. CONSENT FOR PUBLICATION: 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/34711481 | 1. Neuromuscul Disord. 2021 Nov;31(11):1101-1112. doi: 10.1016/j.nmd.2021.09.010.
Epub 2021 Oct 2.
Facioscapulohumeral muscular dystrophy type 2: an update on the clinical,
genetic, and molecular findings.
Jia FF(1), Drew AP(2), Nicholson GA(3), Corbett A(4), Kumar KR(5).
Author information:
(1)Department of Neurology, Concord Repatriation General Hospital, Concord, New
South Wales 2139, Australia.
(2)Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research,
Darlinghurst, New South Wales 2010, Australia.
(3)Department of Neurology, Concord Repatriation General Hospital, Concord, New
South Wales 2139, Australia; Molecular Medicine Laboratory, Concord Repatriation
General Hospital, Concord, New South Wales 2139, Australia; Northcott
Neuroscience Laboratory, ANZAC Research Institute, Concord, New South Wales
2139, Australia; Sydney Medical School, University of Sydney, Camperdown, New
South Wales 2050, Australia.
(4)Department of Neurology, Concord Repatriation General Hospital, Concord, New
South Wales 2139, Australia; Sydney Medical School, University of Sydney,
Camperdown, New South Wales 2050, Australia.
(5)Department of Neurology, Concord Repatriation General Hospital, Concord, New
South Wales 2139, Australia; Kinghorn Centre for Clinical Genomics, Garvan
Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia;
Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord,
New South Wales 2139, Australia; Sydney Medical School, University of Sydney,
Camperdown, New South Wales 2050, Australia. Electronic address:
[email protected].
Facioscapulohumeral muscular dystrophy (FSHD) is a common genetic disease of the
skeletal muscle with a characteristic pattern of weakness. Facioscapulohumeral
muscular dystrophy type 2 (FSHD2) accounts for approximately 5% of all cases of
FSHD and describes patients without a D4Z4 repeat contraction on chromosome 4.
Phenotypically FSHD2 shows virtually no difference from FSHD1 and both forms of
FSHD arise via a common downstream mechanism of epigenetic derepression of the
transcription factor DUX4 in skeletal muscle cells. This results in expression
of DUX4 and target genes leading to skeletal muscle toxicity. Over the past
decade, major progress has been made in our understanding of the genetic and
epigenetic architecture that underlies FSHD2 pathogenesis, as well as the
clinical manifestations and disease progression. These include the finding that
FSHD2 is a digenic disease and that mutations in the genes SMCHD1, DNMT3B, and
more recently LRIF1, can cause FSHD2. FSHD2 is complex and it is important that
clinicians keep abreast of recent developments; this review aims to serve as an
update of the clinical, genetic, and molecular research into this condition.
Copyright © 2021 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.nmd.2021.09.010
PMID: 34711481 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of Competing Interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper. |
http://www.ncbi.nlm.nih.gov/pubmed/24128691 | 1. Neuromuscul Disord. 2013 Dec;23(12):975-80. doi: 10.1016/j.nmd.2013.08.009.
Epub 2013 Aug 31.
Exome sequencing identifies a novel SMCHD1 mutation in facioscapulohumeral
muscular dystrophy 2.
Mitsuhashi S(1), Boyden SE, Estrella EA, Jones TI, Rahimov F, Yu TW, Darras BT,
Amato AA, Folkerth RD, Jones PL, Kunkel LM, Kang PB.
Author information:
(1)Department of Neurology, Boston Children's Hospital and Harvard Medical
School, Boston, MA 02115, USA.
FSHD2 is a rare form of facioscapulohumeral muscular dystrophy (FSHD)
characterized by the absence of a contraction in the D4Z4 macrosatellite repeat
region on chromosome 4q35 that is the hallmark of FSHD1. However,
hypomethylation of this region is common to both subtypes. Recently, mutations
in SMCHD1 combined with a permissive 4q35 allele were reported to cause FSHD2.
We identified a novel p.Lys275del SMCHD1 mutation in a family affected with
FSHD2 using whole-exome sequencing and linkage analysis. This mutation alters a
highly conserved amino acid in the ATPase domain of SMCHD1. Subject III-11 is a
male who developed asymmetrical muscle weakness characteristic of FSHD at 13
years. Physical examination revealed marked bilateral atrophy at biceps brachii,
bilateral scapular winging, some asymmetrical weakness at tibialis anterior and
peroneal muscles, and mild lower facial weakness. Biopsy of biceps brachii in
subject II-5, the father of III-11, demonstrated lobulated fibers and dystrophic
changes. Endomysial and perivascular inflammation was found, which has been
reported in FSHD1 but not FSHD2. Given the previous report of SMCHD1 mutations
in FSHD2 and the clinical presentations consistent with the FSHD phenotype, we
conclude that the SMCHD1 mutation is the likely cause of the disease in this
family.
Copyright © 2013 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.nmd.2013.08.009
PMCID: PMC3851942
PMID: 24128691 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30923442 | 1. J Pediatr Neurol. 2018 Aug;16(4):222-231. doi: 10.1055/s-0037-1604197.
A Pediatric Review of Facioscapulohumeral Muscular Dystrophy.
Mah JK(1), Chen YW(2)(3).
Author information:
(1)Department of Pediatrics and Clinical Neurosciences, Cumming School of
Medicine, University of Calgary, Calgary, Alberta, Canada.
(2)Center for Genetic Medicine Research, Children's National Health System,
Washington, District of Columbia, United States.
(3)Department of Integrative Systems Biology, George Washington University,
Washington, District of Columbia, United States.
Facioscapulohumeral dystrophy is one of the most common forms of muscular
dystrophies worldwide. It is a complex and heterogeneous disease secondary to
insufficient epigenetic repression of D4Z4 repeats and aberrant expression of
DUX4 in skeletal muscles. Type 1 facioscapulohumeral muscular dystrophy (FSHD)
is caused by contraction of D4Z4 repeats on 4q35, whereas type 2 FSHD is
associated with mutations of the SMCHD1 or DNMT3B gene in the presence of a
disease-permissive 4qA haplotype. Classical FSHD is a slowly progressive
disorder with gradual-onset of muscle atrophy and a descending pattern of muscle
weakness. In contrast, early-onset FSHD is associated with a large deletion of
D4Z4 repeats and a more severe disease phenotype, including early loss of
independent ambulation as well as extramuscular manifestations, such as retinal
vasculopathy, hearing loss, and central nervous system (CNS) involvement.
However, the correlation between D4Z4 repeats and disease severity remains
imprecise. The current standard of care guidelines offers comprehensive
assessment and symptomatic management of secondary complications. Several
clinical trials are currently underway for FSHD. New and emerging treatments
focus on correcting the transcriptional misregulation of D4Z4 and reversing the
cytotoxic effects of DUX4. Other potential therapeutic targets include reduction
of inflammation, improving muscle mass, and activating compensatory molecular
pathways. The utility of disease-modifying treatments will depend on selection
of sensitive clinical endpoints as well as validation of muscle magnetic
resonance imaging (MRI) and other biomarkers to detect meaningful changes in
disease progression. Correction of the epigenetic defects using new gene editing
as well as other DUX4 silencing technologies offers potential treatment options
for many individuals with FSHD.
DOI: 10.1055/s-0037-1604197
PMCID: PMC6435288
PMID: 30923442 |
http://www.ncbi.nlm.nih.gov/pubmed/30327220 | 1. J Clin Neurosci. 2018 Dec;58:215-217. doi: 10.1016/j.jocn.2018.10.021. Epub
2018 Oct 13.
Different clinicopathological features between Japanese siblings with
facioscapulohumeral muscular dystrophy 2 with a novel nonsense SMCHD1 mutation
(Arg552(∗)).
Ohta Y(1), Tadokoro K(1), Sasaki R(1), Takahashi Y(1), Sato K(1), Takemoto M(1),
Hishikawa N(1), Shang J(1), Yamashita T(1), Takehisa Y(2), Nishino I(3), Abe
K(4).
Author information:
(1)Department of Neurology, Graduate School of Medicine, Dentistry and
Pharmaceutical Sciences, Okayama University, Okayama, Japan.
(2)Department of Neurology, Japanese Red Cross Okayama Hospital, Okayama, Japan.
(3)Department of Neuromuscular Research, National Institute of Neuroscience,
National Center of Neurology and Psychiatry, Tokyo, Japan.
(4)Department of Neurology, Graduate School of Medicine, Dentistry and
Pharmaceutical Sciences, Okayama University, Okayama, Japan. Electronic address:
[email protected].
Facioscapulohumeral muscular dystrophy (FSHD) 2 is caused by a combination of
heterozygous structural maintenance of chromosomes flexible hinge domain
containing 1 (SMCHD1) mutation plus DNA hypomethylation on D4Z4. Here we report
two Japanese FSHD2 siblings (brother and sister) with a new SMCHD1 nonsense
mutation (a heterogeneous c. 1654C > T substitution, leading to a stop codon
Arg552∗). They showed the typical phenotype of FSHD2 such as asymmetric muscle
weakness and atrophy in bilateral facial, scapular and humeral muscles, but
different clinicopathological features between them. The brother and
asymptomatic mother showed normal D4Z4 methylation plus the same SMCHD1
mutation, but the sister showed the SMCHD1 mutation plus D4Z4 hypomethylation,
suggesting an interesting correlation of the new SMCHD1 nonsense mutation and
D4Z4 hypomethylation.
Copyright © 2018 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.jocn.2018.10.021
PMID: 30327220 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35052449 | 1. Genes (Basel). 2022 Jan 5;13(1):109. doi: 10.3390/genes13010109.
Nucleic Acid-Based Therapeutic Approach for Spinal and Bulbar Muscular Atrophy
and Related Neurological Disorders.
Hirunagi T(1), Sahashi K(1), Meilleur KG(2), Katsuno M(1)(3).
Author information:
(1)Department of Neurology, Nagoya University Graduate School of Medicine, 65
Tsurumai-cho, Syowa-ku, Nagoya 466-8550, Japan.
(2)Research and Clinical Development, Neuromuscular Development Unit, Biogen,
300, Binney Street, Cambridge, MA 02142, USA.
(3)Department of Clinical Research Education, Nagoya University Graduate School
of Medicine, 65 Tsurumai-cho, Syowa-ku, Nagoya 466-8550, Japan.
The recent advances in nucleic acid therapeutics demonstrate the potential to
treat hereditary neurological disorders by targeting their causative genes.
Spinal and bulbar muscular atrophy (SBMA) is an X-linked and adult-onset
neurodegenerative disorder caused by the expansion of trinucleotide
cytosine-adenine-guanine repeats, which encodes a polyglutamine tract in the
androgen receptor gene. SBMA belongs to the family of polyglutamine diseases, in
which the use of nucleic acids for silencing a disease-causing gene, such as
antisense oligonucleotides and small interfering RNAs, has been intensively
studied in animal models and clinical trials. A unique feature of SBMA is that
both motor neuron and skeletal muscle pathology contribute to disease
manifestations, including progressive muscle weakness and atrophy. As both motor
neurons and skeletal muscles can be therapeutic targets in SBMA, nucleic
acid-based approaches for other motor neuron diseases and myopathies may further
lead to the development of a treatment for SBMA. Here, we review studies of
nucleic acid-based therapeutic approaches in SBMA and related neurological
disorders and discuss current limitations and perspectives to apply these
approaches to patients with SBMA.
DOI: 10.3390/genes13010109
PMCID: PMC8775157
PMID: 35052449 [Indexed for MEDLINE]
Conflict of interest statement: K.G.M. is an employee of Biogen. |
http://www.ncbi.nlm.nih.gov/pubmed/28915324 | 1. Compr Physiol. 2017 Sep 12;7(4):1229-1279. doi: 10.1002/cphy.c160039.
Facioscapulohumeral Muscular Dystrophy.
DeSimone AM(1), Pakula A(2)(3), Lek A(2)(3)(4), Emerson CP Jr(1).
Author information:
(1)Wellstone Muscular Dystrophy Program, Department of Neurology, University of
Massachusetts Medical School, Worcester, Massachusetts, USA.
(2)Division of Genetics and Genomics, Boston Children's Hospital, Boston,
Massachusetts, USA.
(3)Department of Pediatrics and Genetics at Harvard Medical School, Boston,
Massachusetts, USA.
(4)Australian Regenerative Medicine Institute, Monash University, Clayton,
Victoria, Australia.
Facioscapulohumeral Muscular Dystrophy is a common form of muscular dystrophy
that presents clinically with progressive weakness of the facial, scapular, and
humeral muscles, with later involvement of the trunk and lower extremities.
While typically inherited as autosomal dominant, facioscapulohumeral muscular
dystrophy (FSHD) has a complex genetic and epigenetic etiology that has only
recently been well described. The most prevalent form of the disease, FSHD1, is
associated with the contraction of the D4Z4 microsatellite repeat array located
on a permissive 4qA chromosome. D4Z4 contraction allows epigenetic derepression
of the array, and possibly the surrounding 4q35 region, allowing misexpression
of the toxic DUX4 transcription factor encoded within the terminal D4Z4 repeat
in skeletal muscles. The less common form of the disease, FSHD2, results from
haploinsufficiency of the SMCHD1 gene in individuals carrying a permissive 4qA
allele, also leading to the derepression of DUX4, further supporting a central
role for DUX4. How DUX4 misexpression contributes to FSHD muscle pathology is a
major focus of current investigation. Misexpression of other genes at the 4q35
locus, including FRG1 and FAT1, and unlinked genes, such as SMCHD1, has also
been implicated as disease modifiers, leading to several competing disease
models. In this review, we describe recent advances in understanding the
pathophysiology of FSHD, including the application of MRI as a research and
diagnostic tool, the genetic and epigenetic disruptions associated with the
disease, and the molecular basis of FSHD. We discuss how these advances are
leading to the emergence of new approaches to enable development of FSHD
therapeutics. © 2017 American Physiological Society. Compr Physiol 7:1229-1279,
2017.
Copyright © 2017 John Wiley & Sons, Inc.
DOI: 10.1002/cphy.c160039
PMID: 28915324 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29980640 | 1. Neurology. 2018 Aug 7;91(6):e562-e570. doi: 10.1212/WNL.0000000000005958. Epub
2018 Jul 6.
FSHD type 2 and Bosma arhinia microphthalmia syndrome: Two faces of the same
mutation.
Mul K(1), Lemmers RJLF(2), Kriek M(2), van der Vliet PJ(2), van den Boogaard
ML(2), Badrising UA(2), Graham JM Jr(2), Lin AE(2), Brand H(2), Moore SA(2),
Johnson K(2), Evangelista T(2), Töpf A(2), Straub V(2), Kapetanovic García S(2),
Sacconi S(2), Tawil R(2), Tapscott SJ(2), Voermans NC(2), van Engelen BGM(2),
Horlings CGC(2), Shaw ND(2), van der Maarel SM(2).
Author information:
(1)From the Department of Neurology (K.M., N.C.V., B.G.M.v.E., C.G.C.H.),
Radboud University Medical Center, Nijmegen; Departments of Human Genetics
(R.J.L.F.L., P.J.v.d.V., M.L.v.d.B., S.M.v.d.M.), Clinical Genetics (M.K.), and
Neurology (U.A.B.), Leiden University Medical Center, Leiden, the Netherlands;
Department of Pediatrics (J.M.G.), Cedars Sinai Medical Center, Los Angeles, CA;
Department of Medical Genetics (A.E.L.), MassGeneral Hospital for Children,
Boston, MA; Center for Genomic Medicine and Department of Neurology (H.B.),
Massachusetts General Hospital, Boston; Department of Pathology (S.A.M.),
University of Iowa Hospitals and Clinics, Iowa City; The John Walton Muscular
Dystrophy Research Centre (K.J., T.E., A.T., V.S.), Institute of Genetic
Medicine, Newcastle University, Newcastle upon Tyne, UK; Neuromuscular Consult
Unit (S.K.G.), Bilbo-Basurtu Erakunde Sanitario Integratua, Organización
Sanitaria Integrada Bilbao-Basurto, Spain; Centre de Référence des Maladies
Neuromusculaires (S.S.), Nice, France; Department of Neurology (R.T.),
University of Rochester Medical Center, NY; Division of Human Biology (S.J.T.),
Fred Hutchinson Cancer Research Center, Seattle, WA; and National Institute of
Environmental Health Sciences (N.D.S.), Research Triangle Park, NC.
[email protected].
(2)From the Department of Neurology (K.M., N.C.V., B.G.M.v.E., C.G.C.H.),
Radboud University Medical Center, Nijmegen; Departments of Human Genetics
(R.J.L.F.L., P.J.v.d.V., M.L.v.d.B., S.M.v.d.M.), Clinical Genetics (M.K.), and
Neurology (U.A.B.), Leiden University Medical Center, Leiden, the Netherlands;
Department of Pediatrics (J.M.G.), Cedars Sinai Medical Center, Los Angeles, CA;
Department of Medical Genetics (A.E.L.), MassGeneral Hospital for Children,
Boston, MA; Center for Genomic Medicine and Department of Neurology (H.B.),
Massachusetts General Hospital, Boston; Department of Pathology (S.A.M.),
University of Iowa Hospitals and Clinics, Iowa City; The John Walton Muscular
Dystrophy Research Centre (K.J., T.E., A.T., V.S.), Institute of Genetic
Medicine, Newcastle University, Newcastle upon Tyne, UK; Neuromuscular Consult
Unit (S.K.G.), Bilbo-Basurtu Erakunde Sanitario Integratua, Organización
Sanitaria Integrada Bilbao-Basurto, Spain; Centre de Référence des Maladies
Neuromusculaires (S.S.), Nice, France; Department of Neurology (R.T.),
University of Rochester Medical Center, NY; Division of Human Biology (S.J.T.),
Fred Hutchinson Cancer Research Center, Seattle, WA; and National Institute of
Environmental Health Sciences (N.D.S.), Research Triangle Park, NC.
OBJECTIVE: To determine whether congenital arhinia/Bosma arhinia microphthalmia
syndrome (BAMS) and facioscapulohumeral muscular dystrophy type 2 (FSHD2), 2
seemingly unrelated disorders both caused by heterozygous pathogenic missense
variants in the SMCHD1 gene, might represent different ends of a broad single
phenotypic spectrum associated with SMCHD1 dysfunction.
METHODS: We examined and/or interviewed 14 patients with FSHD2 and 4 unaffected
family members with N-terminal SMCHD1 pathogenic missense variants to identify
BAMS subphenotypes.
RESULTS: None of the patients with FSHD2 or family members demonstrated any
congenital defects or dysmorphic features commonly found in patients with BAMS.
One patient became anosmic after nasal surgery and one patient was hyposmic; one
man was infertile (unknown cause) but reported normal pubertal development.
CONCLUSION: These data suggest that arhinia/BAMS and FSHD2 do not represent one
phenotypic spectrum and that SMCHD1 pathogenic variants by themselves are
insufficient to cause either of the 2 disorders. More likely, both arhinia/BAMS
and FSHD2 are caused by complex oligogenic or multifactorial mechanisms that
only partially overlap at the level of SMCHD1.
© 2018 American Academy of Neurology.
DOI: 10.1212/WNL.0000000000005958
PMCID: PMC6105048
PMID: 29980640 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17852020 | 1. Amyotroph Lateral Scler. 2008 Feb;9(1):40-2. doi: 10.1080/17482960701553915.
Pure bulbar motor neuron involvement linked to an abnormal CAG repeat expansion
in the androgen receptor gene.
Praline J(1), Guennoc AM, Malinge MC, de Toffol B, Corcia P.
Author information:
(1)ALSCentre, CHRUde Tours, Tours, France. [email protected]
Spinal and bulbar muscular atrophy (SBMA) is an X-linked adult motor neuron
disorder caused by an abnormal CAG-repeat expansion in the first exon of the
androgen receptor gene. This disease associates progressive lower motor neuron
affection and endocrine disturbances. Bulbar symptoms appear usually late in the
clinical course but clinical heterogeneity is demonstrated. We report the case
of a 62-year-old male with a 10-year history of progressive bulbar involvement
related to an abnormal CAG-repeat expansion in the androgen receptor gene. This
atypical phenotype led us to discuss the role of some genetic or environmental
factors in SBMA.
DOI: 10.1080/17482960701553915
PMID: 17852020 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32152060 | 1. Dis Model Mech. 2020 May 26;13(5):dmm042424. doi: 10.1242/dmm.042424.
Deterioration of muscle force and contractile characteristics are early
pathological events in spinal and bulbar muscular atrophy mice.
Gray AL(1), Annan L(1), Dick JRT(1), La Spada AR(2)(3)(4)(5)(6), Hanna MG(1)(7),
Greensmith L(8), Malik B(8).
Author information:
(1)Department of Neuromuscular Diseases, UCL Queen Square Institute of
Neurology, Queen Square, London WC1N 3BG, UK.
(2)Department of Neurology, Duke University School of Medicine, Durham, NC
27710, USA.
(3)Department of Neurobiology, Duke University School of Medicine, Durham, NC
27710, USA.
(4)Department of Cell Biology, Duke University School of Medicine, Durham, NC
27710, USA.
(5)Duke Center for Neurodegeneration and Neurotherapeutics, Duke University
School of Medicine, Durham, NC 27710, USA.
(6)Department of Neuroscience, University of California, San Diego, La Jolla, CA
92093, USA.
(7)UCL MRC International Centre for Genomic Medicine in Neuromuscular Diseases,
UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK.
(8)Department of Neuromuscular Diseases, UCL Queen Square Institute of
Neurology, Queen Square, London WC1N 3BG, UK [email protected]
[email protected].
Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's Disease, is a
late-onset X-linked progressive neuromuscular disease, which predominantly
affects males. The pathological hallmarks of the disease are selective loss of
spinal and bulbar motor neurons, accompanied by weakness, atrophy and
fasciculations of bulbar and limb muscles. SBMA is caused by a CAG repeat
expansion in the gene that encodes the androgen receptor (AR) protein. Disease
manifestation is androgen dependent and results principally from a toxic gain of
AR function. There are currently no effective treatments for this debilitating
disease. It is important to understand the course of the disease in order to
target therapeutics to key pathological stages. This is especially relevant in
disorders such as SBMA, for which disease can be identified before symptom
onset, through family history and genetic testing. To fully characterise the
role of muscle in SBMA, we undertook a longitudinal physiological and
histological characterisation of disease progression in the AR100 mouse model of
SBMA. Our results show that the disease first manifests in skeletal muscle,
before any motor neuron degeneration, which only occurs in late-stage disease.
These findings reveal that alterations in muscle function, including reduced
muscle force and changes in contractile characteristics, are early pathological
events in SBMA mice and suggest that muscle-targeted therapeutics may be
effective in SBMA.This article has an associated First Person interview with the
first author of the paper.
© 2020. Published by The Company of Biologists Ltd.
DOI: 10.1242/dmm.042424
PMCID: PMC7272358
PMID: 32152060 [Indexed for MEDLINE]
Conflict of interest statement: Competing interestsThe authors declare no
competing or financial interests. |
http://www.ncbi.nlm.nih.gov/pubmed/32276665 | 1. Orphanet J Rare Dis. 2020 Apr 10;15(1):90. doi: 10.1186/s13023-020-01366-z.
The French national protocol for Kennedy's disease (SBMA): consensus diagnostic
and management recommendations.
Pradat PF(1), Bernard E(2), Corcia P(3), Couratier P(4), Jublanc C(5), Querin
G(6), Morélot Panzini C(7)(8), Salachas F(9), Vial C(2), Wahbi K(10), Bede
P(6)(11), Desnuelle C(12); French Kennedy’s Disease Writing Group.
Collaborators: Le Forestier N, Echaniz-Laguna A, Querin G, Sorarù G, Perez T,
Ramos C, Goizet C, Desport JC, Pugeat M, Pichon B, Maniez S, Robillard J, Coupe
C, Laurier Betram L, Roy Bellina S, Lévêque N, Penot J, Goutines Caramel V.
Author information:
(1)AP-HP, Groupe Hospitalier Universitaire APHP-Sorbonne Université, site
Pitié-Salpêtrière, Département de Neurologie, Centre de Reference pour la SLA et
les Maladies du Motoneurone, CNRS, INSERM, Laboratoire d'Imagerie Biomédicale,
47 Boulevard de l'Hôpital - F-75634, 13, Paris Cedex, France.
[email protected].
(2)Service d'électromyographie et pathologies neuromusculaire, Centre de
Reference pour la SLA et les Maladies du Motoneurone, CHU Lyon Hôpital
Neurologique P. Wertheimer, Lyon, France.
(3)Département de Neurologie, Centre de Reference pour la SLA et les Maladies du
Motoneurone, CHU Tours, Tours, France.
(4)Département de Neurologie, Centre de Reference pour la SLA et les Maladies du
Motoneurone, CHU Limoges, Limoges, France.
(5)AP-HP, Groupe Hospitalier Universitaire APHP-Sorbonne Université, site
Pitié-Salpêtrière Département d'endocrinologie, Paris, France.
(6)AP-HP, Groupe Hospitalier Universitaire APHP-Sorbonne Université, site
Pitié-Salpêtrière, Département de Neurologie, Centre de Reference pour la SLA et
les Maladies du Motoneurone, CNRS, INSERM, Laboratoire d'Imagerie Biomédicale,
47 Boulevard de l'Hôpital - F-75634, 13, Paris Cedex, France.
(7)AP-HP, Groupe Hospitalier Universitaire APHP-Sorbonne Université, site
Pitié-Salpêtrière, Service de Pneumologie, Médecine Intensive et Réanimation
(Département R3S), F-75013, Paris, France.
(8)Sorbonne Université, INSERM, UMRS1158 Neurophysiologie Respiratoire
Expérimentale et Clinique, F-75005, Paris, France.
(9)AP-HP, Groupe Hospitalier Universitaire APHP-Sorbonne Université, site
Pitié-Salpêtrière, Département de Neurologie, Centre de Reference pour la SLA et
les Maladies du Motoneurone, Paris, France.
(10)AP-HP, CHU Cochin, Service de cardiologie, Centre de référence des maladies
neuromusculaires Nord/Est/Ile de France, Paris, France.
(11)Computational Neuroimaging Group, Trinity College Dublin, Dublin, Ireland.
(12)Pôle Neurosciences - Service de Neurologie, Centre de Référence SLA et les
maladies du neurone moteur, Hôpital Pasteur2, CHU de Nice Université Côte
d'Azur, Nice, France.
BACKGROUND: Kennedy's disease (KD), also known as spinal and bulbar muscular
atrophy (SBMA), is a rare, adult-onset, X-linked recessive neuromuscular disease
caused by CAG expansions in exon 1 of the androgen receptor gene (AR). The
objective of the French national diagnostic and management protocol is to
provide evidence-based best practice recommendations and outline an optimised
care pathway for patients with KD, based on a systematic literature review and
consensus multidisciplinary observations.
RESULTS: The initial evaluation, confirmation of the diagnosis, and management
should ideally take place in a tertiary referral centre for motor neuron
diseases, and involve an experienced multidisciplinary team of neurologists,
endocrinologists, cardiologists and allied healthcare professionals. The
diagnosis should be suspected in an adult male presenting with slowly
progressive lower motor neuron symptoms, typically affecting the lower limbs at
onset. Bulbar involvement (dysarthria and dysphagia) is often a later
manifestation of the disease. Gynecomastia is not a constant feature, but is
suggestive of a suspected diagnosis, which is further supported by
electromyography showing diffuse motor neuron involvement often with
asymptomatic sensory changes. A suspected diagnosis is confirmed by genetic
testing. The multidisciplinary assessment should ascertain extra-neurological
involvement such as cardiac repolarisation abnormalities (Brugada syndrome),
signs of androgen resistance, genitourinary abnormalities, endocrine and
metabolic changes (glucose intolerance, hyperlipidemia). In the absence of
effective disease modifying therapies, the mainstay of management is symptomatic
support using rehabilitation strategies (physiotherapy and speech therapy).
Nutritional evaluation by an expert dietician is essential, and enteral
nutrition (gastrostomy) may be required. Respiratory management centres on the
detection and treatment of bronchial obstructions, as well as screening for
aspiration pneumonia (chest physiotherapy, drainage, positioning, breath
stacking, mechanical insufflation-exsufflation, cough assist machnie,
antibiotics). Non-invasive mechanical ventilation is seldom needed. Symptomatic
pharmaceutical therapy includes pain management, endocrine and metabolic
interventions. There is no evidence for androgen substitution therapy.
CONCLUSION: The French national Kennedy's disease protocol provides management
recommendations for patients with KD. In a low-incidence condition, sharing and
integrating regional expertise, multidisciplinary experience and defining
consensus best-practice recommendations is particularly important.
Well-coordinated collaborative efforts will ultimately pave the way to the
development of evidence-based international guidelines.
DOI: 10.1186/s13023-020-01366-z
PMCID: PMC7149864
PMID: 32276665 [Indexed for MEDLINE]
Conflict of interest statement: The authors have no competing interests to
declare. |
http://www.ncbi.nlm.nih.gov/pubmed/11436124 | 1. Eur J Hum Genet. 2001 Jun;9(6):431-6. doi: 10.1038/sj.ejhg.5200656.
Multiple founder effects in spinal and bulbar muscular atrophy (SBMA, Kennedy
disease) around the world.
Lund A(1), Udd B, Juvonen V, Andersen PM, Cederquist K, Davis M, Gellera C,
Kölmel C, Ronnevi LO, Sperfeld AD, Sörensen SA, Tranebjaerg L, Van Maldergem L,
Watanabe M, Weber M, Yeung L, Savontaus ML.
Author information:
(1)Department of Medical Genetics, University of Turku, Finland. [email protected]
SBMA (spinal and bulbar muscular atrophy), also called Kennedy disease, is an
X-chromosomal recessive adult-onset neurodegenerative disorder caused by death
of the spinal and bulbar motor neurones and dorsal root ganglia. Patients may
also show signs of partial androgen insensitivity. SBMA is caused by a CAG
repeat expansion in the first exon of the androgen receptor (AR) gene on the
X-chromosome. Our previous study suggested that all the Nordic patients with
SBMA originated from an ancient Nordic founder mutation, but the new intragenic
SNP marker ARd12 revealed that the Danish patients derive their disease
chromosome from another ancestor. In search of relationships between patients
from different countries, we haplotyped altogether 123 SBMA families from
different parts of the world for two intragenic markers and 16 microsatellites
spanning 25 cM around the AR gene. The fact that different SBMA founder
haplotypes were found in patients from around the world implies that the CAG
repeat expansion mutation has not been a unique event. No expansion-prone
haplotype could be detected. Trinucleotide diseases often show correlation
between the repeat length and the severity and earlier onset of the disease. The
longer the repeat, the more severe the symptoms are and the onset of the disease
is earlier. A negative correlation between the CAG repeat length and the age of
onset was found in the 95 SBMA patients with defined ages at onset.
DOI: 10.1038/sj.ejhg.5200656
PMID: 11436124 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22476656 | 1. Cell Tissue Res. 2012 Jul;349(1):313-20. doi: 10.1007/s00441-012-1377-9. Epub
2012 Apr 4.
Pathogenesis and molecular targeted therapy of spinal and bulbar muscular
atrophy (SBMA).
Banno H(1), Katsuno M, Suzuki K, Tanaka F, Sobue G.
Author information:
(1)Department of Neurology, Nagoya University Graduate School of Medicine, 65
Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is
an adult-onset, X-linked motor neuron disease characterized by muscle atrophy,
weakness, contraction fasciculations, and bulbar involvement. SBMA is caused by
the expansion of a CAG triplet repeat, encoding a polyglutamine tract within the
first exon of the androgen receptor (AR) gene. The histopathological finding in
SBMA is the loss of lower motor neurons in the anterior horn of the spinal cord
as well as in the brainstem motor nuclei. There is no established
disease-modifying therapy for SBMA. Animal studies have revealed that the
pathogenesis of SBMA depends on the level of serum testosterone, and that
androgen deprivation mitigates neurodegeneration through inhibition of nuclear
accumulation and/or stabilization of the pathogenic AR. Heat shock proteins, the
ubiquitin-proteasome system and transcriptional regulation are also potential
targets for development of therapy for SBMA. Among these therapeutic approaches,
the luteinizing hormone-releasing hormone analogue, leuprorelin, prevents
nuclear translocation of aberrant AR proteins, resulting in a significant
improvement of disease phenotype in a mouse model of SBMA. In a phase 2 clinical
trial of leuprorelin, the patients treated with this drug exhibited decreased
mutant AR accumulation in scrotal skin biopsy. Phase 3 clinical trial showed the
possibility that leuprorelin treatment is associated with improved swallowing
function particularly in patients with a disease duration less than 10 years.
These observations suggest that pharmacological inhibition of the toxic
accumulation of mutant AR is a potential therapy for SBMA.
DOI: 10.1007/s00441-012-1377-9
PMID: 22476656 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16772330 | 1. Hum Mol Genet. 2006 Jul 15;15(14):2225-38. doi: 10.1093/hmg/ddl148. Epub 2006
Jun 13.
Loss of endogenous androgen receptor protein accelerates motor neuron
degeneration and accentuates androgen insensitivity in a mouse model of X-linked
spinal and bulbar muscular atrophy.
Thomas PS Jr(1), Fraley GS, Damian V, Woodke LB, Zapata F, Sopher BL, Plymate
SR, La Spada AR.
Author information:
(1)Department of Laboratory Medicine, University of Washington Medical Center,
Seattle, 98195-7110, USA.
Erratum in
Hum Mol Genet. 2006 Oct 1;15(19):2972. Damien, Vincent [corrected to Damian,
Vincent].
X-linked spinal and bulbar muscular atrophy (SBMA; Kennedy's disease) is a
polyglutamine (polyQ) disease in which the affected males suffer progressive
motor neuron degeneration accompanied by signs of androgen insensitivity, such
as gynecomastia and reduced fertility. SBMA is caused by CAG repeat expansions
in the androgen receptor (AR) gene resulting in the production of AR protein
with an extended glutamine tract. SBMA is one of nine polyQ diseases in which
polyQ expansion is believed to impart a toxic gain-of-function effect upon the
mutant protein, and initiate a cascade of events that culminate in
neurodegeneration. However, whether loss of a disease protein's normal function
concomitantly contributes to the neurodegeneration remains unanswered. To
address this, we examined the role of normal AR function in SBMA by crossing a
highly representative AR YAC transgenic mouse model with 100 glutamines (AR100)
and a corresponding control (AR20) onto an AR null (testicular feminization;
Tfm) background. Absence of endogenous AR protein in AR100Tfm mice had profound
effects upon neuromuscular and endocrine-reproductive features of this SBMA
mouse model, as AR100Tfm mice displayed accelerated neurodegeneration and severe
androgen insensitivity in comparison to AR100 littermates. Reduction in size and
number of androgen-sensitive motor neurons in the spinal cord of AR100Tfm mice
underscored the importance of AR action for neuronal health and survival.
Promoter-reporter assays confirmed that AR transactivation competence diminishes
in a polyQ length-dependent fashion. Our studies indicate that SBMA disease
pathogenesis, both in the nervous system and the periphery, involves two
simultaneous pathways: gain-of-function misfolded protein toxicity and loss of
normal protein function.
DOI: 10.1093/hmg/ddl148
PMID: 16772330 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32631678 | 1. Rev Neurol (Paris). 2020 Dec;176(10):780-787. doi:
10.1016/j.neurol.2020.03.020. Epub 2020 Jul 4.
Metabolic alterations in spinal and bulbar muscular atrophy.
Francini-Pesenti F(1), Vitturi N(2), Tresso S(3), Sorarù G(4).
Author information:
(1)Department of Medicine, University of Padova, via Giustiniani 1, 35128
Padova, Italy. Electronic address: [email protected].
(2)Department of Medicine, University of Padova, via Giustiniani 1, 35128
Padova, Italy. Electronic address: [email protected].
(3)Department of Medicine, University of Padova, via Giustiniani 1, 35128
Padova, Italy. Electronic address: [email protected].
(4)Department of Neurosciences, University of Padova, via Giustiniani 1, 35128
Padova, Italy. Electronic address: [email protected].
Spinal and bulbar muscular atrophy (SBMA) is a rare, X-linked neuromuscular
disease characterised by lower motor neurons degeneration, slowly progressive
myopathy and multisystem involvement. SBMA is caused by trinucleotide repeat
expansion in the first exon of the androgen receptor (AR) gene on chromosome X
that encodes a polyglutamine (polyQ) tract in the AR protein. Disease onset
occurs between 30-60 years of age with easy fatigability, muscle cramps, and
weakness in the limbs. In addition to neuromuscular involvement, in SBMA
phenotype, many non-neural manifestations are present. Recently, some studies
have reported a high prevalence of metabolic and liver disorders in patients
with SBMA. Particularly, fatty liver and insulin resistance (IR) have been found
in many SBMA patients. The alteration of AR function and the androgen
insensitivity can be involved in both fatty liver and IR. In turn, IR and liver
alterations can influence neuromuscular damage through different mechanisms.
These data lead to consider SBMA as a metabolic as well as a neuromuscular
disease. The mechanism of metabolic alterations, their link with the
neuromuscular damage, the effects on the course of disease and their treatment
will have to be yet fully clarified.
Copyright © 2020 Elsevier Masson SAS. All rights reserved.
DOI: 10.1016/j.neurol.2020.03.020
PMID: 32631678 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12189162 | 1. Hum Mol Genet. 2002 Sep 1;11(18):2103-11. doi: 10.1093/hmg/11.18.2103.
A mouse model of spinal and bulbar muscular atrophy.
McManamny P(1), Chy HS, Finkelstein DI, Craythorn RG, Crack PJ, Kola I, Cheema
SS, Horne MK, Wreford NG, O'Bryan MK, De Kretser DM, Morrison JR.
Author information:
(1)Monash Institute of Reproduction and Development, Monash University, 27-31
Wright Street, Clayton, Melbourne, Victoria, 3168, Australia.
Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron
disease, caused by the expansion of a trinucleotide repeat (TNR) in exon 1 of
the androgen receptor (AR) gene. This disorder is characterized by degeneration
of motor and sensory neurons, proximal muscular atrophy, and endocrine
abnormalities, such as gynecomastia and reduced fertility. We describe the
development of a transgenic model of SBMA expressing a full-length human AR
(hAR) cDNA carrying 65 (AR(65)) or 120 CAG repeats (AR(120)), with widespread
expression driven by the cytomegalovirus promoter. Mice carrying the AR(120)
transgene displayed behavioral and motor dysfunction, while mice carrying 65 CAG
repeats showed a mild phenotype. Progressive muscle weakness and atrophy was
observed in AR(120) mice and was associated with the loss of alpha-motor neurons
in the spinal cord. There was no evidence of neurodegeneration in other brain
structures. Motor dysfunction was observed in both male and female animals,
showing that in SBMA the polyglutamine repeat expansion causes a dominant
gain-of-function mutation in the AR. The male mice displayed a progressive
reduction in sperm production consistent with testis defects reported in human
patients. These mice represent the first model to reproduce the key features of
SBMA, making them a useful resource for characterizing disease progression, and
for testing therapeutic strategies for both polyglutamine and motor neuron
diseases.
DOI: 10.1093/hmg/11.18.2103
PMID: 12189162 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16513111 | 1. Exp Neurol. 2006 Jul;200(1):8-18. doi: 10.1016/j.expneurol.2006.01.021. Epub
2006 Mar 2.
Pathogenesis, animal models and therapeutics in spinal and bulbar muscular
atrophy (SBMA).
Katsuno M(1), Adachi H, Waza M, Banno H, Suzuki K, Tanaka F, Doyu M, Sobue G.
Author information:
(1)Department of Neurology, Nagoya University Graduate School of Medicine, 65
Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Spinal and bulbar muscular atrophy (SBMA) is a hereditary neurodegenerative
disease characterized by slowly progressive muscle weakness and atrophy of
bulbar, facial, and limb muscles. The cause of SBMA is expansion of a
trinucleotide CAG repeat, which encodes the polyglutamine tract, in the first
exon of the androgen receptor (AR) gene. SBMA chiefly occurs in adult males,
whereas neurological symptoms are rarely detected in females having mutant AR
gene. The cardinal histopathological finding of SBMA is loss of lower motor
neurons in the anterior horn of spinal cord as well as in brainstem motor
nuclei. Animal models carrying human mutant AR gene recapitulate
polyglutamine-mediated motor neuron degeneration, providing clues to the
pathogenesis of SBMA. There is increasing evidence that testosterone, the ligand
of AR, plays a pivotal role in the pathogenesis of neurodegeneration in SBMA.
The striking success of androgen deprivation therapy in SBMA mouse models has
been translated into clinical trials. In addition, elucidation of
pathophysiology using animal models leads to emergence of candidate drugs to
treat this devastating disease: HSP inducer, Hsp90 inhibitor, and histone
deacetylase inhibitor. Utilizing biomarkers such as scrotal skin biopsy would
improve efficacy of clinical trials to verify the results from animal studies.
Advances in basic and clinical researches on SBMA are now paving the way for
clinical application of potential therapeutics.
DOI: 10.1016/j.expneurol.2006.01.021
PMID: 16513111 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26875173 | 1. J Mol Neurosci. 2016 Mar;58(3):313-6. doi: 10.1007/s12031-016-0720-0. Epub
2016 Feb 13.
Introduction to the Special Issue on Spinal and Bulbar Muscular Atrophy.
Pennuto M(1), Gozes I(2).
Author information:
(1)Dulbecco Telethon Institute Lab of Neurodegenerative Diseases, Centre for
Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123,
Trento, Italy. [email protected].
(2)Lily and Avraham Gildor Chair for the Investigation of Growth Factors, Elton
Laboratory for Neuroendocrinology, Department of Human Molecular Genetics and
Biochemistry, Sackler Faculty of Medicine, Adams Super Center for Brain Studies
and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 69978, Israel.
[email protected].
This special issue is dedicated to spinal and bulbar muscular atrophy (SBMA) and
is based on the conference sponsored by the European Neuromuscular Centre (ENMC)
held in March 2015. SBMA, also known as Kennedy's disease, is a
neurodegenerative disease caused by an expansion of a repeat of the
trinucleotide CAG encoding glutamine in the gene encoding androgen receptor
(AR). Expansion of polyglutamine in the AR results in selective lower motor
neuron degeneration and skeletal muscle atrophy. SBMA belongs to the family of
polyglutamine diseases, which also includes Huntington's disease,
dentatorubral-pallidoluysian atrophy, and spinocerebellar ataxia (SCA) types 1,
2, 3, 6, 7, and 17. Within the family of polyglutamine diseases, SBMA is unique
in its gender-specificity, with full disease manifestation restricted to males.
Since the disease is ligand (androgen)-dependent, SBMA manifests primarily in
males which have high levels of circulating androgens in the serum; females are
usually asymptomatic. Indeed, the polyglutamine-expanded AR is converted to a
neurotoxic species upon binding to androgens. The mechanisms through which
androgen binding triggers the disease are under investigation. Although several
therapeutic strategies have been proposed to date, there is currently no
effective therapy to arrest or delay disease progression in patients.
DOI: 10.1007/s12031-016-0720-0
PMID: 26875173 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17359355 | 1. Neuropathol Appl Neurobiol. 2007 Apr;33(2):135-51. doi:
10.1111/j.1365-2990.2007.00830.x.
Pathogenesis and molecular targeted therapy of spinal and bulbar muscular
atrophy.
Adachi H(1), Waza M, Katsuno M, Tanaka F, Doyu M, Sobue G.
Author information:
(1)Department of Neurology, Nagoya University Graduate School of Medicine,
Nagoya, Japan.
Spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease is a motor
neurone disease characterized by muscle atrophy, weakness, contraction
fasciculations and bulbar involvement. SBMA mainly affects males, while females
are usually asymptomatic. SBMA is caused by expansion of a polyglutamine
(polyQ)-encoding CAG trinucleotide repeat in the androgen receptor (AR) gene. AR
belongs to the heat shock protein 90 (Hsp90) client protein family. The
histopathologic hallmarks of SBMA are diffuse nuclear accumulation and nuclear
inclusions of the mutant AR with expanded polyQ in residual motor neurones in
the brainstem and spinal cord as well as in some other visceral organs. There is
increasing evidence that the ligand of AR and molecular chaperones play a
crucial role in the pathogenesis of SBMA. The success of androgen deprivation
therapy in SBMA mouse models has been translated into clinical trials. In
addition, elucidation of its pathophysiology using animal models has led to the
development of disease-modifying drugs, that is, Hsp90 inhibitor and Hsp
inducer, which inhibit the pathogenic process of neuronal degeneration. SBMA is
a slowly progressive disease by nature. The degree of nuclear accumulation of
mutant AR in scrotal skin epithelial cells was correlated with that in spinal
motor neurones in autopsy specimens; therefore, the results of scrotal skin
biopsy may be used to assess the efficacy of therapeutic trials. Clinical and
pathological parameters that reflect the pathogenic process of SBMA should be
extensively investigated.
DOI: 10.1111/j.1365-2990.2007.00830.x
PMID: 17359355 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35726299 | 1. Front Mol Neurosci. 2022 Jun 3;15:931301. doi: 10.3389/fnmol.2022.931301.
eCollection 2022.
Exploring the Role of Posttranslational Modifications in Spinal and Bulbar
Muscular Atrophy.
Gogia N(1), Ni L(1), Olmos V(1), Haidery F(2), Luttik K(3)(4), Lim
J(1)(3)(4)(5).
Author information:
(1)Department of Genetics, Yale School of Medicine, Yale University, New Haven,
CT, United States.
(2)Yale College, Yale University, New Haven, CT, United States.
(3)Department of Neuroscience, Yale School of Medicine, Yale University, New
Haven, CT, United States.
(4)Interdepartmental Neuroscience Program, Yale University, New Haven, CT,
United States.
(5)Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale School
of Medicine, Yale University, New Haven, CT, United States.
Spinal and Bulbar Muscular Atrophy (SBMA) is an X-linked adult-onset progressive
neuromuscular disease that affects the spinal and bulbar motor neurons and
skeletal muscles. SBMA is caused by expansion of polymorphic CAG trinucleotide
repeats in the Androgen Receptor (AR) gene, resulting in expanded glutamine
tract in the AR protein. Polyglutamine (polyQ) expansion renders the mutant AR
protein toxic, resulting in the formation of mutant protein aggregates and cell
death. This classifies SBMA as one of the nine known polyQ diseases. Like other
polyQ disorders, the expansion of the polyQ tract in the AR protein is the main
genetic cause of the disease; however, multiple other mechanisms besides the
polyQ tract expansion also contribute to the SBMA disease pathophysiology.
Posttranslational modifications (PTMs), including phosphorylation, acetylation,
methylation, ubiquitination, and SUMOylation are a category of mechanisms by
which the functionality of AR has been found to be significantly modulated and
can alter the neurotoxicity of SBMA. This review summarizes the different PTMs
and their effects in regulating the AR function and discusses their pathogenic
or protective roles in context of SBMA. This review also includes the
therapeutic approaches that target the PTMs of AR in an effort to reduce the
mutant AR-mediated toxicity in SBMA.
Copyright © 2022 Gogia, Ni, Olmos, Haidery, Luttik and Lim.
DOI: 10.3389/fnmol.2022.931301
PMCID: PMC9206542
PMID: 35726299
Conflict of interest statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/29478604 | 1. Handb Clin Neurol. 2018;148:625-632. doi: 10.1016/B978-0-444-64076-5.00040-5.
Spinal and bulbar muscular atrophy.
Lieberman AP(1).
Author information:
(1)Department of Pathology, University of Michigan Medical School, Ann Arbor,
MI, United States. Electronic address: [email protected].
Spinal and bulbar muscular atrophy (SBMA) is an adult-onset degenerative
disorder of the neuromuscular system resulting in slowly progressive weakness
and atrophy of the proximal limb and bulbar muscles. The disease is caused by
the expansion of a CAG/glutamine tract in the amino-terminus of the androgen
receptor. That SBMA exclusively affects males reflects the fact that critical
pathogenic events are hormone-dependent. These include translocation of the
polyglutamine androgen receptor from the cytoplasm to the nucleus and unfolding
of the mutant protein. Studies of the pathology of SBMA subjects have revealed
nuclear aggregates of the mutant androgen receptor, loss of lower motor neurons
in the brainstem and spinal cord, and both neurogenic and myopathic changes in
skeletal muscle. Mechanisms underlying disease pathogenesis include toxicity in
both lower motor neurons and skeletal muscle, where effects on transcription,
intracellular transport, and mitochondrial function have been documented.
Therapies to treat SBMA patients remain largely supportive, although
experimental approaches targeting androgen action or promoting degradation of
the mutant androgen receptor protein or the encoding RNA are under active study.
Copyright © 2018 Elsevier B.V. All rights reserved.
DOI: 10.1016/B978-0-444-64076-5.00040-5
PMID: 29478604 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17854832 | 1. J Neurol Sci. 2008 Jan 15;264(1-2):100-5. doi: 10.1016/j.jns.2007.08.012. Epub
2007 Sep 12.
Spinal and bulbar muscular atrophy: skeletal muscle pathology in male patients
and heterozygous females.
Sorarù G(1), D'Ascenzo C, Polo A, Palmieri A, Baggio L, Vergani L, Gellera C,
Moretto G, Pegoraro E, Angelini C.
Author information:
(1)Department of Neurological Sciences, University of Padova, Italy.
[email protected]
Spinal and bulbar muscular atrophy (SBMA) is an adult form of X-linked motor
neuron disease caused by an expansion of a CAG repeat sequence in the first exon
of the androgen receptor (AR) gene. Nuclear accumulation of mutant AR with
expanded polyglutamines in motor neurons is a major pathogenic mechanism. To
characterize muscle involvement in SBMA the skeletal muscle biopsies of 8 SBMA
patients and 3 female carriers were studied. Six of 8 SBMA patients showed
myogenic changes together with the neurogenic atrophy in their muscle biopsy.
Myopathic abnormalities did not correlate with disease duration and were more
prominent in the muscle of patients with an higher degree of disability. In all
patients plasma CK levels were more elevated than what usually occurs in
denervative diseases. Both neurogenic and myopathic changes were also observed
in female carriers. Here we suggest that myopathic changes in SBMA muscle are
not only related to denervation and that muscle satellite cells may have a role
in the pathogenesis of muscle damage.
DOI: 10.1016/j.jns.2007.08.012
PMID: 17854832 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8545913 | 1. Trends Neurosci. 1995 Oct;18(10):459-61. doi: 10.1016/0166-2236(95)94497-s.
Spinal and bulbar muscular atrophy: a trinucleotide-repeat expansion
neurodegenerative disease.
Brooks BP(1), Fischbeck KH.
Author information:
(1)University of Pennsylvania School of Medicine, Dept of Neurology,
Philadelphia 19104, USA.
Spinal and bulbar muscular atrophy (SBMA) is an X-linked, adult-onset motor
neuronopathy that is caused by expansion of a trinucleotide (CAG) repeat in the
androgen-receptor gene. The length of this repeat varies as it is passed down
through SBMA families, and correlates inversely with the age of onset of the
disease. The motor-neuron degeneration that occurs in this disease is probably
caused by a toxic gain of function in the androgen-receptor protein. Subsequent
to the identification of the mutation in SBMA, other inherited neurodegenerative
diseases have been found to be caused by the expansion of CAG repeats in the
coding regions of other genes. Because these diseases probably share a common
pathogenesis, investigation of SBMA might help to determine a general mechanism
of neuronal degeneration.
DOI: 10.1016/0166-2236(95)94497-s
PMID: 8545913 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15133611 | 1. J Mol Med (Berl). 2004 May;82(5):298-307. doi: 10.1007/s00109-004-0530-7. Epub
2004 Feb 27.
Spinal and bulbar muscular atrophy: ligand-dependent pathogenesis and
therapeutic perspectives.
Katsuno M(1), Adachi H, Tanaka F, Sobue G.
Author information:
(1)Department of Neurology, Nagoya University Graduate School of Medicine, 65
Tsurumai-cho, Showa-ku, 466-8550 Nagoya, Japan.
Spinal and bulbar muscular atrophy (SBMA) is a late-onset motor neuron disease
characterized by proximal muscle atrophy, weakness, contraction fasciculations,
and bulbar involvement. SBMA exclusively affects males, while females are
usually asymptomatic. The molecular basis of SBMA is the expansion of a
trinucleotide CAG repeat, which encodes the polyglutamine (polyQ) tract in the
first exon of the androgen receptor (AR) gene. The histopathological hallmark is
the presence of nuclear inclusions containing mutant truncated ARs with expanded
polyQ tracts in the residual motor neurons in the brainstem and spinal cord, as
well as in some other visceral organs. The AR ligand, testosterone, accelerates
AR dissociation from heat shock proteins and thus its nuclear translocation.
Ligand-dependent nuclear accumulation of mutant ARs has been implicated in the
pathogenesis of SBMA. Transgenic mice carrying the full-length human AR gene
with an expanded polyQ tract demonstrate neuromuscular phenotypes, which are
profound in males. Their SBMA-like phenotypes are rescued by castration, and
aggravated by testosterone administration. Leuprorelin, an LHRH agonist that
reduces testosterone release from the testis, inhibits nuclear accumulation of
mutant ARs, resulting in the rescue of motor dysfunction in the male transgenic
mice. However, flutamide, an androgen antagonist promoting nuclear translocation
of the AR, yielded no therapeutic effect. The degradation and cleavage of the AR
protein are also influenced by the ligand, contributing to the pathogenesis.
Testosterone thus appears to be the key molecule in the pathogenesis of SBMA, as
well as main therapeutic target of this disease.
DOI: 10.1007/s00109-004-0530-7
PMID: 15133611 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20687495 | 1. Adv Exp Med Biol. 2010;685:64-74. doi: 10.1007/978-1-4419-6448-9_6.
Clinical features and molecular mechanisms of spinal and bulbar muscular atrophy
(SBMA).
Katsuno M(1), Banno H, Suzuki K, Adachi H, Tanaka F, Sobue G.
Author information:
(1)Department of Neurology, Nagoya University Graduate School of Medicine, 65
Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. [email protected]
Spinal and bulbar muscular atrophy (SBMA) is an adult-onset neurodegenerative
disease characterized by slowly progressive muscle weakness and atrophy. The
cause of this disease is the expansion of a trinucleotide CAG repeat, which
encodes the polyglutamine tract, within the first exon of the androgen receptor
(AR) gene. SBMA exclusively occurs in adult males, whereas both heterozygous and
homozygous females are usually asymptomatic. Lower motor neurons in the anterior
horn of the spinal cord and those in the brainstem motor nuclei are
predominantly affected in SBMA, and other neuronal and nonneuronal tissues are
also widely involved to some extent. Testosterone-dependent nuclear accumulation
of the pathogenic AR protein has been considered to be a fundamental step of
neurodegenerative process, which is followed by several molecular events such as
transcriptional dysregulation, axonal transport disruption and mitochondrial
dysfunction. Results of animal studies suggest that androgen deprivation and
activation of protein quality control systems are potential therapies for SBMA.
DOI: 10.1007/978-1-4419-6448-9_6
PMID: 20687495 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15111251 | 1. Neurotox Res. 2001 Jul;3(3):259-75. doi: 10.1007/BF03033265.
Characterization of intracellular aggregates using fluorescently-tagged
polyglutamine-expanded androgen receptor.
Panet-Raymond V(1), Gottlieb B, Beitel LK, Schipper H, Timiansky M, Pinsky L,
Trifiro MA.
Author information:
(1)Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish
General Hospital, 3755 Cote-Ste-Catherine Rd., Montreal, Quebec, Canada H3T 1E2.
Spinal bulbar muscular atrophy (SBMA) is a classic CAG-repeat neurodegenerative
disease. It is caused by expansion of a polyglutamine (polyGln) tract in the
androgen receptor (AR). Recent evidence has indicated a potential role for
nuclear and cytoplasmic inclusions in the pathogenesis of these diseases. We
have used blue and green fluorescently-tagged AR to show that both wild-type
(WT) and poly-Gln-expanded full-length AR can form aggregates and that
aggregation is not related to cytotoxicity. Twenty to thirty-five percent of all
cell types transfected into COS cells showed aggregation containing both amino-
and carboxy-terminal fluorescent tags. The aggregates reacted with (F39.4.1), an
anti-AR antibody and with IC2, an expanded polyGln tract antibody. Western
analysis of protein extracts revealed little evidence of proteolysis although
some cleavage of the fusion proteins was seen. The general caspase inhibitor,
Z-DEVD-FMK, did not affect aggregation in either wild type or polyGln-expanded
GFP-AR transfected cells. Surprisingly, addition of Mibolerone a synthetic
androgen significantly decreased inclusion formation in both WT and
polyGln-expanded AR-transfected cells. Overall, we show that both WT and polyGln
expanded full-length AR are found in aggregates and that proteolysis is not a
requirement for aggregation. Our results also suggest that toxicity is not
related to intracellular aggregation of polyGln expanded AR.
DOI: 10.1007/BF03033265
PMID: 15111251 |
http://www.ncbi.nlm.nih.gov/pubmed/24785145 | 1. Presse Med. 2014 May;43(5):580-6. doi: 10.1016/j.lpm.2014.03.005. Epub 2014
Apr 29.
[SBMA: a rare disease but a classic ALS mimic syndrome].
[Article in French]
Pradat PF(1).
Author information:
(1)AP-HP, groupe hospitalier Pitié-Salpêtrière, département des maladies du
système nerveux, 47, boulevard de l'Hôpital, 75651 Paris cedex, France; Sorbonne
universités, UPMC université Paris 06, Inserm, CNRS, laboratoire d'imagerie
biomédicale, 75006 Paris, France. Electronic address:
[email protected].
Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disorder of
lower motor neurons characterized by proximal limb muscular atrophy, bulbar
involvement, marked fasciculation, hand tremor and gynaecomastia. SBMA is caused
by a CAG-repeat expansion in the androgen receptor gene on the X-chromosome. Due
to its mode of transmission, only male are symptomatic and clinical features
appear progressively in adulthood. Motor signs and symptoms are restricted to
lower motor neuron involvement, in contrast with amyotrophic lateral sclerosis
(ALS) characterized by the association with upper motor neuron involvement. The
diminution of sensory potential at electroneuromyogram is a major criteria
discriminating between SBMA and ALS. Diagnostic confirmation is based on genetic
testing.
Copyright © 2014 Elsevier Masson SAS. All rights reserved.
DOI: 10.1016/j.lpm.2014.03.005
PMID: 24785145 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21952871 | 1. J Neurol. 2012 Apr;259(4):712-9. doi: 10.1007/s00415-011-6251-2. Epub 2011 Sep
28.
Difference in chronological changes of outcome measures between untreated and
placebo-treated patients of spinal and bulbar muscular atrophy.
Hashizume A(1), Katsuno M, Banno H, Suzuki K, Suga N, Tanaka F, Sobue G.
Author information:
(1)Department of Neurology, Nagoya University Graduate School of Medicine,
Nagoya 466-8550, Japan.
Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, X-linked motor
neuron disease characterized by muscle atrophy, weakness, and bulbar
involvement. The aim of this study was to analyze the differential change of
various outcome measures by comparing the progression of motor impairment in the
two independent groups: placebo-treated group (PTG) and natural history group
(NHG). For the PTG, we analyzed 99 patients who participated in a previous
double-blind phase III clinical trial and received placebo. For the NHG, a total
of 34 patients were followed with no specific treatment. The characteristics of
both groups did not differ at baseline except for disease duration. Although the
6 min walk distance (6MWD) showed almost the same progression in both groups
(-14.7 ± 7.3 m in NHG, -14.0 ± 4.7 m in PTG; NS), there was a significant
difference of progression in the ALSFRS-R between the NHG and PTG (-1.18 ± 0.38,
-0.14 ± 0.24; p = 0.03). A similar tendency was also seen in the subgroup
analysis of the patients whose disease durations were less than 10 years.
Although the relationship between the ALSFRS-R and 6MWD at week 48 was similar
to that at baseline in the NHG, the slope of the regression at week 48 was
significantly milder than at baseline in the PTG (p = 0.04). In conclusion,
these two groups demonstrated a large difference in the chronological analysis
of a motor function score, but showed similar changes in objective measures of
walking capacity. These findings should be thoroughly considered when designing
clinical trials for slowly progressive neurodegenerative diseases such as SBMA.
DOI: 10.1007/s00415-011-6251-2
PMID: 21952871 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35821212 | 1. Cell Death Dis. 2022 Jul 13;13(7):601. doi: 10.1038/s41419-022-05001-6.
Mid1 is associated with androgen-dependent axonal vulnerability of motor neurons
in spinal and bulbar muscular atrophy.
Ogura Y(1), Sahashi K(2), Hirunagi T(1), Iida M(1), Miyata T(3), Katsuno
M(4)(5).
Author information:
(1)Department of Neurology, Nagoya University Graduate School of Medicine,
Nagoya, Japan.
(2)Department of Neurology, Nagoya University Graduate School of Medicine,
Nagoya, Japan. [email protected].
(3)Department of Anatomy and Cell Biology, Nagoya University Graduate School of
Medicine, Nagoya, Japan.
(4)Department of Neurology, Nagoya University Graduate School of Medicine,
Nagoya, Japan. [email protected].
(5)Department of Clinical Research Education, Nagoya University Graduate School
of Medicine, Nagoya, Japan. [email protected].
Spinal and bulbar muscular atrophy (SBMA) is an adult-onset hereditary
neurodegenerative disease caused by the expansions of CAG repeats in the
androgen receptor (AR) gene. Androgen-dependent nuclear accumulation of
pathogenic AR protein causes degeneration of lower motor neurons, leading to
progressive muscle weakness and atrophy. While the successful induction of
SBMA-like pathology has been achieved in mouse models, mechanisms underlying
motor neuron vulnerability remain unclear. In the present study, we performed a
transcriptome-based screening for genes expressed exclusively in motor neurons
and dysregulated in the spinal cord of SBMA mice. We found upregulation of Mid1
encoding a microtubule-associated RNA binding protein which facilitates the
translation of CAG-expanded mRNAs. Based on the finding that lower motor neurons
begin expressing Mid1 during embryonic stages, we developed an organotypic slice
culture system of the spinal cord obtained from SBMA mouse fetuses to study the
pathogenic role of Mid1 in SBMA motor neurons. Impairment of axonal regeneration
arose in the spinal cord culture in SBMA mice in an androgen-dependent manner,
but not in mice with non-CAG-expanded AR, and was either exacerbated or
ameliorated by Mid1 overexpression or knockdown, respectively. Hence, an early
Mid1 expression confers vulnerability to motor neurons, at least by inducing
axonogenesis defects, in SBMA.
© 2022. The Author(s).
DOI: 10.1038/s41419-022-05001-6
PMCID: PMC9276699
PMID: 35821212 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/22158719 | 1. Arch Neurol. 2012 Apr;69(4):436-40. doi: 10.1001/archneurol.2011.2308. Epub
2011 Dec 12.
Molecular pathophysiology and disease-modifying therapies for spinal and bulbar
muscular atrophy.
Katsuno M(1), Banno H, Suzuki K, Adachi H, Tanaka F, Sobue G.
Author information:
(1)Department of Neurology, Nagoya University Graduate School of Medicine, 65
Tsurumai-cho, Showa-ku, Nagoya, Japan.
Spinal and bulbar muscular atrophy (SBMA), or Kennedy disease, is an adult-onset
lower motor neuron disease characterized by slowly progressive muscle weakness
and atrophy. The disease is caused by the expansion of a trinucleotide CAG
repeat encoding a polyglutamine tract within the first exon of the androgen
receptor (AR) gene. During the 2 decades since the discovery of the AR gene
mutation in SBMA, basic and clinical research have deepened our understanding of
the disease phenotype and pathophysiology. Spinal and bulbar muscular atrophy
exclusively affects men, whereas women homozygous for the AR mutation do not
fully develop the disease. The ligand-dependent nuclear accumulation of
pathogenic AR protein is central to the pathogenesis, although additional steps,
eg, DNA binding and interdomain interactions of AR, are required for toxicity.
Downstream molecular events, eg, transcriptional dysregulation, axonal transport
disruption, and mitochondrial dysfunction, are implicated in the
neurodegeneration in SBMA. Pathogenic AR-induced myopathy also contributes to
the degeneration of motor neurons. Several potential therapies, including
hormonal manipulation, have emerged from animal studies, some of which have been
tested in clinical trials.
DOI: 10.1001/archneurol.2011.2308
PMID: 22158719 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30006721 | 1. J Neurol. 2019 Mar;266(3):565-573. doi: 10.1007/s00415-018-8968-7. Epub 2018
Jul 13.
Kennedy's disease (spinal and bulbar muscular atrophy): a clinically oriented
review of a rare disease.
Breza M(1), Koutsis G(2).
Author information:
(1)Neurogenetics Unit, 1st Department of Neurology, Eginition Hospital, Medical
School, National and Kapodistrian University of Athens, 72-74 Vasilissis Sofias,
11528, Athens, Greece. [email protected].
(2)Neurogenetics Unit, 1st Department of Neurology, Eginition Hospital, Medical
School, National and Kapodistrian University of Athens, 72-74 Vasilissis Sofias,
11528, Athens, Greece.
Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a
rare, X-linked hereditary lower motor neuron disease, characterized by
progressive muscular weakness. An expanded trinucleotide repeat (CAG > 37) in
the androgen receptor gene (AR), encoding glutamine, is the mutation responsible
for Kennedy's disease. Toxicity of this mutant protein affects both motor
neurons and muscles. In this review, we provide a comprehensive, clinically
oriented overview of the current literature regarding Kennedy's disease,
highlighting gaps in our knowledge that remain to be addressed in further
research. Kennedy's disease mimics are also discussed, as are ongoing and
recently completed therapeutic endeavours.
