FSHD: copy number variations on the theme of muscular dystrophy

Cabianca, Daphne S.; Gabellini, Davide

doi:10.1084/jem20713oia38

Cited by 18 publications

(22 citation statements)

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“…23 Another aspect is the known clinical variability even within the families that was already observed by the first describers of the disease, Landouzy and Dejerine in 1886. 46 Mutations in SMCHD1 explain only a fraction of patients with typical FSHD phenotype and no D4Z4 contraction. These findings give rise to the assumption for other genetic, epigenetic or environmental disease modifiers in FSHD.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic approach for FSHD revisited: SMCHD1 mutations cause FSHD2 and act as modifiers of disease severity in FSHD1

et al. 2014

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Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscular disorder with a wide clinical variability. Contractions of the D4Z4 macrosatellite repeat on chromosome 4q35 are the molecular basis of the pathophysiology. Recently, in a subset of patients without D4Z4 repeat contractions, variants in the SMCHD1 gene have been identified that lead to hypomethylation of D4Z4 and thus DUX4 transcription, which causes FSHD type 2. In this study, we have screened 55 FSHD1-negative and 40 FSHD1-positive patients from unrelated families for potentially pathogenic variants in SMCHD1 by nextgeneration sequencing (NGS). We identified variants in SMCHD1 in 11 index patients, including missense, splice site and nonsense mutations. We developed a pyrosequencing assay to determine the methylation status of the D4Z4 repeat array and found significantly lower methylation levels for FSHD2 patients than for healthy controls and FSHD1 patients. Two out of eleven SMCHD1 mutation carriers had moderately contracted D4Z4 alleles thus these patients are suffering from FSHD1 and 2. Comparing the phenotype of patients, all FSHD2 patients were relatively mildly affected while patients with FSHD1+2 were much more severely affected than expected from their D4Z4 copy number. Our findings confirm the role of SMCHD1 mutations in FSHD2 and as a modifier of disease severity. With SMCHD1 variants found in 16.4% of phenotypic FSHD patients without D4Z4 repeat contractions, the incidence of FSHD2 is rather high and hence we suggest including sequencing of SMCHD1, haplotyping and methylation analysis in the workflow of molecular FSHD diagnostics.

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Section: Discussionmentioning

confidence: 99%

Diagnostic approach for FSHD revisited: SMCHD1 mutations cause FSHD2 and act as modifiers of disease severity in FSHD1

et al. 2014

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“…All current models predict that deletion of D4Z4 repeats results in the de-regulation of a candidate gene(s), located in the FSHD region, leading to disease (Cabianca and Gabellini, 2010;. While the two most accepted FSHD candidate genes are DUX4 and FRG1, the molecular and cellular mechanism following their de-regulation and finally causing the disease remains elusive.…”

Section: Discussionmentioning

confidence: 99%

“…Facioscapulohumeral muscular dystrophy (FSHD, OMIM 158900) is the third most common muscular dystrophy, exhibits autosomal dominant inheritance and has no cure (Cabianca and Gabellini, 2010). FSHD typically arises with a reduction of facial and shoulder girdle muscle mass.…”

Section: Introductionmentioning

confidence: 99%

Facioscapulohumeral muscular dystrophy region gene 1 over-expression causes primary defects of myogenic stem cells

Xynos

Neguembor

Caccia

et al. 2013

Journal of Cell Science

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SummaryOverexpression of facioscapulohumeral muscular dystrophy region gene 1 (FRG1) in mice, frogs and worms leads to muscular and vascular abnormalities. Nevertheless, the mechanism that follows FRG1 overexpression and finally leads to muscular defects is currently unknown. Here, we show that the earliest phenotype displayed by mice overexpressing FRG1 is a postnatal muscle-growth defect. Long before the development of muscular dystrophy, FRG1 mice also exhibit a muscle regeneration impairment. Ex vivo and in vivo experiments revealed that FRG1 overexpression causes myogenic stem cell activation and proliferative, clonogenic and differentiation defects. A comparative gene expression profiling of muscles from young pre-dystrophic wild-type and FRG1 mice identified differentially expressed genes in several gene categories and networks that could explain the emerging tissue and myogenic stem cell defects. Overall, our study provides new insights into the pathways regulated by FRG1 and suggests that muscle stem cell defects could contribute to the pathology of FRG1 mice.

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“…Unaffected individuals have unshortened arrays with 410 D4Z4 repeats, whereas contraction to 1-10 repeats is associated with FSHD. 2,3 A small percentage of FSHD subjects (FSHD2) show the FSHD muscle weakness pattern but do not have a contracted 4q D4Z4 array. 4 Recent work has suggested that both types of FSHD are characterized by expression and stabilization of mRNA produced from an open reading frame in the most telomeric D4Z4 repeat that encodes a potentially toxic protein: a long isoform of DUX4.…”

Section: Introductionmentioning

confidence: 99%

A unique library of myogenic cells from facioscapulohumeral muscular dystrophy subjects and unaffected relatives: family, disease and cell function

et al. 2011

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To explore possible mechanisms of pathology in facioscapulohumeral muscular dystrophy (FSHD), we generated a novel library of myogenic cells composed of paired cultures derived from FSHD subjects and unaffected first-degree relatives. We prepared cells from biopsies of both biceps and deltoid muscles obtained from each of 10 FSHD and 9 unaffected donors. We used this new collection to determine how family background and disease affected patterns of growth and differentiation, expression of a panel of candidate, and muscle-specific genes, and responses to exogenous stressors. We found that FSHD and unaffected cells had, on average, indistinguishable patterns of differentiation, gene expression, and dose-response curves to staurosporine, paraquat, hydrogen peroxide, and glutathione depletion. Differentiated FSHD and unaffected cultures were both more sensitive to glutathione depletion than proliferating cultures, but showed similar responses to paraquat, staurosporine, and peroxide. For stress responses, the sample size was sufficient to detect a 10% change in effect at the observed variability with a power of 499%. In contrast, for each of these properties, we found significant differences among cells from different cohorts, and these differences were independent of disease status, gender, or muscle biopsied. Thus, though none of the properties we examined could be used to reliably distinguish between FSHD and unaffected cells, family of origin was an important contributor to gene-expression patterns and stressor responses in cultures of both FSHD and unaffected myogenic cells.

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FSHD: copy number variations on the theme of muscular dystrophy

Cited by 18 publications

References 1 publication

Diagnostic approach for FSHD revisited: SMCHD1 mutations cause FSHD2 and act as modifiers of disease severity in FSHD1

Diagnostic approach for FSHD revisited: SMCHD1 mutations cause FSHD2 and act as modifiers of disease severity in FSHD1

Facioscapulohumeral muscular dystrophy region gene 1 over-expression causes primary defects of myogenic stem cells

A unique library of myogenic cells from facioscapulohumeral muscular dystrophy subjects and unaffected relatives: family, disease and cell function

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