DOI: 10.1007/s00415-018-8968-7
PMID: 30006721 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8749704 | 1. Ital J Neurol Sci. 1995 Oct;16(7):467-71. doi: 10.1007/BF02229324.
Kennedy's disease: clinical and molecular study of two Italian families.
Pareyson D(1), Castellotti B, Botti S, Defanti CA, Gellera C, Taroni F,
Sghirlanzoni A.
Author information:
(1)Divisione di Neurologia, Istituto Nazionale Neurologico C. Besta, IRCCS,
Milano.
Kennedy's disease, or spinal and bulbar muscular atrophy (SBMA), is a rare
X-linked motoneuron disorder with variable signs of androgen insensitivity. It
is associated with the expansion of a trinucleotide CAG repeat within the
androgen receptor (AR) gene. We here report our clinical and molecular findings
in two Italian families with Kennedy's disease. The increased size of the CAG
repeat was demonstrated in four affected males and seven carrier females.
DOI: 10.1007/BF02229324
PMID: 8749704 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19399234 | 1. Int J Mol Sci. 2009 Mar;10(3):1000-12. doi: 10.3390/ijms10031000. Epub 2009
Mar 10.
Neuropathology and therapeutic intervention in spinal and bulbar muscular
atrophy.
Banno H(1), Katsuno M, Suzuki K, Tanaka F, Sobue G.
Author information:
(1)Department of Neurology, Nagoya University Graduate School of Medicine,
Showa-ku, Japan. [email protected]
Spinal and bulbar muscular atrophy (SBMA) is a hereditary motor neuron disease
caused by the expansion of a polyglutamine tract in the androgen receptor (AR).
The histopathological finding in SBMA is loss of lower motor neurons in the
anterior horn of the spinal cord as well as in the brainstem motor nuclei.
Animal studies have revealed that the pathogenesis of SBMA depends on the level
of serum testosterone, and that androgen deprivation mitigates neurodegeneration
through inhibition of nuclear accumulation of the pathogenic AR. Heat shock
proteins, ubiquitin-proteasome system and transcriptional regulation are also
potential targets of therapy development for SBMA.
DOI: 10.3390/ijms10031000
PMCID: PMC2672015
PMID: 19399234 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19078709 | 1. J Clin Neuromuscul Dis. 2003 Jun;4(4):165-7. doi:
10.1097/00131402-200306000-00001.
Kennedy's Disease Initially Manifesting as an Endocrine Disorder.
Battaglia F(1), Le Galudec V, Cossee M, Tranchant C, Warter JM, Echaniz-Laguna
A.
Author information:
(1)From the *Département de Neurologie and the daggerService d'Endocrinologie et
des Maladies de la Nutrition, Hôpital Civil de Strasbourg, Strasbourg, France;
and the double daggerService de Diagnostic Génétique, CHRU de Strasbourg,
Faculté de Médecine, Strasbourg, France.
Spinal and bulbar muscular atrophy (SBMA, or Kennedy's disease) is an X-linked,
late-onset neuro-endocrine disorder characterized by degeneration of motor
neurons in the spinal cord and brainstem and partial androgen insensitivity. We
describe the case of a 59-year-old man who presented with diabetes mellitus,
hypercholesterolemia, testicular atrophy, gynecomastia, and elevated serum
creatine kinase (CK) levels. He did not have a familial history of motor neuron
disease or neuromuscular symptoms or physical signs. Electromyographic (EMG)
examination showed evidence of widespread denervation in muscles of different
segmental innervation. Genetic studies found an abnormal 43 CAG repeat in the
androgen receptor gene, leading to the diagnosis of SBMA. This report highlights
the fact that SBMA can present with a pure endocrine phenotype and an absence of
neuromuscular complaints or physical signs.
DOI: 10.1097/00131402-200306000-00001
PMID: 19078709 |
http://www.ncbi.nlm.nih.gov/pubmed/25811990 | 1. PLoS One. 2015 Mar 26;10(3):e0122279. doi: 10.1371/journal.pone.0122279.
eCollection 2015.
Genotype-phenotype correlation in Chinese patients with spinal and bulbar
muscular atrophy.
Ni W(1), Chen S(2), Qiao K(3), Wang N(1), Wu ZY(4).
Author information:
(1)Department of Neurology and Institute of Neurology, First Affiliated
Hospital, Fujian Medical University, Fuzhou, China.
(2)Department of Neurology and Institute of Neurology, First Affiliated
Hospital, Fujian Medical University, Fuzhou, China; Department of Neurology and
Institute of Neurology, Second Affiliated Hospital, Zhejiang University School
of Medicine, Hangzhou, China.
(3)Department of Neurology and Institute of Neurology, Huashan Hospital,
Shanghai Medical College, Fudan University, Shanghai, China.
(4)Department of Neurology and Institute of Neurology, First Affiliated
Hospital, Fujian Medical University, Fuzhou, China; Department of Neurology and
Institute of Neurology, Second Affiliated Hospital, Zhejiang University School
of Medicine, Hangzhou, China; Department of Neurology and Institute of
Neurology, Huashan Hospital, Shanghai Medical College, Fudan University,
Shanghai, China.
Spinal and bulbar muscular atrophy (SBMA) is an X-linked recessive motor neuron
disease characterized by slowly progressive weakness and atrophy of proximal
limbs and bulbar muscles. To assess the genotype-phenotype correlation in
Chinese patients, we identified 155 patients with SBMA and retrospectively
examined available data from laboratory tests and neurophysiological analyses.
Correlations between genotype and phenotype were analyzed. There was an inverse
correlation between the length of CAG repeats and age at first muscle weakness
(p<0.0001). The serum creatine kinase level showed a significant inverse
correlation with disease duration and the age at examination (p=0.019 and
p=0.004, respectively). Unlike previous classification of motor- and
sensory-dominant phenotypes, all findings of nerve conduction, except the
amplitudes of median nerve compound motor action potential, were positively
correlated to the length of CAG repeats. A significant decline in sensory nerve
action potential amplitudes may assist differential diagnosis of SBMA.
DOI: 10.1371/journal.pone.0122279
PMCID: PMC4374859
PMID: 25811990 [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/36152336 | 1. Am J Med Genet C Semin Med Genet. 2022 Jun;190(2):197-205. doi:
10.1002/ajmg.c.32000. Epub 2022 Sep 24.
Newborn screening for Duchenne muscular dystrophy-early detection and diagnostic
algorithm for female carriers of Duchenne muscular dystrophy.
Gruber D(1)(2), Lloyd-Puryear M(3), Armstrong N(4), Scavina M(4)(5), Tavakoli
NP(6), Brower AM(7), Caggana M(6), Chung WK(8).
Author information:
(1)Department of Pediatrics, Cohen Children's Medical Center, Northwell Health,
New Hyde Park, New York, USA.
(2)Departments of Pediatrics and Cardiology, Donald and Barbara Zucker School of
Medicine at Hofstra/Northwell, Hempstead, New York, USA.
(3)Eunice Kennedy Shriver National Institute of Child Health and Human
Development (Retired), National Institutes of Health, Bethesda, Maryland, USA.
(4)Parent Project Muscular Dystrophy, Washington, District of Columbia, USA.
(5)Nemours Children's Health, Delaware, Wilmington, Delaware, USA.
(6)Division of Genetics, Wadsworth Center, New York State Department of Health,
Albany, New York, USA.
(7)American College of Medical Genetics and Genomics, Bethesda, Maryland, USA.
(8)Department of Pediatrics, Columbia University Irving Medical Center, New
York, New York, USA.
Duchenne muscular dystrophy (DMD) is the most common pediatric-onset form of
muscular dystrophy, occurring in 1 in 5,000 live male births. DMD is a
multi-system disease resulting in muscle weakness with progressive deterioration
of skeletal, heart, and smooth muscle, and learning disabilities.
Pathogenic/likely pathogenic (P/LP) variants in the DMD gene, which encodes
dystrophin protein, cause dystrophinopathy. All males with a P/LP variant in the
X-linked DMD gene are expected to be affected. Two to 20% of female
heterozygotes with a P/LP variant develop symptoms of dystrophinopathy ranging
from mild muscle weakness to significant disability similar to Becker muscular
dystrophy. Recently, with improvements in therapies and testing methodology,
there is stronger evidence supporting newborn screening (NBS) for DMD for males
and females because females may also develop symptoms. A consented pilot study
to screen newborns for DMD was initiated in New York State (NYS) and conducted
from 2019 to 2021. The identification of female carriers and the realization of
the subsequent uncertainty of providers concerning follow-up during the pilot
led to the development of algorithms for screening and diagnosis of carrier
females, including both NBS and cascade molecular testing of family members.
© 2022 The Authors. American Journal of Medical Genetics Part C: Seminars in
Medical Genetics published by Wiley Periodicals LLC.
DOI: 10.1002/ajmg.c.32000
PMCID: PMC9826042
PMID: 36152336 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21155054 | 1. Yonsei Med J. 2011 Jan;52(1):192-5. doi: 10.3349/ymj.2011.52.1.192.
Three cases of manifesting female carriers in patients with Duchenne muscular
dystrophy.
Song TJ(1), Lee KA, Kang SW, Cho H, Choi YC.
Author information:
(1)Departments of 1Neurology and 2Laboratory Medicine, Brain Korea 21 Project
for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
Duchenne muscular dystrophy usually affects males. However, females are also
affected in rare instances. Approximately 8% of female Duchenne muscular
dystrophy (DMD) carriers are manifesting carriers and have muscle weakness to
some extent. We investigated the clinical features of 3 female patients with
dystrophinopathy diagnosed by clinical, pathological, and genetic studies at our
neuromuscular disease clinic. The onset age of manifesting symptoms varied (8-28
years). Muscle weakness grade varied as follows: patient 1 showed asymmetrical
bilateral proximal upper and lower extremities weakness, patient 2 showed
asymmetrical bilateral upper extremities weakness similar to scapulohumoral
muscular dystrophy, and patient 3 had only bilateral asymmetric proximal lower
extremities weakness. Two patients had familial histories of DMD (their sons
were diagnosed with DMD), but the 1 remaining patient had no familial history of
DMD. The serum creatine kinase level was elevated in all patients, but it was
not correlated with muscular weakness. An electromyography study showed findings
of myopathy in all patients. One patient was diagnosed with a DMD carrier by a
muscle biopsy with an immunohistochemical stain (dystrophin). The remaining 2
patients with familial history of DMD were diagnosed by multiplex
ligation-dependent probe amplification (MLPA). There were inconsistent clinical
features in the female carriers. An immunohistochemical analysis of dystrophin
could be useful for female carrier patients. Also, multiplex ligation-dependent
probe amplification is essential for the diagnosis of a manifesting female
carrier DMD in female myopathic patients because conventional multiplex PCR
could not detect the duplication and is less accurate compared to MLPA.
DOI: 10.3349/ymj.2011.52.1.192
PMCID: PMC3017697
PMID: 21155054 [Indexed for MEDLINE]
Conflict of interest statement: The authors have no financial conflicts of
interest. |
http://www.ncbi.nlm.nih.gov/pubmed/27660108 | 1. J Cardiovasc Magn Reson. 2016 Sep 22;18(1):61. doi: 10.1186/s12968-016-0281-y.
Myocardial late gadolinium enhancement is associated with clinical presentation
in Duchenne muscular dystrophy carriers.
Wexberg P(1)(2), Avanzini M(3), Mascherbauer J(4), Pfaffenberger S(4),
Freudenthaler B(3), Bittner R(5), Bernert G(6), Weidinger F(3).
Author information:
(1)2nd Medical Department, Krankenanstalt Rudolfstiftung, Vienna, Austria.
[email protected].
(2)SVA-Gesundheitszentrum, Hartmanngasse 2b, Vienna, A-1051, Austria.
[email protected].
(3)2nd Medical Department, Krankenanstalt Rudolfstiftung, Vienna, Austria.
(4)Division of Cardiology, Department Of Internal Medicine II, Medical
University of Vienna, Vienna, Austria.
(5)Neuromuscular Research Department, Center of Anatomy & Cell Biology, Medical
University of Vienna, Vienna, Austria.
(6)Gottfried von Preyer Children Hospital, Vienna, Austria.
BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked recessive disease
that occurs in males leading to immobility and death in early adulthood. Female
carriers of DMD are generally asymptomatic, yet frequently develop dilated
cardiomyopathy. This study aims to detect early cardiac manifestation in DMD
using cardiovascular magnetic resonance (CMR) and to evaluate its association
with clinical symptoms.
METHODS: Clinical assessment of DMD carriers included six minutes walk tests
(6MWT), blood analysis, electrocardiography, echocardiography, and CMR using
FLASH sequences to detect late gadolinium enhancement (LGE). T1-mapping using
the Modified Look-Locker Inversion recovery (MOLLI) sequence was performed
quantify extracellular volume (ECV).
RESULTS: Of 20 carriers (age 39.47 ± 12.96 years) 17 (89.5 %) were clinically
asymptomatic. ECV was mildly elevated (29.79 ± 2.92 %) and LGE was detected in
nine cases (45 %). LGE positive carriers had lower left ventricular ejection
fraction in CMR (64.36 ± 5.78 vs. 56.67 ± 6.89 %, p = 0.014), higher bothCK
(629.89 ± 317.48 vs. 256.18 ± 109.10 U/l, p = 0.002) and CK-MB (22.13 ± 5.25 vs.
12.11 ± 2.21 U/l, p = 0.001), as well as shorter walking distances during the
6MWT (432.44 ± 96.72 vs. 514.91 ± 66.80 m, p = 0.037). 90.9 % of subjects
without LGE had normal pro-BNP, whereas in 66.7 % of those presenting LGE
pro-BNP was elevated (p = 0.027). All individuals without LGE were in the NYHA
class I, whereas all those in NYHA classes II and III showed positive for LGE
(p = 0.066).
CONCLUSIONS: Myocardial involvement shown as LGE in CMR occurs in a substantial
number of DMD carriers; it is associated with clinical and morphometric signs of
incipient heart failure. LGE is thus a sensitive parameter for the early
diagnosis of cardiomyopathy in DMD carriers.
TRIAL REGISTRATION: Clinicaltrials.gov, NCT01712152 Trial registration: October
19, 2012. First patient enrolled: September 27, 2012 (retrospectively
registered).
DOI: 10.1186/s12968-016-0281-y
PMCID: PMC5034448
PMID: 27660108 |
http://www.ncbi.nlm.nih.gov/pubmed/32022138 | 1. Arq Neuropsiquiatr. 2020 Mar;78(3):143-148. doi: 10.1590/0004-282X20190168.
Epub 2020 Feb 3.
Functional performance and muscular strength in symptomatic female carriers of
Duchenne muscular dystrophy.
Silva THD(1), Anequini IP(1), Fávero FM(2), Voos MC(1), Oliveira ASB(2), Telles
JAR(1), Caromano FA(1).
Author information:
(1)Departamento de Fisioterapia, Fonoaudiologia e Terapia Ocupacional, Faculdade
de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.
(2)Departamento de Neurologia/Neurocirurgia, Escola Paulista de Medicina,
Universidade Federal de São Paulo, São Paulo, SP, Brazil.
Comment in
Arq Neuropsiquiatr. 2020 Sep;78(9):598-599. doi: 10.1590/0004-282X20200061.
Duchenne muscular dystrophy (DMD) usually affects men. However, women are also
affected in rare instances. Approximately 8% of female DMD carriers have muscle
weakness and cardiomyopathy. The early identification of functional and motor
impairments can support clinical decision making.
OBJECTIVE: To investigate the motor and functional impairments of 10 female
patients with dystrophinopathy diagnosed with clinical, pathological, genetic
and immunohistochemical studies.
METHODS: A descriptive study of a sample of symptomatic female carriers of DMD
mutations. The studied variables were muscular strength and functional
performance.
RESULTS: The prevalence was 10/118 (8.4%) symptomatic female carriers. Deletions
were found in seven patients. The age of onset of symptoms in female carriers of
DMD was quite variable. Pseudohypertrophy of calf muscles, muscular weakness,
compensatory movements and longer timed performance on functional tasks were
observed in most of the cases. Differently from males with DMD, seven female
patients showed asymmetrical muscular weakness. The asymmetric presentation of
muscle weakness was frequent and affected posture and functionality in some
cases. The functional performance presents greater number of compensatory
movements. Time of execution of activities was not a good biomarker of
functionality for this population, because it does not change in the same
proportion as the number of movement compensations.
CONCLUSION: Clinical manifestation of asymmetrical muscle weakness and
compensatory movements, or both can be found in female carriers of DMD
mutations, which can adversely affect posture and functional performance of
these patients.
DOI: 10.1590/0004-282X20190168
PMID: 32022138 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27098336 | 1. Hum Genet. 2016 Jul;135(7):685-98. doi: 10.1007/s00439-016-1666-6. Epub 2016
Apr 21.
Determining the role of skewed X-chromosome inactivation in developing muscle
symptoms in carriers of Duchenne muscular dystrophy.
Viggiano E(1), Ergoli M(1), Picillo E(1), Politano L(2).
Author information:
(1)Cardiomyology and Medical Genetics, Department of Experimental Medicine, I
Policlinico, Second University of Naples, Piazza Miraglia, 80138, Naples, Italy.
(2)Cardiomyology and Medical Genetics, Department of Experimental Medicine, I
Policlinico, Second University of Naples, Piazza Miraglia, 80138, Naples, Italy.
[email protected].
Duchenne and Becker dystrophinopathies (DMD and BMD) are X-linked recessive
disorders caused by mutations in the dystrophin gene that lead to absent or
reduced expression of dystrophin in both skeletal and heart muscles. DMD/BMD
female carriers are usually asymptomatic, although about 8 % may exhibit muscle
or cardiac symptoms. Several mechanisms leading to a reduced dystrophin have
been hypothesized to explain the clinical manifestations and, in particular, the
role of the skewed XCI is questioned. In this review, the mechanism of XCI and
its involvement in the phenotype of BMD/DMD carriers with both a normal
karyotype or with X;autosome translocations with breakpoints at Xp21 (locus of
the DMD gene) will be analyzed. We have previously observed that DMD carriers
with moderate/severe muscle involvement, exhibit a moderate or extremely skewed
XCI, in particular if presenting with an early onset of symptoms, while DMD
carriers with mild muscle involvement present a random XCI. Moreover, we found
that among 87.1 % of the carriers with X;autosome translocations involving the
locus Xp21 who developed signs and symptoms of dystrophinopathy such as proximal
muscle weakness, difficulty to run, jump and climb stairs, 95.2 % had a skewed
XCI pattern in lymphocytes. These data support the hypothesis that skewed XCI is
involved in the onset of phenotype in DMD carriers, the X chromosome carrying
the normal DMD gene being preferentially inactivated and leading to a
moderate-severe muscle involvement.
DOI: 10.1007/s00439-016-1666-6
PMID: 27098336 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24135430 | 1. J Neurol Sci. 2014 Jan 15;336(1-2):36-41. doi: 10.1016/j.jns.2013.09.036. Epub
2013 Oct 5.
Symptomatic female carriers of Duchenne muscular dystrophy (DMD): genetic and
clinical characterization.
Giliberto F(1), Radic CP(2), Luce L(1), Ferreiro V(3), de Brasi C(2), Szijan
I(4).
Author information:
(1)Genetica y Biologia Molecular, Facultad de Farmacia y Bioquimica, Universidad
de Buenos Aires, Argentina.
(2)Laboratorio de Genetica Molecular de Hemofilia, Instituto de Medicina
Experimental IMEX, CONICET-Academia Nacional de Medicina, Buenos Aires,
Argentina.
(3)Laboratorio de Genetica Molecular Diagnostica (GENOS S.A.), Buenos Aires,
Argentina.
(4)Genetica y Biologia Molecular, Facultad de Farmacia y Bioquimica, Universidad
de Buenos Aires, Argentina. Electronic address: [email protected].
Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused by
mutations in the dystrophin gene and is characterized by muscle degeneration and
death. DMD affects males; females being asymptomatic carriers of mutations.
However, some of them manifest symptoms due to a translocation between X
chromosome and an autosome or to a heterozygous mutation leading to inactivation
of most of their normal X chromosome. Six symptomatic female carriers and two
asymptomatic were analyzed by: I) Segregation of STRs-(CA)n and MLPA assays to
detect a hemizygous alteration, and II) X chromosome inactivation pattern to
uncover the reason for symptoms in these females. The symptomatic females shared
mild but progressive muscular weakness and increased serum creatin kinase (CK)
levels. Levels of dystrophin protein were below normal or absent in many fibers.
Segregation of STRs-(CA)n revealed hemizygous patterns in three patients, which
were confirmed by MLPA. In addition, this analysis showed a duplication in
another patient. X chromosome inactivation assay revealed a skewed X
inactivation pattern in the symptomatic females and a random inactivation
pattern in the asymptomatic ones. Our results support the hypothesis that the
DMD phenotype in female carriers of a dystrophin mutation has a direct
correlation with a skewed X-chromosome inactivation pattern.
© 2013.
DOI: 10.1016/j.jns.2013.09.036
PMID: 24135430 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26113120 | 1. Eur Heart J Cardiovasc Imaging. 2016 Mar;17(3):326-33. doi:
10.1093/ehjci/jev161. Epub 2015 Jun 25.
Cardiac involvement in female Duchenne and Becker muscular dystrophy carriers in
comparison to their first-degree male relatives: a comparative cardiovascular
magnetic resonance study.
Florian A(1), Rösch S(2), Bietenbeck M(1), Engelen M(1), Stypmann J(1),
Waltenberger J(1), Sechtem U(2), Yilmaz A(3).
Author information:
(1)Department of Cardiology and Angiology, University Hospital Münster,
Albert-Schweitzer-Campus 1, Building A1, Münster 48149, Germany.
(2)Division of Cardiology, Robert-Bosch-Krankenhaus, Stuttgart, Germany.
(3)Department of Cardiology and Angiology, University Hospital Münster,
Albert-Schweitzer-Campus 1, Building A1, Münster 48149, Germany
[email protected] [email protected].
AIMS: Duchenne (DMD) and Becker (BMD) muscular dystrophies are X-linked
recessive disorders associated with both skeletal myopathy and progressive
cardiomyopathy in males. Female DMD/BMD carriers (DMDc/BMDc) are mostly free of
skeletal muscle symptoms, but they are also prone to cardiomyopathy. The aim of
the current study was to characterize the frequency, pattern, and extent of
cardiomyopathy in female DMD/BMD carriers (DMDc/BMDc) in comparison to their
first-degree male MD relatives.
METHODS AND RESULTS: Thirty-six (age 44 ± 14 years) female MD carriers (20 DMDc
and 16 BMDc) constituted the 'MD carrier group' and were prospectively enrolled.
All MD carriers underwent a complete CMR study comprising cine- and late
gadolinium enhancement (LGE) imaging. In 22 of these women ('female MD carrier
comparison group', 7 DMD and 15 BMD), at least one first-degree male relative
with a previously established diagnosis of MD underwent the same CMR protocol
and was assigned to the 'male MD comparison group' (n = 24, 6 DMD and 18 BMD).
In the total MD carrier group, 17 (47%) MD carriers had at least one
pathological CMR finding [5 (14%) with a reduced left ventricular ejection
fraction (LV-EF) and 16 (44%) with the presence of LGE]. All LGE-positive
patients (n = 16) showed non-ischaemic LGE with subepicardial involvement of the
LV lateral free wall being the most frequent pattern (13/16, 81%). Compared with
BMDc, DMDc demonstrated more frequently a pathological CMR result (65 vs. 19%; P
= 0.008)--in spite of being significantly younger (40 ± 11 vs. 50 ± 16 years, P
= 0.038). In the male MD comparison group, the same LGE pattern as in female
carriers was seen, but with a significantly higher prevalence of cardiac
abnormalities compared with their female carrier relatives constituting the
female MD comparison group (75 vs. 27%; P = 0.003).
CONCLUSION: Cardiac involvement is a frequent finding in female carriers of DMD,
but less frequently observed in carriers of BMD. Those DMDc and BMDc with
cardiac involvement demonstrate the same myocardial fibrosis pattern as their
male counterparts with overt disease.
Published on behalf of the European Society of Cardiology. All rights reserved.
© The Author 2015. For permissions please email: [email protected].
DOI: 10.1093/ehjci/jev161
PMID: 26113120 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31326192 | 1. Neuromuscul Disord. 2019 Jul;29(7):487-496. doi: 10.1016/j.nmd.2019.05.003.
Epub 2019 May 10.
Inflammation-induced fibrosis in skeletal muscle of female carriers of Duchenne
muscular dystrophy.
Preuße C(1), von Moers A(2), Kölbel H(3), Pehl D(4), Goebel HH(5), Schara U(3),
Stenzel W(6).
Author information:
(1)Department of Neuropathology, Charité - Universitätsmedizin, Charité Campus
Mitte, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu
Berlin, and Berlin Institute of Health (BIH), Berlin, Germany; Department of
Paediatrics and Neuropaediatrics, DRK Klinikum Westend, Berlin, Germany.
(2)Department of Paediatrics and Neuropaediatrics, DRK Klinikum Westend, Berlin,
Germany.
(3)Department of Neuropaediatrics, Neuromuscular Centre, Universitätsklinikum,
Essen, Germany.
(4)Department of Neuropathology, Charité - Universitätsmedizin, Charité Campus
Mitte, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu
Berlin, and Berlin Institute of Health (BIH), Berlin, Germany.
(5)Department of Neuropathology, Charité - Universitätsmedizin, Charité Campus
Mitte, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu
Berlin, and Berlin Institute of Health (BIH), Berlin, Germany; Department of
Neuropathology, Universitätsmedizin Mainz, Mainz, Germany.
(6)Department of Neuropathology, Charité - Universitätsmedizin, Charité Campus
Mitte, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu
Berlin, and Berlin Institute of Health (BIH), Berlin, Germany. Electronic
address: [email protected].
Female carriers of DMD gene mutations may be symptomatic and show variable
skeletal as well as cardiac muscle symptoms. Skeletal muscle can exhibit
morphological alterations. However, inflammatory, degenerative and fibrotic
changes as seen in Duchenne boys have not been specifically analysed yet, so we
addressed the question whether skeletal muscle of female carriers show such
alterations. Thirteen carriers with an age range of 3 to 50 years were studied
retrospectively. Five out of 13 women had clinically affected relatives.
Clinically, most women showed mild muscle weakness, while the CK levels were
increased in nine of them. Histomorphological analyses highlighted the typical
mosaic pattern of dystrophin-positive and -negative fibres. Regenerating fibres
were diffusely scattered and focally pronounced, while endo- and perimysial
fibrosis was a variable but constant feature. Infiltration of CD206+TGFß+
macrophages and scattered T cells was noted in the endomysium. TGFb and CCL18,
were significantly increased. However, gene expression of markers involved in
Th1/Th2 immunity did not reach statistical significance compared to non-diseased
controls. In summary, skeletal muscle of clinically manifest female DMD gene
mutation carriers shows mild fibrosis and increased regeneration associated with
endomysial CD206+TGFβ+ and STAT6+ macrophages, which are most likely involved in
fibrotic remodelling.
Copyright © 2019 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.nmd.2019.05.003
PMID: 31326192 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33788896 | 1. PLoS One. 2021 Mar 31;16(3):e0249472. doi: 10.1371/journal.pone.0249472.
eCollection 2021.
Impact of estrogen deficiency on diaphragm and leg muscle contractile function
in female mdx mice.
Vang P(1), Baumann CW(1), Barok R(1), Larson AA(2), Dougherty BJ(1)(3), Lowe
DA(1)(3).
Author information:
(1)Division of Rehabilitation Science, Department of Rehabilitation Medicine,
University of Minnesota, Minneapolis, Minnesota, United States of America.
(2)Department of Integrative Biology and Physiology, University of Minnesota,
Minneapolis, Minnesota, United States of America.
(3)Division of Physical Therapy, Department of Rehabilitation Medicine,
University of Minnesota, Minneapolis, Minnesota, United States of America.
Female carriers of Duchenne muscular dystrophy (DMD) presenting with DMD
symptomology similar to males with DMD, such as skeletal muscle weakness and
cardiomyopathy, are termed manifesting carriers. There is phenotypic variability
among manifesting carriers including the age of onset, which can range from the
first to fourth decade of life. In females, estrogen levels typically begin to
decline during the fourth decade of life and estrogen deficiency contributes to
loss of muscle strength and recovery of strength following injury. Thus, we
questioned whether the decline of estrogen impacts the development of DMD
symptoms in females. To address this question, we studied 6-8 month-old
homozygous mdx female mice randomly assigned to a sham or ovariectomy (OVX)
surgical group. In vivo whole-body plethysmography assessed ventilatory function
and diaphragm muscle strength was measured in vitro before and after fatigue.
Anterior crural muscles were analyzed in vivo for contractile function, fatigue,
and in response to eccentric contraction (ECC)-induced injury. For the latter,
50 maximal ECCs were performed by the anterior crural muscles to induce injury.
Body mass, uterine mass, hypoxia-hypercapnia ventilatory response, and fatigue
index were analyzed by a pooled unpaired t-test. A two-way ANOVA was used to
analyze ventilatory measurements. Fatigue and ECC-injury recovery experiments
were analyzed by a two-way repeated-measures ANOVA. Results show no differences
between sham and OVX mdx mice in ventilatory function, strength, or recovery of
strength after fatigue in the diaphragm muscle or anterior crural muscles (p ≥
0.078). However, OVX mice had significantly greater eccentric torque loss and
blunted recovery of strength after ECC-induced injury compared to sham mice (p ≤
0.019). Although the results show that loss of estrogen has minimal impact on
skeletal muscle contractile function in female mdx mice, a key finding suggests
that estrogen is important in muscle recovery in female mdx mice after injury.
DOI: 10.1371/journal.pone.0249472
PMCID: PMC8011782
PMID: 33788896 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/26718981 | 1. Pediatr Neurol. 2016 Feb;55:58-63. doi: 10.1016/j.pediatrneurol.2015.11.004.
Epub 2015 Nov 26.
Genetic and Early Clinical Manifestations of Females Heterozygous for
Duchenne/Becker Muscular Dystrophy.
Papa R(1), Madia F(2), Bartolomeo D(1), Trucco F(1), Pedemonte M(1), Traverso
M(2), Broda P(1), Bruno C(3), Zara F(2), Minetti C(4), Fiorillo C(5).
Author information:
(1)Paediatric Neurology and Neuromuscular Disorders Unit, Istituto G. Gaslini,
Genoa, Italy.
(2)Laboratory of Neurogenetics and Neuroscience, Istituto G.Gaslini, Genoa,
Italy.
(3)Centre of Myology and Neurodegenerative Disorders, Istituto G.Gaslini, Genoa,
Italy.
(4)Paediatric Neurology and Neuromuscular Disorders Unit, Istituto G. Gaslini,
Genoa, Italy; DINOGMI, University of Genoa, Genoa, Italy.
(5)DINOGMI, University of Genoa, Genoa, Italy. Electronic address:
[email protected].
BACKGROUND: Female carriers of Duchenne muscular dystrophy (DMD), although
usually asymptomatic, develop muscle weakness up to 17% of the time, and a third
present cardiac abnormalities or cognitive impairment. Clinical features of DMD
carriers during childhood are poorly known.
PATIENTS: We describe a cohort of pediatric DMD carriers, providing clinical,
genetic, and histopathologic features, with a mean follow-up of 7 years.
RESULTS: Fifteen females with a DMD mutation (age range 5 to 18 years) were
included. Seven patients (46%) presented with clinically evident symptoms and
signs such as limb girdle weakness, abnormal gait, and exercise intolerance. The
other eight patients (53%) were evaluated because of an incidental finding of
elevated level of creatine kinase. Creatine kinase level was elevated in all,
ranging from 392 to 13,000 U/L. Calf hypertrophy was observed in eight patients
(53%). No patient developed respiratory or cardiac involvement. The most
frequent complication was scoliosis (46%). Four patients (29%) also presented
minor learning disabilities or behavioral problems. We performed
electromyography in half of patients, showing myopathic pattern in four (53%).
Muscle biopsy revealed a mosaic reduction of dystrophin in nine available cases.
DMD gene mutations were mostly deletions (71%), resulting in loss of reading
frame in five patients (36%). The three patients who experienced the most severe
disease course were affected either by a nonsense or frameshift mutation.
CONCLUSIONS: Our analysis suggests that DMD gene mutations may be suspected in a
female child with persistently elevated levels of creatine kinase. Evidence of
scoliosis, calf hypertrophy, or myopathic pattern at electromyography may also
be helpful, and muscle biopsy is always indicative. DMD carriers should be
followed for subtle orthopedic and psychiatric complications during childhood.
Copyright © 2016 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.pediatrneurol.2015.11.004
PMID: 26718981 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10674846 | 1. Intern Med. 2000 Jan;39(1):34-8. doi: 10.2169/internalmedicine.39.34.
A female carrier of Duchenne muscular dystrophy complicated with cardiomyopathy.
Ogata H(1), Nakagawa H, Hamabe K, Hattori A, Ishikawa Y, Ishikawa Y, Saito M,
Minami R.
Author information:
(1)Department of Internal Medicine, Sapporo Social Insurance General Hospital.
Comment in
Intern Med. 2000 Jan;39(1):2-3. doi: 10.2169/internalmedicine.39.2.
A 45-year-old female carrier of Duchenne muscular dystrophy (DMD) complicated
with cardiomyopathy is described. She had no symptoms of muscle weakness or
heart failure. Her chest X-ray film revealed marked cardiomegaly. Echocardiogram
showed marked enlargement and severe hypokinesis of the left ventricle. In
myocardial scintigraphic images, perfusion defects of the myocardium were
revealed. Dystrophin immunostaining of myocardial biopsy specimens showed a
mosaic pattern of dystrophin-negative and -positive fibers. Cardiomyopathy is
sometimes the only clinical symptom in female carriers of DMD. They are thought
to be in a high risk group for developing heart failure.
DOI: 10.2169/internalmedicine.39.34
PMID: 10674846 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29862154 | 1. Intractable Rare Dis Res. 2018 May;7(2):120-125. doi: 10.5582/irdr.2018.01003.
Muscular and cardiac manifestations in a Duchenne-carrier harboring a dystrophin
deletion of exons 12-29.
Finsterer J(1), Stöllberger C(2), Freudenthaler B(2), Simoni D(3), Höftberger
R(3), Wagner K(4).
Author information:
(1)Krankenanstalt Rudolfstiftung, Vienna, Austria.
(2)2nd Medical Department with Cardiology and Intensive Care Medicine,
Krankenanstalt Rudolfstiftung, Vienna, Austria.
(3)Institute of Neurology, Medical University of Vienna, Vienna, Austria.
(4)Institute for Human Genetics, Medical University of Graz, Graz, Austria.
Female carriers of mutations in the dystrophin gene (DMD-carriers) may manifest
clinically in the skeletal muscle, the heart, or both. Cardiac involvement may
manifest before, after, or together with the muscle manifestations. A 46y female
developed slowly progressive weakness of the lower and upper limbs with
left-sided predominance since age 26y. Muscle enzymes were repeatedly elevated
and muscle biopsy showed absence of dystrophin. MLPA analysis revealed a
deletion of exons 12-29. After starting steroids at age 39y, she developed
palpitations and exertional dyspnoea. Cardiac MRI at age 41y revealed mildly
reduced systolic function, a slightly enlarged left ventricle, mild hypokinesia
of the entire myocardium, and focal, transmural late gadolinium enhancement
(LGE) of the midventricular lateral wall. She did not tolerate beta-blockers but
profited from ivabradine and lisinopril. In conclusion, muscle manifestations in
DMD-carriers with deletions of exons 12-29 may start years before cardiac
involvement becomes clinically apparent. Progressive worsening of systolic
function in DMD-carriers is attributable to progressive myocardial fibrosis, as
demonstrated by LGE. Steroids may trigger the development of cardiac disease in
DMD-carriers.
DOI: 10.5582/irdr.2018.01003
PMCID: PMC5982619
PMID: 29862154 |
http://www.ncbi.nlm.nih.gov/pubmed/10382696 | 1. Lancet. 1999 Jun 19;353(9170):2116-9. doi: 10.1016/s0140-6736(98)10028-4.
Signs and symptoms of Duchenne muscular dystrophy and Becker muscular dystrophy
among carriers in The Netherlands: a cohort study.
Hoogerwaard EM(1), Bakker E, Ippel PF, Oosterwijk JC, Majoor-Krakauer DF,
Leschot NJ, Van Essen AJ, Brunner HG, van der Wouw PA, Wilde AA, de Visser M.
Author information:
(1)Department of Neurology, Academic Medical Centre, Amsterdam, The Netherlands.
BACKGROUND: Carriers of Duchenne muscular dystrophy (DMD) and Becker muscular
dystrophy (BMD) may show muscle weakness or dilated cardiomyopathy. Studies
focusing on skeletal-muscle involvement were done before DNA analysis was
possible. We undertook a cross-sectional study in a population of definite
carriers to estimate the proportion and to assess the clinical profile of
carriers with symptoms. We also assessed a possible correlation between genotype
and phenotype.
METHODS: Carriers of DMD and BMD, aged 18-60 years, were traced through the
files of the central register kept at the Department of Human Genetics in
Leiden, Netherlands. For each carrier who agreed to participate a medical
history was taken, and muscle-strength assessment by hand-held dynamometry and
manual muscle testing and cardiological assessment were done.
FINDINGS: 129 carriers of muscular dystrophy (85 DMD, 44 BMD) participated in
the study. In 90 women from 52 (70%) families, 37 different mutations were
found. 28 (22%) women had symptoms. 22 (17%) had muscle weakness, varying from
mild to moderately severe. Muscle weakness was found in carriers of DMD and BMD,
but dilated cardiomyopathy was found only in seven (8%) carriers of DMD, of whom
one had concomitant muscle weakness. There was an unexpectedly high proportion
of left-ventricle dilation (18%). No genotype-phenotype correlation was found.
INTERPRETATION: Clinical manifestation of muscle weakness, dilated
cardiomyopathy, or both can be found in about a fifth of carriers of DMD and
BMD. If left-ventricle dilation is taken into account, the proportion of
carriers with symptoms is even higher, amounting to 40%.
DOI: 10.1016/s0140-6736(98)10028-4
PMID: 10382696 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32762558 | 1. Am J Physiol Heart Circ Physiol. 2020 Sep 1;319(3):H582-H603. doi:
10.1152/ajpheart.00333.2019. Epub 2020 Aug 7.
Enhanced dimethylarginine degradation improves coronary flow reserve and
exercise tolerance in Duchenne muscular dystrophy carrier mice.
Garbincius JF(1), Merz LE(1), Cuttitta AJ(1), Bayne KV(1), Schrade S(1),
Armstead EA(1), Converso-Baran KL(2), Whitesall SE(1)(2), D'Alecy LG(1)(2),
Michele DE(1)(2)(3).
Author information:
(1)Department of Molecular and Integrative Physiology, University of Michigan,
Ann Arbor, Michigan.
(2)Physiology Phenotyping Core, University of Michigan, Ann Arbor, Michigan.
(3)Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
Duchenne muscular dystrophy (DMD) is an X-linked disease caused by null
mutations in dystrophin and characterized by muscle degeneration. Cardiomyopathy
is common and often prevalent at similar frequency in female DMD carriers
irrespective of whether they manifest skeletal muscle disease. Impaired muscle
nitric oxide (NO) production in DMD disrupts muscle blood flow regulation and
exaggerates postexercise fatigue. We show that circulating levels of endogenous
methylated arginines including asymmetric dimethylarginine (ADMA), which act as
NO synthase inhibitors, are elevated by acute necrotic muscle damage and in
chronically necrotic dystrophin-deficient mice. We therefore hypothesized that
excessive ADMA impairs muscle NO production and diminishes exercise tolerance in
DMD. We used transgenic expression of dimethylarginine dimethylaminohydrolase 1
(DDAH), which degrades methylated arginines, to investigate their contribution
to exercise-induced fatigue in DMD. Although infusion of exogenous ADMA was
sufficient to impair exercise performance in wild-type mice, transgenic DDAH
expression did not rescue exercise-induced fatigue in dystrophin-deficient male
mdx mice. Surprisingly, DDAH transgene expression did attenuate exercise-induced
fatigue in dystrophin-heterozygous female mdx carrier mice. Improved exercise
tolerance was associated with reduced heart weight and improved cardiac
β-adrenergic responsiveness in DDAH-transgenic mdx carriers. We conclude that
DDAH overexpression increases exercise tolerance in female DMD carriers,
possibly by limiting cardiac pathology and preserving the heart's responses to
changes in physiological demand. Methylated arginine metabolism may be a new
target to improve exercise tolerance and cardiac function in DMD carriers or act
as an adjuvant to promote NO signaling alongside therapies that partially
restore dystrophin expression in patients with DMD.NEW & NOTEWORTHY Duchenne
muscular dystrophy (DMD) carriers are at risk for cardiomyopathy. The nitric
oxide synthase inhibitor asymmetric dimethylarginine (ADMA) is released from
damaged muscle in DMD and impairs exercise performance. Transgenic expression of
dimethylarginine dimethylaminohydrolase to degrade ADMA prevents cardiac
hypertrophy, improves cardiac function, and improves exercise tolerance in DMD
carrier mice. These findings highlight the relevance of ADMA to muscular
dystrophy and have important implications for therapies targeting nitric oxide
in patients with DMD and DMD carriers.
DOI: 10.1152/ajpheart.00333.2019
PMCID: PMC7509273
PMID: 32762558 [Indexed for MEDLINE]
Conflict of interest statement: No conflicts of interest, financial or
otherwise, are declared by the authors. |
http://www.ncbi.nlm.nih.gov/pubmed/25976773 | 1. Pediatr Cardiol. 2015 Oct;36(7):1495-501. doi: 10.1007/s00246-015-1192-7. Epub
2015 May 16.
Myocardial Fibrosis and Left Ventricular Dysfunction in Duchenne Muscular
Dystrophy Carriers Using Cardiac Magnetic Resonance Imaging.
Lang SM(1), Shugh S(2), Mazur W(3), Sticka JJ(2), Rattan MS(4), Jefferies JL(2),
Taylor MD(2).
Author information:
(1)Arkansas Children's Hospital, University of Arkansas for Medical Sciences, 1
Children's Way, Little Rock, AR, USA. [email protected].
(2)The Heart Institute, Cincinnati Children's Hospital Medical Center, 3333
Burnet Ave, Cincinnati, OH, USA.
(3)The Ohio Heart and Vascular Center at The Christ Hospital, 2123 Auburn Ave,
Suite 138, Cincinnati, OH, USA.
(4)Department of Radiology, Cincinnati Children's Hospital Medical Center, 3333
Burnet Ave, Cincinnati, OH, USA.
The goal of our study was to characterize the degree of myocardial fibrosis and
left ventricular dysfunction in our cohort of Duchenne muscular dystrophy (DMD)
carriers using cardiac magnetic resonance imaging (CMR). Seventy percent of
males with DMD have mothers who are carriers of the Xp21 mutation. Carrier
phenotypic characteristics range from asymptomatic to left ventricular (LV)
dysfunction and cardiomyopathy. The true prevalence of cardiac involvement in
DMD carriers is unknown. We performed a retrospective observational study. All
female DMD carriers who underwent clinical CMR studies at Cincinnati Children's
Hospital Medical Center from December 6, 2006, to August 28, 2013, were
evaluated. Patients underwent standard CMR assessment with LV function
assessment and late gadolinium enhancement (LGE). In addition, offline feature
tracking strain analysis was performed on the basal, mid, and apical short axis.
Twenty-two patients were studied, of which 20 underwent adequate testing for
myocardial LGE. Four of 22 patients (18 %) were found to have LV dysfunction
(ejection fraction <55 %). Seven of 20 DMD carriers (35 %) were found to have
LGE. The patients with evidence of LGE had an overall trend to lower absolute
deformation parameters; however, this did not meet statistical significance when
correcting for multiple comparisons. Our study demonstrates a high rate of LGE
as well as LV dysfunction in DMD carriers. Cardiovascular and musculoskeletal
symptoms were not statistically different between those with and without cardiac
involvement. This study demonstrates the importance of surveillance CMR
evaluation of DMD carriers.
DOI: 10.1007/s00246-015-1192-7
PMID: 25976773 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24846915 | 1. Yi Chuan. 2014 Jan;36(1):21-9. doi: 10.3724/sp.j.1005.2014.00021.
[Research progress in the mouse models of Charcot-Marie-Tooth disease type 2
(CMT2)].
[Article in Chinese]
Yu Z(1), Luan C(1), Gu M(1).
Author information:
(1)Department of Medical Genetics, Shanghai Jiao Tong University School of
Medicine, Shanghai 200025, China.
Charcot-Marie-Tooth disease (CMT) is a kind of common hereditary motor and
sensory neuropathies with a global prevalence of about 1 in 2500. Clinically,
CMT can be divided into two main types: a demyelinating type (CMT1, CMT3, CMT4
and CMTX1) and an axonal type (CMT2). Up to now, about 17 unique genes related
to CMT2 have been mapped and cloned. However, the pathogenesis of these
disease-causing genes is still unknown. The mouse models have been playing an
important role in understanding the molecular mechanism of CMT2. Recently, near
10 transgenic, knock-in and knock-out mouse models of CMT2 have been generated.
In this review, we briefly introduce the construction strategy of the CMT2 mouse
models, summarize the research progress of the CMT2 mouse models, and analyze in
detail a few typical mouse models of CMT2.
DOI: 10.3724/sp.j.1005.2014.00021
PMID: 24846915 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34540429 | 1. Cureus. 2021 Aug 15;13(8):e17201. doi: 10.7759/cureus.17201. eCollection 2021
Aug.
Impact of Customized and Sustained Physiotherapy in Charcot-Marie-Tooth Disease.
Chitapure T(1), Jethwani D(2), Zubair Ahmed S(3), Panigrahy C(4).
Author information:
(1)Assistant Professor, MGM School of Physiotherapy, Aurangabad, a constituent
unit of MGMIHS, Navi Mumbai, IND.
(2)Associate Professor, Department of Physiotherapy, Tilak Maharashtra
Vidyapeeth Jayantrao Tilak College of Physiotherapy, Pune, IND.
(3)Neurophysiotherapy, Royal College of Physiotherapy, Malegaon, IND.
(4)Musculoskeletal Physiotherapy, Tilak Maharashtra Vidyapeeth Jayantrao Tilak
College of Physiotherapy, Pune, IND.
Charcot-Marie-Tooth (CMT) disease is the most inherited form of peripheral
neuropathy. This condition is also known as hereditary motor and sensory
neuropathy (HMSN), which is a slowly progressive neuropathy affecting peripheral
nerves and causes sensory loss, weakness and muscle wasting. This primarily
involves distal muscles of feet, lower legs, hands and forearm. CMT is the most
frequently inherited peripheral neuropathy known to affect 1 in 2500
individuals. There are four types: CMT1, CMT2, CMT3 and CMT4, depending upon the
involvement of specific gene deficit, inheritance pattern, age of onset and
whether the primary defect results in an abnormality of the myelin or axon of
the nerve. Diagnosis of CMT is done based on physical examination, genetic
testing, and electromyography (EMG) and nerve conduction velocity (NCV) test
results. Symptoms of weakness progress from distal to proximal, i.e., it begins
from feet and ankles. CMT is a known length dependent neuropathy which results
in foot drop and later weakness of hands and forearm becomes evident. Due to the
involvement of sensory nerve fibres, sensations like heat, touch, pain and most
prominently vibration is also present distally. Long standing effects of CMT
leads to the development of deformity and/or contractures which may involve
forefoot, hindfoot, toes and/or long finger flexors. As physiotherapy is a means
to maintain and/or gain maximum possible functional independence, consistency of
the treatment becomes the most important factor. This case report intends to
show that consistency in performing physiotherapeutic exercises helps in gaining
maximum possible functional independence. This case report is a discussion of a
25-year-old male patient referred to the physiotherapy department with the
polyneuropathy type symptoms with his history and investigation reports being
consistent with that of Charcot-Marie-Tooth disease.
Copyright © 2021, Chitapure et al.
DOI: 10.7759/cureus.17201
PMCID: PMC8439527
PMID: 34540429
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/9686263 | 1. Rev Neurol (Paris). 1997 Dec;153(12):727-36.
[Charcot-Marie-Tooth disease: electromyography is still useful in diagnosis and
classification].
[Article in French]
Birouk N(1), Maisonobe T, Le Forestier N, Gouider R, Léger JM, Bouche P.
Author information:
(1)Service d'Explorations Fonctionnelles, Neurologie, Hôpital de la Salpêtrière,
Paris.
Genetic heterogeneity was known for a long time in Charcot-Marie-Tooth disease
(CMT). The recent findings in molecular biology emphasized the distinction in
different types of the disease. Nevertheless, electrophysiological examinations
are of a great interest to detect asymptomatic patients, to classify the
different forms and to make correlations with the clinical and histological
features. Current classification is based on genetic and electrophysiologic
data. CMT1, or hypertrophic form in which mutations or a duplication were found
on chromosome 17 is the most frequent (CMT1A), CMT2 is the neuronal form, CMT3
is termed the Dejerine-Sottas disease, CMT4 recessive forms, CMT5 a form with
associated pyramidal features, and CMTX. The electrophysiologic aspects of these
different types are reported.
PMID: 9686263 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32504000 | 1. Sci Rep. 2020 Jun 5;10(1):9262. doi: 10.1038/s41598-020-66266-5.
Energy metabolism and mitochondrial defects in X-linked Charcot-Marie-Tooth
(CMTX6) iPSC-derived motor neurons with the p.R158H PDK3 mutation.
Perez-Siles G(1)(2), Cutrupi A(3)(4), Ellis M(3), Screnci R(5), Mao D(6), Uesugi
M(6), Yiu EM(7)(8)(9), Ryan MM(7)(8)(9), Choi BO(10), Nicholson G(3)(11),
Kennerson ML(12)(13)(14).
Author information:
(1)Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney,
Australia. [email protected].
(2)Sydney Medical School, University of Sydney, Sydney, Australia.
[email protected].
(3)Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney,
Australia.
(4)Sydney Medical School, University of Sydney, Sydney, Australia.
(5)School of Life Sciences, University of Technology Sydney, Sydney, NSW,
Australia.
(6)Institute for Integrated Cell-Material Sciences and Institute for Chemical
Research, Kyoto University, Kyoto, Japan.
(7)Department of Neurology, Royal Children's Hospital, Flemington Road,
Parkville, VIC, Australia.
(8)Neuroscience Research, Murdoch Children's Research Institute, Melbourne, VIC,
Australia.
(9)Department of Paediatrics, The University of Melbourne, Melbourne, VIC,
Australia.
(10)Department of Neurology, Samsung Medical Center, Sungkyunkwan University
School of Medicine, Seoul, Korea.
(11)Molecular Medicine Laboratory, Concord Repatriation General Hospital,
Sydney, Australia.
(12)Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney,
Australia. [email protected].
(13)Sydney Medical School, University of Sydney, Sydney, Australia.
[email protected].
(14)Molecular Medicine Laboratory, Concord Repatriation General Hospital,
Sydney, Australia. [email protected].
Charcot-Marie-Tooth (CMT) is a group of inherited diseases clinically and
genetically heterogenous, characterised by length dependent degeneration of
axons of the peripheral nervous system. A missense mutation (p.R158H) in the
pyruvate dehydrogenase kinase 3 gene (PDK3) has been identified as the genetic
cause for an X-linked form of CMT (CMTX6) in two unrelated families. PDK3 is one
of four PDK isoenzymes that regulate the activity of the pyruvate dehydrogenase
complex (PDC). The balance between kinases (PDKs) and phosphatases (PDPs)
determines the extend of oxidative decarboxylation of pyruvate to generate
acetyl CoA, critically linking glycolysis and the energy producing Krebs cycle.
We had shown the p.R158H mutation causes hyperactivity of PDK3 and CMTX6
fibroblasts show hyperphosphorylation of PDC, leading to reduced PDC activity
and ATP production. In this manuscript we have generated induced pluripotent
stem cells (iPSCs) by re-programming CMTX6 fibroblasts (iPSCCMTX6). We also have
engineered an isogenic control (iPSCisogenic) and demonstrated that genetic
correction of the p.R158H mutation reverses the CMTX6 phenotype. Patient-derived
motor neurons (MNCMTX6) show increased phosphorylation of the PDC, energy
metabolism defects and mitochondrial abnormalities, including reduced velocity
of trafficking mitochondria in the affected axons. Treatment of the MNCMTX6 with
a PDK inhibitor reverses PDC hyperphosphorylation and the associated functional
deficits founds in the patient motor neurons, demonstrating that the MNCMTX6 and
MNisogenic motor neurons provide an excellent neuronal system for compound
screening approaches to identify drugs for the treatment of CMTX6.
DOI: 10.1038/s41598-020-66266-5
PMCID: PMC7275085
PMID: 32504000 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/16775364 | 1. Neuromolecular Med. 2006;8(1-2):3-22. doi: 10.1385/nmm:8:1-2:3.
Clinical and electrophysiological aspects of Charcot-Marie-Tooth disease.
Pareyson D(1), Scaioli V, Laurà M.
Author information:
(1)Division of Biochemistry and Genetics, Carlo Besta National Neurological
Institute, via Celoria, 11, 20133, Milan, Italy. [email protected]
Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous group of
disorders sharing the same clinical phenotype, characterized by distal limb
muscle wasting and weakness, usually with skeletal deformities, distal sensory
loss, and abnormalities of deep tendon reflexes. Mutations of genes involved in
different functions eventually lead to a length-dependent axonal degeneration,
which is the likely basis of the distal predominance of the CMT phenotype. Nerve
conduction studies are important for classification, diagnosis, and
understanding of pathophysiology. The subdivision into demyelinating CMT1 and
axonal CMT2 types was a milestone and is still valid for the majority of
patients. However, exceptions to this partition are increasing. Intermediate
conduction velocities are often found in males with X-linked CMT (CMTX), and
different intermediate CMT types have been identified. Moreover, for some genes,
different mutations may result either in demyelinating CMT with slow conduction,
or in axonal CMT. Nerve conduction slowing is uniform and diffuse in the most
common CMT1A associated with the 17p12 duplication, whereas it is often
asymmetric and nonhomogeneous in CMTX, sometimes rendering difficult the
differential diagnosis with acquired inflammatory neuropathies. The
demyelinating recessive forms, termed CMT4, usually have early onset and run a
more severe course than the dominant types. Pure motor CMT types are now
classified as distal hereditary motor neuronopathy. The diagnostic approach to
the identification of the CMT subtype is complex and cannot be based on the
clinical phenotype alone, as different forms are often clinically
indistinguishable. However, there are features that may be of help in addressing
molecular investigation in a single patient. Late onset, prominent or peculiar
sensory manifestations, autonomic nervous system dysfunction, cranial nerve
involvement, upper limb predominance, subclinical central nervous system
abnormalities, severe scoliosis, early-onset glaucoma, neutropenia are findings
helpful for diagnosis.
DOI: 10.1385/nmm:8:1-2:3
PMID: 16775364 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24198383 | 1. J Neurol Neurosurg Psychiatry. 2014 May;85(5):486-92. doi:
10.1136/jnnp-2013-306387. Epub 2013 Nov 6.
Novel C12orf65 mutations in patients with axonal neuropathy and optic atrophy.
Tucci A(1), Liu YT, Preza E, Pitceathly RD, Chalasani A, Plagnol V, Land JM,
Trabzuni D, Ryten M; UKBEC; Jaunmuktane Z, Reilly MM, Brandner S, Hargreaves I,
Hardy J, Singleton AB, Abramov AY, Houlden H.
Author information:
(1)Department of Molecular Neuroscience and Reta Lila Weston Research
Laboratories, UCL Institute of Neurology and The National Hospital for Neurology
and Neurosurgery, , London, UK.
OBJECTIVE: Charcot-Marie Tooth disease (CMT) forms a clinically and genetically
heterogeneous group of disorders. Although a number of disease genes have been
identified for CMT, the gene discovery for some complex form of CMT has lagged
behind. The association of neuropathy and optic atrophy (also known as CMT type
6) has been described with autosomaldominant, recessive and X-linked modes of
inheritance. Mutations in Mitofusin 2 have been found to cause dominant forms of
CMT6. Phosphoribosylpyrophosphate synthetase-I mutations cause X-linked CMT6,
but until now, mutations in the recessive forms of disease have never been
identified.
METHODS: We here describe a family with three affected individuals who inherited
in an autosomal recessive fashion a childhood onset neuropathy and optic
atrophy. Using homozygosity mapping in the family and exome sequencing in two
affected individuals we identified a novel protein-truncating mutation in the
C12orf65 gene, which encodes for a protein involved in mitochondrial
translation. Using a variety of methods we investigated the possibility of
mitochondrial impairment in the patients cell lines.
RESULTS: We described a large consanguineous family with neuropathy and optic
atrophy carrying a loss of function mutation in the C12orf65 gene. We report
mitochondrial impairment in the patients cell lines, followed by multiple lines
of evidence which include decrease of complex V activity and stability (blue
native gel assay), decrease in mitochondrial respiration rate and reduction of
mitochondrial membrane potential.
CONCLUSIONS: This work describes a mutation in the C12orf65 gene that causes
recessive form of CMT6 and confirms the role of mitochondrial dysfunction in
this complex axonal neuropathy.
DOI: 10.1136/jnnp-2013-306387
PMCID: PMC3995331
PMID: 24198383 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20163430 | 1. Dev Med Child Neurol. 2010 Apr;52(4):328-30. doi:
10.1111/j.1469-8749.2010.03613.x. Epub 2010 Feb 12.
Mechanisms of disease and clinical features of mutations of the gene for
mitofusin 2: an important cause of hereditary peripheral neuropathy with
striking clinical variability in children and adults.
Ouvrier R(1), Grew S.
Author information:
(1)The Children's Hospital at Westmead, NSW, Australia. [email protected]
<[email protected]>
Mitofusin 2, a large transmembrane GTPase located in the outer mitochondrial
membrane, promotes membrane fusion and is involved in the maintenance of the
morphology of axonal mitochondria. Mutations of the gene encoding mitofusin 2
(MFN2) have recently been identified as the cause of approximately one-third of
dominantly inherited cases of the axonal degenerative forms of
Charcot-Marie-Tooth disease (CMT type 2A) and of rarer variants. The latter
include a severe, early-onset axonal neuropathy, which may occur in autosomal
dominant or recessive forms, as well as some instances associated with pyramidal
tract involvement (CMT type 5), with optic atrophy (CMT type 6), and,
occasionally, with alterations of cerebral white matter. All individuals with a
dominantly or recessively inherited or otherwise unexplained, chronic
progressive axonal degenerative polyneuropathy should be tested for mutations of
MFN2.
DOI: 10.1111/j.1469-8749.2010.03613.x
PMID: 20163430 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12901697 | 1. J Neuropathol Exp Neurol. 2003 Jul;62(7):699-714. doi: 10.1093/jnen/62.7.699.
Dominantly inherited peripheral neuropathies.
Vallat JM(1).
Author information:
(1)Neurology Department, University Hospital, Limoges, France. [email protected]
Since 1886, the year that Charcot and Marie and Tooth described a genetic
"peroneal muscular atrophy syndrome," electrophysiological and histological
studies of the peripheral nervous system have greatly aided the characterization
of this syndrome, which falls among the hereditary sensory-motor neuropathies.
Two principal forms of Charcot-Marie-Tooth (CMT) disease have been
distinguished: CMT 1, corresponding to a demyelinating type, and CMT 2,
corresponding to an axonal type. The modes of transmission of these types are
variable, recessive or dominant, autosomal, or X-linked. Our discussion here is
confined to the dominant forms. In recent years, advances in molecular biology
have greatly modified the approach to CMT disease and related neuropathies (such
as hereditary neuropathy with liability to pressure palsies). With increased
knowledge of responsible gene mutations and several other loci identified by
linkage studies, our understanding of the pathophysiology of these neuropathies
is increasing; however, with greater understanding, the classification of these
disorders is becoming more complex. In this review we present and discuss the
currently characterized subtypes, with emphasis on their known histological
aspects. While nerve biopsy has lost its diagnostic importance in certain forms
of the disease, such as CMT 1A, CMT 1B, and X-linked CMT (CMT X), it remains
important for better characterizing the lesions of CMT 2 and forms of genetic
peroneal atrophy in which DNA study is unrevealing.
DOI: 10.1093/jnen/62.7.699
PMID: 12901697 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28364294 | 1. J Neurol. 2017 Aug;264(8):1655-1677. doi: 10.1007/s00415-017-8474-3. Epub 2017
Mar 31.
Intermediate Charcot-Marie-Tooth disease: an electrophysiological reappraisal
and systematic review.
Berciano J(1)(2), García A(3), Gallardo E(4), Peeters K(5), Pelayo-Negro AL(6),
Álvarez-Paradelo S(3), Gazulla J(7), Martínez-Tames M(8), Infante J(6),
Jordanova A(5).
Author information:
(1)Service of Neurology, Hospital Universitario Marqués de Valdecilla, Instituto
de Investigación Marqués de Valdecilla (IDIVAL), Universidad de Cantabria (UC),
and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas
(CIBERNED), Santander, Spain. [email protected].
(2)Professor Emeritus, Department of Medicine and Psychiatry, "Edificio Escuela
Universitaria de Enfermería (cuarta planta)", Avda. de Valdecilla s/n,
University of Cantabria, 39008, Santander, Spain. [email protected].
(3)Service of Clinical Neurophysiology, Hospital Universitario Marqués de
Valdecilla, Instituto de Investigación Marqués de Valdecilla (IDIVAL),
Universidad de Cantabria (UC), and Centro de Investigación Biomédica en Red de
Enfermedades Neurodegenerativas (CIBERNED), Santander, Spain.
(4)Service of Radiology, Hospital Universitario Marqués de Valdecilla, Instituto
de Investigación Marqués de Valdecilla (IDIVAL), Universidad de Cantabria (UC),
and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas
(CIBERNED), Santander, Spain.
(5)VIB Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
(6)Service of Neurology, Hospital Universitario Marqués de Valdecilla, Instituto
de Investigación Marqués de Valdecilla (IDIVAL), Universidad de Cantabria (UC),
and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas
(CIBERNED), Santander, Spain.
(7)Service of Neurology, Hospital Universitario Miguel Servet, Saragossa, Spain.
(8)Universidad de Cantabria (UC), Santander, Spain.
Charcot-Marie-Tooth disease (CMT) is the most frequent form of inherited
neuropathy with great variety of phenotypes, inheritance patterns, and causative
genes. According to median motor nerve conduction velocity (MNCV), CMT is
divided into demyelinating (CMT1) with MNCV below 38 m/s, axonal (CMT2) with
MNCV above 38 m/s, and intermediate CMT with MNCV between 25 and 45 m/s. In each
category, transmission may be autosomal dominant, autosomal recessive, or
X-linked. The nosology of intermediate CMT is controversial because of concerns
about electrophysiological delimitation. A systematic computer-based literature
search was conducted on PubMed, using the following MeSH: (1) intermediate
Charcot-Marie-Tooth; (2) X-linked intermediate Charcot-Marie-Tooth; and (3)
X-linked Charcot-Marie-Tooth and electrophysiology. We retrieved 225 articles
reporting X-linked CMT or intermediate CMT with electrophysiological
information. After eligibility, 156 papers were used for this review. In
assessing median MNCV, compound muscle action potential (CMAP) amplitudes were
taken into account. In cases with attenuated CMAP and wherever possible,
proximal median MNCV was used for accurate definition of conduction slowing in
the intermediate range. In the vast majority of males with X-linked CMT
associated with GJB1 mutation (CMTX1), median MNCV was intermediate. CMT
associated with DRP2 mutation is another well-documented X-linked intermediate
disorder. Autosomal dominant intermediate CMT (DI-CMT) encompasses 11 different
types; six of them with assigned phenotype MIM number and the remaining five
being unnumbered. Based on available electrophysiological information, we wonder
if DI-CMTA should be reclassified within CMT2. Autosomal recessive intermediate
CMT (RI-CMT) covers four numbered MIM phenotypes though, in accordance with
reported electrophysiology, two of them (RI-CMTB and RI-CMTD) should probably be
reclassified within AR-CMT2. We conclude that intermediate CMT is a complex
inherited syndrome, whose characterization requires a specific
electrophysiological protocol comprising evaluation of upper limb proximal nerve
trunks when distal CMAP amplitudes are reduced, and that an updated version of
MIM phenotype numbering is needed.
DOI: 10.1007/s00415-017-8474-3
PMID: 28364294 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8810804 | 1. Nihon Rinsho. 1996 Aug;54(8):2243-51.
[Molecular basis of Charcot-Marie-Tooth neuropathy].
[Article in Japanese]
Hayasaka K(1).
Author information:
(1)Department of Pediatrics, Yamagata University School of Medicine.
Charcot-Marie-Tooth neuropathy (CMT) is the most common inherited peripheral
neuropathy. CMT is classified into type types on the basis of pathological and
electrophysiological findings: type 1(CMT1), characterized by decreased nerve
conduction velocities and by "onion bulb" formation: type 2(CMT2), in which
nerve conduction velocities are normal and "onion bulb" formations are rarely
seen. CMT1 loci map to chromosome 17 (CMT1A), chromosome 1(CMT1B), another
unknown autosome (CMT1C) and the X chromosome (CMTX). Recent work has identified
the gene products corresponding to CMT1A, CMT1B and CMTX as peripheral myelin
protein-22(PMP22), Po and connexin 32, respectively. Dejerine-Sottas disease has
been identified as being caused by the mutation of PMP-22 or Po gene.
PMID: 8810804 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1549221 | 1. Neurology. 1992 Mar;42(3 Pt 1):597-601. doi: 10.1212/wnl.42.3.597.
Linkage studies in Charcot-Marie-Tooth disease type 2: evidence that CMT types 1
and 2 are distinct genetic entities.
Loprest LJ(1), Pericak-Vance MA, Stajich J, Gaskell PC, Lucas AM, Lennon F,
Yamaoka LH, Roses AD, Vance JM.
Author information:
(1)Department of Medicine, Duke University Medical Center, Durham, NC.
Charcot-Marie-Tooth disease (CMT), the most common inherited peripheral
neuropathy, is a progressive sensorimotor neuropathy divided into types 1 and 2
based upon electrophysiologic and neuropathologic differences. The more common
autosomal dominant form of CMT type 1 (hereditary motor and sensory neuropathy
type I) is genetically heterogeneous, with genes located on chromosomes 1 (type
1B) or 17 (type 1A). However, no locus for CMT type 2 is known. We have
performed linkage studies on three large multigenerational CMT type 2 families
using probes from chromosome 1 and chromosome 17, which span their respective
linkage regions. Multipoint analysis of the chromosome 17 markers excluded
linkage over an area of 45 cM--15 cM proximal and 30 cM distal to the region
containing CMT type 1A. Multipoint analysis of the chromosome 1 markers exclude
linkage 15 cM proximal and 20 cM distal to FC-gamma-RII in the region of CMT 1B.
These data indicate that CMT type 2 is genetically distinct from CMT type 1.
DOI: 10.1212/wnl.42.3.597
PMID: 1549221 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30871534 | 1. BMC Med Genomics. 2019 Mar 13;12(Suppl 2):43. doi: 10.1186/s12920-019-0488-5.
Genotype-phenotype correlations in FSHD.
Zernov N(1), Skoblov M(2)(3).
Author information:
(1)Research Center for Medical Genetics, Moscow, Russia. [email protected].
(2)Research Center for Medical Genetics, Moscow, Russia.
(3)School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia.
BACKGROUND: Facial-scapular-humeral myodystrophy Landouzy-Dejerine (FSHD) is an
autosomal dominant disease, the basis of its pathogenesis is ectopic expression
of the transcription factor DUX4 in skeletal muscle. There are two types of the
disease: FSHD1 (MIM:158900) and FSHD2 (MIM: 158901), which have different
genetic causes but are phenotypically indistinguishable. In FSHD1, partial
deletion of the D4Z4 repeats on the 4th chromosome affects the expression of
DUX4, whereas FSHD2 is caused by the mutations in the protein regulating the
methylation status of chromatin - SMCHD1. High variability of clinical picture,
both intra - and inter-family indicates a large number of factors influencing
clinical picture. There are key genetic, epigenetic and gender factors that
influence the expressivity and penetrance of the disease. Using only one of
these factors allows just a rough prediction of the course of the disease, which
indicates the combined effect of all of the factors on the DUX4 expression and
on the clinical picture.
RESULTS: In this paper, we analyzed the impact of genetic, epigenetic and gender
differences on phenotype and the possibility of using them for disease prognosis
and family counselling.
CONCLUSIONS: Key pathogenesis factors have been identified for FSHD. However,
the pronounced intra - and inter-family polymorphism of manifestations indicates
a large number of modifiers of the pathological process, many of which remain
unknown.
DOI: 10.1186/s12920-019-0488-5
PMCID: PMC6416831
PMID: 30871534 [Indexed for MEDLINE]
Conflict of interest statement: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: Not
applicable. CONSENT FOR PUBLICATION: 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/8128981 | 1. Am J Med Sci. 1993 Sep;306(3):177-84. doi: 10.1097/00000441-199309000-00010.
Molecular basis of Charcot-Marie-Tooth disease type 1A: gene dosage as a novel
mechanism for a common autosomal dominant condition.
Roa BB(1), Lupski JR.
Author information:
(1)Institute for Molecular Genetics, Baylor College of Medicine, Houston, TX
77030.
Charcot-Marie-Tooth disease (CMT) comprises a clinically and genetically
heterogeneous group of polyneuropathies. Two major types can be distinguished
based on electrophysiologic phenotypes: CMT type 1 (CMT1) displays uniformly
decreased nerve conduction velocity associated with a demyelinating hypertrophic
neuropathy, and CMT type 2 (CMT2) displays normal or near-normal nerve
conduction velocity associated with a neuronal defect. Charcot-Marie-Tooth
disease type 1A (CMT1A) is the most common form, exhibiting autosomal dominant
inheritance and linkage to chromosome 17p11.2p12. This review will focus on the
underlying molecular mechanisms leading to CMT1A. DNA duplication of a 1.5-Mb
region is associated with CMT1A in the majority of cases. A defined segmental
DNA duplication that cosegregates with a disease in a dominant Mendelian pattern
had been unprecedented. A candidate gene for CMT1A, PMP22, which maps within the
duplication and encodes a myelin-specific protein, was identified from studies
on the trembler and tremblerJ mouse models for CMT. Point mutations in PMP22
have since been identified in cases of familial, non-duplication CMT1A. The
genetic data presents two alternative molecular mechanisms involving the PMP22
gene that result in the same clinical and electrophysiologic phenotype of CMT1A.
The impact of the underlying molecular mechanisms on the prospects for
therapeutic development are discussed.
DOI: 10.1097/00000441-199309000-00010
PMID: 8128981 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15549395 | 1. Hum Genet. 2005 Jan;116(1-2):23-7. doi: 10.1007/s00439-004-1199-2. Epub 2004
Nov 11.
Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type
2A.
Kijima K(1), Numakura C, Izumino H, Umetsu K, Nezu A, Shiiki T, Ogawa M,
Ishizaki Y, Kitamura T, Shozawa Y, Hayasaka K.
Author information:
(1)Department of Pediatrics, Yamagata University School of Medicine, 2-2-2
Iida-nishi, Yamagata 990-9585, Japan.
Charcot-Marie-Tooth disease (CMT) has been classified into two types, CMT1 and
CMT2, demyelinating and axonal forms, respectively. CMT2 has been further
subdivided into eight groups by linkage studies. CMT2A is linked to chromosome
1p35-p36 and mutation in the kinesin family member 1B-beta (KIF1B) gene had been
reported in one pedigree. However, no mutation in KIF1B was detected in other
pedigrees with CMT2A and the mutations in the mitochondrial fusion protein
mitofusin 2 (MFN2) gene were recently detected in those pedigrees. MFN2, a
mitochondrial transmembrane GTPase, regulates the mitochondrial network
architecture by fusion of mitochondria. We studied MFN2 in 81 Japanese patients
with axonal or unclassified CMT and detected seven mutations in seven unrelated
patients. Six of them were novel and one of them was a de novo mutation. Most
mutations locate within or immediately upstream of the GTPase domain or within
two coiled-coil domains, which are critical for the functioning or mitochondrial
targeting of MFN2. Formation of a mitochondrial network would be required to
maintain the functional peripheral nerve axon.
DOI: 10.1007/s00439-004-1199-2
PMID: 15549395 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29436205 | 1. Yonsei Med J. 2018 Mar;59(2):337-340. doi: 10.3349/ymj.2018.59.2.337.
FAT1 Gene Alteration in Facioscapulohumeral Muscular Dystrophy Type 1.
Park HJ(#)(1), Lee W(#)(2), Kim SH(3), Lee JH(4), Shin HY(4), Kim SM(4), Park
KD(5), Lee JH(6), Choi YC(7).
Author information:
(1)Department of Neurology, Gangneung Asan Hospital, University of Ulsan College
of Medicine, Gangneung, Korea.
(2)Department of Chemistry, Yonsei University, Seoul, Korea.
(3)Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.
(4)Department of Neurology, Yonsei University College of Medicine, Seoul, Korea.
(5)Department of Neurology, Mokdong Hospital, Ewha Womans University School of
Medicine, Seoul, Korea.
(6)Department of Clinical Pharmacology and Therapeutics, College of Medicine,
Kyung Hee University, Seoul, Korea.
(7)Department of Neurology, Yonsei University College of Medicine, Seoul, Korea.
[email protected].
(#)Contributed equally
Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is caused by contraction
of the D4Z4 repeat array. Recent studies revealed that the FAT1 expression is
associated with disease activity of FSHD, and the FAT1 alterations result in
myopathy with a FSHD-like phenotype. We describe a 59-year-old woman with both
contracted D4Z4 repeat units and a FAT1 mutation. Shoulder girdle muscle
weakness developed at the age of 56 years, and was followed by proximal leg
weakness. When we examined her at 59 years of age, she displayed asymmetric and
predominant weakness of facial and proximal muscles. Muscle biopsy showed
increased variation in fiber size and multifocal degenerating fibers with
lymphocytic infiltration. Southern blot analysis revealed 8 D4Z4 repeat units,
and targeted sequencing of modifier genes demonstrated the c.10331 A>G variant
in the FAT1 gene. This FAT1 variant has previously been reported as pathogenic
variant in a patient with FSHD-like phenotype. Our study is the first report of
a FAT1 mutation in a FSHD1 patient, and suggests that FAT1 alterations might
work as a genetic modifier.
© Copyright: Yonsei University College of Medicine 2018.
DOI: 10.3349/ymj.2018.59.2.337
PMCID: PMC5823839
PMID: 29436205 [Indexed for MEDLINE]
Conflict of interest statement: The authors have no financial conflicts of
interest. |
http://www.ncbi.nlm.nih.gov/pubmed/27822859 | 1. Methods Mol Biol. 2017;1492:107-125. doi: 10.1007/978-1-4939-6442-0_7.
Analyzing Copy Number Variation Using Pulsed-Field Gel Electrophoresis:
Providing a Genetic Diagnosis for FSHD1.
Lemmers RJ(1).
Author information:
(1)Department of Human Genetics, Leiden University Medical Center, 2333, ZA,
Leiden, The Netherlands. [email protected].
The myopathy facioscapulohumeral muscular dystrophy type 1 (FSHD1) is caused by
copy number variation of the D4Z4 macrosatellite repeat on chromosome 4. In
unaffected individuals the number of 3.3 kb D4Z4 units varies between 8 and 100,
whereas 1-10 units are seen in FSHD1 cases. A homologous and heterogenous D4Z4
array can be found on chromosome 10q, but contractions of this array are
typically not associated with FSHD. Discriminating between the chromosome 4 and
chromosome 10 D4Z4 arrays, as well as determining the array size, requires the
use of pulsed-field gel electrophoresis, Southern blotting, and the isolation of
high-quality DNA.
DOI: 10.1007/978-1-4939-6442-0_7
PMID: 27822859 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24755953 | 1. Eur J Hum Genet. 2015 Jan;23(1):67-71. doi: 10.1038/ejhg.2014.58. Epub 2014
Apr 23.
Identification of two novel SMCHD1 sequence variants in families with FSHD-like
muscular dystrophy.
Winston J(1), Duerden L(1), Mort M(1), Frayling IM(1), Rogers MT(1), Upadhyaya
M(1).
Author information:
(1)Institute of Medical Genetics, School of Medicine, Cardiff University,
Cardiff, UK.
Facioscapulohumeral muscular dystrophy 1 (FSHD1) is caused by a contraction in
the number of D4Z4 repeats on chromosome 4, resulting in relaxation of D4Z4
chromatin causing inappropriate expression of DUX4 in skeletal muscle. Clinical
severity is inversely related to the number of repeats. In contrast, FSHD2
patients also have inappropriate expression of DUX4 in skeletal muscle, but due
to constitutional mutations in SMCHD1 (structural maintenance of chromosomes
flexible hinge domain containing 1), which cause global hypomethylation and
hence general relaxation of chromatin. Thirty patients originally referred for
FSHD testing were screened for SMCHD1 mutations. Twenty-nine had >11 D4Z4
repeats. SMCHD1 c.1040+1G>A, a pathogenic splice-site variant, was identified in
a FSHD1 family with a borderline number of D4Z4 repeats (10) and a variable
phenotype (in which a LMNA1 sequence variant was previously described), and
SMCHD1 c.2606 G>T, a putative missense variant (p.Gly869Val) with strong in
vitro indications of pathogenicity, was identified in a family with an unusual
muscular dystrophy with some FSHD-like features. The two families described here
emphasise the genetic complexity of muscular dystrophies. As SMCHD1 has a wider
role in global genomic methylation, the possibility exists that it could be
involved in other complex undiagnosed muscle disorders. Thus far, only 15
constitutional mutations have been identified in SMCHD1, and these two sequence
variants add to the molecular and phenotypic spectrum associated with FSHD.
DOI: 10.1038/ejhg.2014.58
PMCID: PMC4266742
PMID: 24755953 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30122154 | 1. Epigenetics Chromatin. 2018 Aug 20;11(1):47. doi: 10.1186/s13072-018-0215-z.
Sporadic DUX4 expression in FSHD myocytes is associated with incomplete
repression by the PRC2 complex and gain of H3K9 acetylation on the contracted
D4Z4 allele.
Haynes P(1), Bomsztyk K(2), Miller DG(3)(4).
Author information:
(1)Departments of Pediatrics and Genome Sciences, University of Washington,
Seattle, WA, USA.
(2)Department of Medicine, University of Washington, Seattle, WA, USA.
(3)Departments of Pediatrics and Genome Sciences, University of Washington,
Seattle, WA, USA. [email protected].
(4)University of Washington, Campus Box 358056, 850 Republican Street, Room
N416, Seattle, WA, 98109, USA. [email protected].
BACKGROUND: Facioscapulohumeral muscular dystrophy 1 (FSHD1) has an autosomal
dominant pattern of inheritance and primarily affects skeletal muscle. The
genetic cause of FSHD1 is contraction of the D4Z4 macrosatellite array on
chromosome 4 alleles associated with a permissive haplotype causing infrequent
sporadic expression of the DUX4 gene. Epigenetically, the contracted D4Z4 array
has decreased cytosine methylation and an open chromatin structure. Despite
these genetic and epigenetic changes, the majority of FSHD myoblasts are able to
repress DUX4 transcription. In this study we hypothesized that histone
modifications distinguish DUX4 expressing and non-expressing cells from the same
individuals.
RESULTS: FSHD myocytes containing the permissive 4qA haplotype with a long
terminal D4Z4 unit were sorted into DUX4 expressing and non-expressing groups.
We found similar CpG hypomethylation between the groups of FSHD-affected cells
suggesting that CpG hypomethylation is not sufficient to trigger DUX4
expression. A survey of histone modifications present at the D4Z4 region during
cell lineage commitment revealed that this region is bivalent in FSHD iPS cells
with both H3K4me3 activating and H3K27me3 repressive marks present, making D4Z4
poised for DUX4 activation in pluripotent cells. After lineage commitment, the
D4Z4 region becomes univalent with H3K27me3 in FSHD and non-FSHD control
myoblasts and a concomitant increase in H3K4me3 in a small fraction of cells.
Chromatin immunoprecipitation (ChIP) for histone modifications, chromatin
modifier proteins and chromatin structural proteins on sorted FSHD myocytes
revealed that activating H3K9Ac modifications were ~ fourfold higher in DUX4
expressing FSHD myocytes, while the repressive H3K27me3 modification was
~ fourfold higher at the permissive allele in DUX4 non-expressing FSHD myocytes
from the same cultures. Similarly, we identified EZH2, a member of the polycomb
repressive complex involved in H3K27 methylation, to be present more frequently
on the permissive allele in DUX4 non-expressing FSHD myocytes.
CONCLUSIONS: These results implicate PRC2 as the complex primarily responsible
for DUX4 repression in the setting of FSHD and H3K9 acetylation along with
reciprocal loss of H3K27me3 as key epigenetic events that result in DUX4
expression. Future studies focused on events that trigger H3K9Ac or augment PRC2
complex activity in a small fraction of nuclei may expose additional drug
targets worthy of study.
DOI: 10.1186/s13072-018-0215-z
PMCID: PMC6100714
PMID: 30122154 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24128691 | 1. Neuromuscul Disord. 2013 Dec;23(12):975-80. doi: 10.1016/j.nmd.2013.08.009.
Epub 2013 Aug 31.
Exome sequencing identifies a novel SMCHD1 mutation in facioscapulohumeral
muscular dystrophy 2.
Mitsuhashi S(1), Boyden SE, Estrella EA, Jones TI, Rahimov F, Yu TW, Darras BT,
Amato AA, Folkerth RD, Jones PL, Kunkel LM, Kang PB.
Author information:
(1)Department of Neurology, Boston Children's Hospital and Harvard Medical
School, Boston, MA 02115, USA.
FSHD2 is a rare form of facioscapulohumeral muscular dystrophy (FSHD)
characterized by the absence of a contraction in the D4Z4 macrosatellite repeat
region on chromosome 4q35 that is the hallmark of FSHD1. However,
hypomethylation of this region is common to both subtypes. Recently, mutations
in SMCHD1 combined with a permissive 4q35 allele were reported to cause FSHD2.
We identified a novel p.Lys275del SMCHD1 mutation in a family affected with
FSHD2 using whole-exome sequencing and linkage analysis. This mutation alters a
highly conserved amino acid in the ATPase domain of SMCHD1. Subject III-11 is a
male who developed asymmetrical muscle weakness characteristic of FSHD at 13
years. Physical examination revealed marked bilateral atrophy at biceps brachii,
bilateral scapular winging, some asymmetrical weakness at tibialis anterior and
peroneal muscles, and mild lower facial weakness. Biopsy of biceps brachii in
subject II-5, the father of III-11, demonstrated lobulated fibers and dystrophic
changes. Endomysial and perivascular inflammation was found, which has been
reported in FSHD1 but not FSHD2. Given the previous report of SMCHD1 mutations
in FSHD2 and the clinical presentations consistent with the FSHD phenotype, we
conclude that the SMCHD1 mutation is the likely cause of the disease in this
family.
Copyright © 2013 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.nmd.2013.08.009
PMCID: PMC3851942
PMID: 24128691 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24075187 | 1. Am J Hum Genet. 2013 Oct 3;93(4):744-51. doi: 10.1016/j.ajhg.2013.08.004. Epub
2013 Sep 26.
The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by
FSHD1.
Sacconi S(1), Lemmers RJ, Balog J, van der Vliet PJ, Lahaut P, van Nieuwenhuizen
MP, Straasheijm KR, Debipersad RD, Vos-Versteeg M, Salviati L, Casarin A,
Pegoraro E, Tawil R, Bakker E, Tapscott SJ, Desnuelle C, van der Maarel SM.
Author information:
(1)Neuromuscular Diseases Centre, University Hospital of Nice, 06000 Nice,
France; CNRS UMR7277, IBV, Faculty of Medicine, University of Nice, 06108 Nice,
France. Electronic address: [email protected].
Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is caused by contraction
of the D4Z4 repeat array on chromosome 4 to a size of 1-10 units. The residual
number of D4Z4 units inversely correlates with clinical severity, but
significant clinical variability exists. Each unit contains a copy of the DUX4
retrogene. Repeat contractions are associated with changes in D4Z4 chromatin
structure that increase the likelihood of DUX4 expression in skeletal muscle,
but only when the repeat resides in a genetic background that contains a DUX4
polyadenylation signal. Mutations in the structural maintenance of chromosomes
flexible hinge domain containing 1 (SMCHD1) gene, encoding a chromatin modifier
of D4Z4, also result in the increased likelihood of DUX4 expression in
individuals with a rare form of FSHD (FSHD2). Because SMCHD1 directly binds to
D4Z4 and suppresses somatic expression of DUX4, we hypothesized that SMCHD1 may
act as a genetic modifier in FSHD1. We describe three unrelated individuals with
FSHD1 presenting an unusual high clinical severity based on their upper-sized
FSHD1 repeat array of nine units. Each of these individuals also carries a
mutation in the SMCHD1 gene. Familial carriers of the FSHD1 allele without the
SMCHD1 mutation were only mildly affected, suggesting a modifier effect of the
SMCHD1 mutation. Knocking down SMCHD1 in FSHD1 myotubes increased DUX4
expression, lending molecular support to a modifier role for SMCHD1 in FSHD1. We
conclude that FSHD1 and FSHD2 share a common pathophysiological pathway in which
the FSHD2 gene can act as modifier for disease severity in families affected by
FSHD1.
Copyright © 2013 The American Society of Human Genetics. Published by Elsevier
Inc. All rights reserved.
DOI: 10.1016/j.ajhg.2013.08.004
PMCID: PMC3791262
PMID: 24075187 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24882751 | 1. Biochim Biophys Acta. 2015 Apr;1852(4):607-14. doi:
10.1016/j.bbadis.2014.05.021. Epub 2014 May 29.
Facioscapulohumeral muscular dystrophy.
Sacconi S(1), Salviati L(2), Desnuelle C(3).
Author information:
(1)Centre de référence des Maladies Neuromusculaires, Hôpital Archet 1, 151,
route de Saint Antoine de Ginestière, 06202 Nice, France; CNRS UMR7277, Inserm
U1091, iBV - Institute of Biology Valrose, UNS Université Nice Sophia-Antipolis,
Faculté de Médecine, 28 Avenue Valombrose, 06189 Nice Cedex, France. Electronic
address: [email protected].
(2)Clinical Genetics Unit, Dept. of Woman and Child Health, University of
Padova, Italy; IRP Città della Speranza, Padova, Italy.
(3)Centre de référence des Maladies Neuromusculaires, Hôpital Archet 1, 151,
route de Saint Antoine de Ginestière, 06202 Nice, France; CNRS UMR7277, Inserm
U1091, iBV - Institute of Biology Valrose, UNS Université Nice Sophia-Antipolis,
Faculté de Médecine, 28 Avenue Valombrose, 06189 Nice Cedex, France.
Facioscapulohumeral muscular dystrophy (FSHD) is characterized by a typical and
asymmetric pattern of muscle involvement and disease progression. Two forms of
FSHD, FSHD1 and FSHD2, have been identified displaying identical clinical
phenotype but different genetic and epigenetic basis. Autosomal dominant FSHD1
(95% of patients) is characterized by chromatin relaxation induced by pathogenic
contraction of a macrosatellite repeat called D4Z4 located on the 4q subtelomere
(FSHD1 patients harbor 1 to 10 D4Z4 repeated units). Chromatin relaxation is
associated with inappropriate expression of DUX4, a retrogene, which in muscles
induces apoptosis and inflammation. Consistent with this hypothesis, individuals
carrying zero repeat on chromosome 4 do not develop FSHD1. Not all D4Z4
contracted alleles cause FSHD. Distal to the last D4Z4 unit, a polymorphic site
with two allelic variants has been identified: 4qA and 4qB. 4qA is in cis with a
functional polyadenylation consensus site. Only contractions on 4qA alleles are
pathogenic because the DUX4 transcript is polyadenylated and translated into
stable protein. FSHD2 is instead a digenic disease. Chromatin relaxation of the
D4Z4 locus is caused by heterozygous mutations in the SMCHD1 gene encoding a
protein essential for chromatin condensation. These patients also harbor at
least one 4qA allele in order to express stable DUX4 transcripts. FSHD1 and
FSHD2 may have an additive effect: patients harboring D4Z4 contraction and
SMCHD1 mutations display a more severe clinical phenotype than with either
defect alone. Knowledge of the complex genetic and epigenetic defects causing
these diseases is essential in view of designing novel therapeutic strategies.
This article is part of a Special Issue entitled: Neuromuscular Diseases:
Pathology and Molecular Pathogenesis.
Copyright © 2014 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.bbadis.2014.05.021
PMID: 24882751 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14634647 | 1. Nat Genet. 2003 Dec;35(4):315-7. doi: 10.1038/ng1262. Epub 2003 Nov 23.
Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral
muscular dystrophy.
van Overveld PG(1), Lemmers RJ, Sandkuijl LA, Enthoven L, Winokur ST, Bakels F,
Padberg GW, van Ommen GJ, Frants RR, van der Maarel SM.
Author information:
(1)Department of Human Genetics, Center for Human and Clinical Genetics, Leiden
University Medical Center, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
The autosomal dominant myopathy facioscapulohumeral muscular dystrophy (FSHD1,
OMIM 158900) is caused by contraction of the D4Z4 repeat array on 4qter. We show
that this contraction causes marked hypomethylation of the contracted D4Z4
allele in individuals with FSHD1. Individuals with phenotypic FSHD1, who are
clinically identical to FSHD1 but have an unaltered D4Z4, also have
hypomethylation of D4Z4. These results strongly suggest that hypomethylation of
D4Z4 is a key event in the cascade of epigenetic events causing FSHD1.
DOI: 10.1038/ng1262
PMID: 14634647 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31518905 | 1. Stem Cell Res. 2019 Oct;40:101560. doi: 10.1016/j.scr.2019.101560. Epub 2019
Aug 28.
Generation of genetically matched hiPSC lines from two mosaic
facioscapulohumeral dystrophy type 1 patients.
van der Wal E(1), den Hamer B(1), van der Vliet PJ(1), Tok M(2), Brands T(3),
Eussen B(3), Lemmers RJLF(1), Freund C(4), de Klein A(3), Buijsen RAM(1), van
Roon-Mom WMC(1), Tawil R(5), van der Maarel SM(1), de Greef JC(6).
Author information:
(1)Department of Human Genetics, Leiden University Medical Center, Leiden, the
Netherlands.
(2)LUMC hiPSC Core Facility, Department of Cell and Chemical Biology, LUMC,
Leiden, the Netherlands.
(3)Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
(4)LUMC hiPSC Core Facility, Department of Anatomy and Embryology, LUMC, Leiden,
the Netherlands.
(5)Department of Neurology, University of Rochester Medical Center, Rochester,
New York, USA.
(6)Department of Human Genetics, Leiden University Medical Center, Leiden, the
Netherlands. Electronic address: [email protected].
Facioscapulohumeral dystrophy type 1 (FSHD1) is caused by contraction of the
D4Z4 repeat array on chromosome 4q resulting in sporadic misexpression of the
transcription factor DUX4 in skeletal muscle tissue. In ~4% of families, de novo
D4Z4 contractions occur after fertilization resulting in somatic mosaicism with
control and FSHD1 cell populations present within the same patient.
Reprogramming of mosaic fibroblasts from two FSHD1 patients into human induced
pluripotent stem cells (hiPSCs) generated genetically matched control and FSHD1
hiPSC lines. All hiPSC lines contained a normal karyotype, expressed
pluripotency genes and differentiated into cells from the three germ layers.
Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.
DOI: 10.1016/j.scr.2019.101560
PMID: 31518905 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23593020 | 1. PLoS Genet. 2013 Apr;9(4):e1003415. doi: 10.1371/journal.pgen.1003415. Epub
2013 Apr 4.
Intrinsic epigenetic regulation of the D4Z4 macrosatellite repeat in a
transgenic mouse model for FSHD.
Krom YD(1), Thijssen PE, Young JM, den Hamer B, Balog J, Yao Z, Maves L, Snider
L, Knopp P, Zammit PS, Rijkers T, van Engelen BG, Padberg GW, Frants RR, Tawil
R, Tapscott SJ, van der Maarel SM.
Author information:
(1)Department of Human Genetics, Leiden University Medical Center, Leiden, The
Netherlands.
Facioscapulohumeral dystrophy (FSHD) is a progressive muscular dystrophy caused
by decreased epigenetic repression of the D4Z4 macrosatellite repeats and
ectopic expression of DUX4, a retrogene encoding a germline transcription factor
encoded in each repeat. Unaffected individuals generally have more than 10
repeats arrayed in the subtelomeric region of chromosome 4, whereas the most
common form of FSHD (FSHD1) is caused by a contraction of the array to fewer
than 10 repeats, associated with decreased epigenetic repression and variegated
expression of DUX4 in skeletal muscle. We have generated transgenic mice
carrying D4Z4 arrays from an FSHD1 allele and from a control allele. These mice
recapitulate important epigenetic and DUX4 expression attributes seen in
patients and controls, respectively, including high DUX4 expression levels in
the germline, (incomplete) epigenetic repression in somatic tissue, and
FSHD-specific variegated DUX4 expression in sporadic muscle nuclei associated
with D4Z4 chromatin relaxation. In addition we show that DUX4 is able to
activate similar functional gene groups in mouse muscle cells as it does in
human muscle cells. These transgenic mice therefore represent a valuable animal
model for FSHD and will be a useful resource to study the molecular mechanisms
underlying FSHD and to test new therapeutic intervention strategies.
DOI: 10.1371/journal.pgen.1003415
PMCID: PMC3616921
PMID: 23593020 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/32703466 | 1. Neurol Clin. 2020 Aug;38(3):529-540. doi: 10.1016/j.ncl.2020.03.003.
Case Studies on the Genetic and Clinical Diagnosis of Facioscapulohumeral
Muscular Dystrophy.
Hamel J(1), Tawil R(2).
Author information:
(1)Department of Neurology, University of Rochester Medical Center, 601 Elmwood
Avenue, Box 673, Rochester, NY 14642, USA. Electronic address:
[email protected].
(2)Department of Neurology, University of Rochester Medical Center, 601 Elmwood
Avenue, Box 673, Rochester, NY 14642, USA.
Facioscapulohumeral muscular dystrophy is the second most common adult muscular
dystrophy and is caused by DUX4 protein. DUX4 is expressed when the locus on
chromosome 4q35 is hypomethylated. The clinical features can be nearly
pathognomonic with facial weakness, scapular winging, and abdominal weakness
with a positive Beevor sign. Diagnosis of late-onset or milder disease is often
more challenging. Diseases mimicking the facioscapulohumeral muscular dystrophy
phenotype should be recognized. We present 6 cases to illustrate both clinical
and genetic diagnostic challenges in facioscapulohumeral muscular dystrophy and
provide examples on how to navigate the different steps of genetic testing.
Copyright © 2020 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ncl.2020.03.003
PMID: 32703466 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32576599 | 1. J Pharmacol Exp Ther. 2020 Sep;374(3):489-498. doi: 10.1124/jpet.119.264689.
Epub 2020 Jun 23.
p38α Regulates Expression of DUX4 in a Model of Facioscapulohumeral Muscular
Dystrophy.
Rojas LA(1), Valentine E(2), Accorsi A(2), Maglio J(2), Shen N(2), Robertson
A(2), Kazmirski S(2), Rahl P(2), Tawil R(2), Cadavid D(2), Thompson LA(2), Ronco
L(2), Chang AN(2), Cacace AM(2), Wallace O(2).
Author information:
(1)Fulcrum Therapeutics, Cambridge, Massachusetts (L.A.R., E.V., A.A., J.M.,
N.S., A.R., S.K., P.R., D.C., L.A.T., L.R., A.N.C., A.M.C., O.W.) and University
of Rochester Medical Center, Department of Neurology, Rochester, New York (R.T.)
[email protected].
(2)Fulcrum Therapeutics, Cambridge, Massachusetts (L.A.R., E.V., A.A., J.M.,
N.S., A.R., S.K., P.R., D.C., L.A.T., L.R., A.N.C., A.M.C., O.W.) and University
of Rochester Medical Center, Department of Neurology, Rochester, New York
(R.T.).
Facioscapulohumeral muscular dystrophy (FSHD) is caused by the loss of
repression at the D4Z4 locus leading to aberrant double homeobox 4 (DUX4)
expression in skeletal muscle. Activation of this early embryonic transcription
factor results in the expression of its target genes causing muscle fiber death.
Although progress toward understanding the signals driving DUX4 expression has
been made, the factors and pathways involved in the transcriptional activation
of this gene remain largely unknown. Here, we describe the identification and
characterization of p38α as a novel regulator of DUX4 expression in FSHD
myotubes. By using multiple highly characterized, potent, and specific
inhibitors of p38α/β, we show a robust reduction of DUX4 expression, activity,
and cell death across patient-derived FSHD1 and FSHD2 lines. RNA-seq profiling
reveals that a small number of genes are differentially expressed upon p38α/β
inhibition, the vast majority of which are DUX4 target genes. Our results reveal
a novel and apparently critical role for p38α in the aberrant activation of DUX4
in FSHD and support the potential of p38α/β inhibitors as effective therapeutics
to treat FSHD at its root cause. SIGNIFICANCE STATEMENT: Using patient-derived
facioscapulohumeral muscular dystrophy (FSHD) myotubes, we characterize the
pharmacological relationships between p38α/β inhibition, double homeobox 4
(DUX4) expression, its downstream transcriptional program, and muscle cell
death. p38α/β inhibition results in potent and specific DUX4 downregulation
across multiple genotypes without significant effects in the process of
myogenesis in vitro. These findings highlight the potential of p38α/β inhibitors
for the treatment of FSHD, a condition that today has no approved therapies.
Copyright © 2020 The Author(s).
DOI: 10.1124/jpet.119.264689
PMID: 32576599 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35795638 | 1. Front Med (Lausanne). 2022 Jun 20;9:906112. doi: 10.3389/fmed.2022.906112.
eCollection 2022.
Case Report: Kearns Sayre Syndrome Complicated With Postpartum Cardiac Failure.
Han C(1), Jia Z(1), Zhao G(1), Chen W(1), Hu Y(1), Liu H(1).
Author information:
(1)Department of Obstetrics and Gynecology, Cheeloo College of Medicine, Qilu
Hospital (Qingdao), Shandong University, Qingdao, China.
Kearns Sayre Syndrome (KSS) is a rare mitochondrial disease characterized by a
primary dysfunction of the mitochondrial respiratory chain. Cardiac involvement
is a poor prognostic factor of KSS. Pregnancy and delivery in a KSS patient with
cardiac involvement is uncommon, and strategies for the supervision and
management of this group remain unclear. Herein, we report and discuss pregnancy
and delivery complicated with acute cardiopulmonary failure in a woman with KSS.
Copyright © 2022 Han, Jia, Zhao, Chen, Hu and Liu.
DOI: 10.3389/fmed.2022.906112
PMCID: PMC9251117
PMID: 35795638
Conflict of interest statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35721635 | 1. Pan Afr Med J. 2022 Mar 18;41:226. doi: 10.11604/pamj.2022.41.226.33085.
eCollection 2022.
Ophthalmologic school-based screening revealing Kearns-Sayre syndrome: a case
report.
Ennejjar A(1)(2), Moutamani S(1), Boutaj T(1), Touil W(2), Amazouzi A(1),
Cherkaoui O(1).
Author information:
(1)Ophthalmology Department "A", Ibn Sina University Hospital (Hôpital des
Spécialités), Mohammed V University, Rabat, Morocco.
(2)Neurology Department "B", Ibn Sina University Hospital (Hôpital des
Spécialités), Mohammed V University, Rabat, Morocco.
Kearns-Sayre syndrome is a rare mitochondrial disorder. It had a triad of
features, including progressive external ophthalmoplegia, pigmentary
retinopathy, and an alteration of cardiac conduction. The ocular manifestations
include bilateral ptosis, progressive external ophthalmoplegia, and atypical
pigmentary retinopathy. We report the case of a 9-year-old Moroccan patient who
has been diagnosed with Kearns-Sayre syndrome during an ophthalmologic
school-based screening. This case highlights the interest of school-based
screening in the diagnosis and management of a rare disease.
Copyright: Amine Ennejjar et al.
DOI: 10.11604/pamj.2022.41.226.33085
PMCID: PMC9167473
PMID: 35721635 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/35073857 | 1. BMC Ophthalmol. 2022 Jan 24;22(1):35. doi: 10.1186/s12886-021-02224-7.
Kearns-Sayre syndrome with a novel large-scale deletion: a case report.
Zhu Q(1), Chen C(1), Yao J(2).
Author information:
(1)Department of Ophthalmology, the First Affiliated Hospital of Soochow
University, 188 Shizi Sreet, Suzhou, 215006, PR China.
(2)Department of Ophthalmology, the First Affiliated Hospital of Soochow
University, 188 Shizi Sreet, Suzhou, 215006, PR China. [email protected].
BACKGROUND: Kearns-Sayre syndrome (KSS) is a rare, multisystem mitochondrial
encephalomyopathy. We report a case of KSS with a novel 7.6-kb deletion as
assessed through a long-range polymerase chain reaction (PCR) study in the
blood. In addition, optical coherence tomography angiography (OCTA) confirmed
deep retinal capillary atrophy for the first time.
CASE PRESENTATION: A 13-year-old patient presented with progressive vision loss
and difficulty with eye opening and was diagnosed with progressive external
ophthalmoplegia and retinitis pigmentosa (RP). The patient also experienced
heart block, vestibular dysfunction, growth retardation and multiple
demyelinating lesions. A long-range PCR study in the blood revealed a
large-scale Chrm: 6341-13,993 deletion, which was first reported and broadened
the genetic spectrum of this disease. The patient underwent complete ophthalmic
examination, medical history review and gene detection, resulting in a
confirmation of the diagnosis of KSS. The patient was given a pair of applicable
glasses to wear and was followed up every 3 months. An implantable pacemaker was
also installed based on the advice of the physician.
CONCLUSIONS: We reported a novel large-scale deletion in the mitochondrial DNA
of KSS, and OCTA was used for the first time to confirm deep retinal capillary
atrophy. Furthermore, because ophthalmic symptoms are often the primary
manifestation of KSS, the relationship between ophthalmology and mitochondrial
diseases should be emphasised.
© 2022. The Author(s).
DOI: 10.1186/s12886-021-02224-7
PMCID: PMC8785533
PMID: 35073857 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no competing
interests. |
http://www.ncbi.nlm.nih.gov/pubmed/36181358 | 1. Mol Genet Genomic Med. 2023 Jan;11(1):e2059. doi: 10.1002/mgg3.2059. Epub 2022
Oct 1.
Kearns-Sayre syndrome case. Novel 5,9 kb mtDNA deletion.
Grigalionienė K(1), Burnytė B(1), Balkelienė D(1), Ambrozaitytė L(1), Utkus
A(1).
Author information:
(1)Department of Human and Medical Genetics, Institute of Biomedical Sciences,
Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
BACKGROUND: Kearns-Sayre syndrome (KSS) is a rare multisystem mitochondrial
disorder characterized by onset before 20 years of age and a typical clinical
triad: progressive external ophthalmoplegia, pigmentary retinopathy and cardiac
conduction anomalies. In most cases KSS is caused by spontaneous heteroplasmic
single large-scale mitochondrial DNA (mtDNA) deletions. Long-range polymerase
chain reaction (LR-PCR), next generation sequencing (NGS) and multiplex
ligation-dependent probe amplification (MLPA) are the most widely applied
methods for the identification of mtDNA deletions. Here, we report the case of
20-year-old male who presented with classic Kearns-Sayre syndrome, confirmed by
novel 5,9 kb mtDNA deletion.
METHODS AND RESULTS: LR-PCR and MLPA methods were applied to identify the
mitochondrial DNA deletion for the patient, but the results were conflicting.
Molecular analysis using primer walking and Sanger sequencing identified a novel
5888 base pairs mtDNA deletion (NC_012920.1:m.6069_11956del) with CAAC
nucleotides repeat sequence at the breakpoints.
CONCLUSION: Our study enriched the mtDNA variation spectrum associated with KSS
and demonstrated the importance of choosing relevant molecular genetic methods.
© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley
Periodicals LLC.
DOI: 10.1002/mgg3.2059
PMCID: PMC9834195
PMID: 36181358 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that this research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/1638160 | 1. Eur J Ophthalmol. 1992 Jan-Mar;2(1):15-20. doi: 10.1177/112067219200200104.
Kearns-Sayre syndrome: a case report and review.
Gross-Jendroska M(1), Schatz H, McDonald HR, Johnson RN.
Author information:
(1)Free University of Berlin, Germany.
In 1958, Kearns and Sayre described a multisystem entity, now known as
Kearns-Sayre syndrome (KSS). The syndrome is defined as exhibiting a triad of
thus far unexplained degenerative conditions: progressive external
ophthalmoplegia, retinal pigmentary degeneration, and heart block. Commonly
accompanying findings include cerebellar dysfunction and CSF protein levels
above 100 mg/dl. Symptoms usually appear in early childhood, but the onset has
been seen occasionally in young adults. KSS is a mitochondrial disorder that
occurs rarely; the actual incidence is unknown. Ocular findings consist of
bilateral ptosis, chronic progressive external ophthalmoplegia, and pigmentary
retinopathy. Corneal clouding and optic neuritis are infrequent. We herein
report a classic case of Kearns Sayre syndrome and discuss the findings.
DOI: 10.1177/112067219200200104
PMID: 1638160 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26949540 | 1. Oxf Med Case Reports. 2016 Mar 3;2016(3):34-6. doi: 10.1093/omcr/omw007.
eCollection 2016 Mar.
A rare case of Kearns-Sayre syndrome in a 17-year-old Venezuelan male with
bilateral ptosis as the initial presentation.
Leal M(1), Dhoble C(2), Lee J(1), Lopez D(1), Menéndez LS(3).
Author information:
(1)Universidad del Zulia Facultad de Medicina , Maracaibo, Zulia , Venezuela.
(2)N.K.P. Salve Institute of Medical Sciences and Research Center , Nagpur ,
India.
(3)Universidad Anahuac Mexico Norte , Huixquilucan , Mexico.
Kearns-Sayre syndrome (KSS) was first described in 1958 as 'a rare neuromuscular
disorder defined by a characteristic triad of progressive external
ophthalmoplegia, pigmentary retinopathy, atrioventricular block and cerebellar
ataxia'. The prevalence rate of KSS is ∼1-3 per 100 000 individuals. Here, we
report a rare case of a 17-year-old Venezuelan male with KSS.
DOI: 10.1093/omcr/omw007
PMCID: PMC4776051
PMID: 26949540 |
http://www.ncbi.nlm.nih.gov/pubmed/22875312 | 1. Eur J Pediatr. 2013 Apr;172(4):557-61. doi: 10.1007/s00431-012-1798-1. Epub
2012 Aug 9.
A rare case report of simultaneous presentation of myopathy, Addison's disease,
primary hypoparathyroidism, and Fanconi syndrome in a child diagnosed with
Kearns-Sayre syndrome.
Tzoufi M(1), Makis A, Chaliasos N, Nakou I, Siomou E, Tsatsoulis A, Zikou A,
Argyropoulou M, Bonnefont JP, Siamopoulou A.
Author information:
(1)Child Health Department, Medical School, University of Ioannina, P.O. Box
1187, 45110 Ioannina, Greece.
Kearns-Sayre syndrome (KSS) is a rare mitochondrial DNA deletion syndrome
defined as the presence of ophthalmoplegia, pigmentary retinopathy, onset less
than age 20 years, and one of the following: cardiac conduction defects,
cerebellar syndrome, or cerebrospinal fluid protein above 100 mg/dl. KSS may
affect many organ systems causing endocrinopathies, encephalomyopathy,
sensorineural hearing loss, and renal tubulopathy. Clinical presentation at
diagnosis is quite heterogeneous and, usually, few organs are affected with
progression to generalized disease early in adulthood. We present the case of a
boy with KSS presenting at the age of 5 years with myopathy, Addison's disease,
primary hypoparathyroidism, and Fanconi syndrome. The proper replacement
treatment along with the administration of mitochondrial metabolism-improving
agents had a brief ameliorating effect, but gradual severe multisystemic
deterioration was inevitable over the next 5 years.
CONCLUSION: This report highlights the fact that in case of simultaneous
presentation of polyendocrinopathies and renal disease early in childhood, KSS
should be considered.
DOI: 10.1007/s00431-012-1798-1
PMID: 22875312 [Indexed for MEDLINE] |