Hypomethylation is restricted to the D4Z4 repeat array in phenotypic FSHD

Greef, Jessica C. de; Wohlgemuth, M.; Chan, On Ying A.; Hansson, Kerstin; Smeets, Dominique; Frants, Rune R.; Weemaes, C.M.R.; Padberg, George W.; Maarel, Silvère M. van der

doi:10.1212/01.wnl.0000271391.44352.fe

Cited by 70 publications

(75 citation statements)

References 27 publications

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“…However, in these patients also no D4Z4 hypomethylation was observed, suggestive of the possible presence of an additional muscular dystrophy in this family. In addition, in one of these two patients there was insufficient clinical certainty of FSHD [25] .…”

Section: Figurementioning

confidence: 90%

“…Interestingly, DNA methylation of the proximal D4Z4 repeat unit on the disease allele was significantly reduced in patients with FSHD1, both in DNA isolated from peripheral blood lymphocytes (PBLs) and from muscle [24] . Also in a small group of FSHD2 patients without D4Z4 contraction but with clinical symptoms indistinguishable from FSHD1 patients, significant D4Z4 hypomethylation at both chromosome 4q alleles was observed [24,25] .…”

Section: Introductionmentioning

confidence: 87%

“…Methylation levels )20% were only detected in a small cohort of FSHD2 patients while FSHD1 patients showed on average 33% methylation at the FseI restriction site [24] . Some FSHD2 cases have been described before [24,25] , but most of them were collected recently. In all of them, we observed significant CpoI hypomethylation in proximal and internal units on chromosomes 4q and 10q (Figure 2A, 3A and 3B; P)0.002).…”

Section: D4z4 Hypomethylation On Chromosomes 4q and 10q In Fshd2 Patimentioning

confidence: 99%

“…Previously, we have sequenced several candidate genes involved in chromatin structure, including DNMT1, DNMT3A, DNMT3B, DNMT3L, MTHFS, LMNA, CBX2, CBX5 and SUV39H1, in a subset of FSHD2 patients. However, no disease-specific SNPs or mutations were identified [25] . Furthermore, the hypomethylation in FSHD2 patients seems restricted to D4Z4, as no hypomethylation of other repeats, including satellite 2 and 3 DNA, _-satellite DNA and the NBL2 repeat, was observed in these patients [25] .…”

Section: Fshd1 and Fshd2 Share A Common Epigenetic Disease Mechanismmentioning

confidence: 99%

“…However, no disease-specific SNPs or mutations were identified [25] . Furthermore, the hypomethylation in FSHD2 patients seems restricted to D4Z4, as no hypomethylation of other repeats, including satellite 2 and 3 DNA, _-satellite DNA and the NBL2 repeat, was observed in these patients [25] . As judged from the fact that all FSHD2 patients in our collection carry at least one pathogenic 4qA161 allele (Table 1), we hypothesize that to develop FSHD a change in the chromatin structure of D4Z4 and a 4qA161 allele are required, as was already noted in FSHD1 patients, where the D4Z4 contraction is always associated with the 4qA161 haplotype [17] .…”

Section: Fshd1 and Fshd2 Share A Common Epigenetic Disease Mechanismmentioning

confidence: 99%

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Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD

et al. 2009

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Facioscapulohumeral muscular dystrophy (FSHD), caused by partial deletion of the D4Z4 macrosatellite repeat on chromosome 4q, has a complex genetic and epigenetic etiology. To develop FSHD, D4Z4 contraction needs to occur on a specific genetic background. Only contractions associated with the 4qA161 haplotype cause FSHD. In addition, contraction of the D4Z4 repeat in FSHD patients is associated with significant D4Z4 hypomethylation. To date however, the methylation status of contracted repeats on non-pathogenic haplotypes has not been studied. We have performed a detailed methylation study of the D4Z4 repeat on chromosome 4q and on a highly homologous repeat on chromosome 10q. We show that patients with a D4Z4 deletion (FSHD1) have D4Z4-restricted hypomethylation. Importantly, controls with a D4Z4 contraction on a non-pathogenic chromosome 4q haplotype or on chromosome 10q also demonstrate hypomethylation. In fifteen FSHD families without D4Z4 contractions but with at least one 4qA161 haplotype (FSHD2), we observed D4Z4-restricted hypomethylation on chromosomes 4q and 10q. This finding implies that a genetic defect resulting in D4Z4 hypomethylation underlies FSHD2. In conclusion, we describe two ways to develop FSHD; (1) contraction-dependent or (2) contraction-independent D4Z4 hypomethylation on the 4qA161 subtelomere.

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Section: Figurementioning

confidence: 90%

Section: Introductionmentioning

confidence: 87%

Section: D4z4 Hypomethylation On Chromosomes 4q and 10q In Fshd2 Patimentioning

confidence: 99%

Section: Fshd1 and Fshd2 Share A Common Epigenetic Disease Mechanismmentioning

confidence: 99%

Section: Fshd1 and Fshd2 Share A Common Epigenetic Disease Mechanismmentioning

confidence: 99%

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Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD

et al. 2009

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Facioscapulohumeral Muscular Dystrophy: Genetics

Magdinier

Upadhyaya

2018

Encyclopedia of Life Sciences

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Facioscapulohumeral muscular dystrophy (FSHD) is the third most common inherited muscular dystrophy that presents clinically with progressive weakness of the facial, scapular and humeral muscles, with later involvement of the trunk and lower extremities. FSHD is a unique disease with complex genetic and epigenetic aetiology and the underlying biological mechanisms are still not fully deciphered. FSHD1 is more frequent (95%) and is associated with the contraction of the D4Z4 macrosatellite repeat array located on a permissive 4qA chromosome combined with decreased methylation of cytosines at the 4q35‐linked D4Z4 units. D4Z4 contraction allows epigenetic derepression of the D4Z4 array allowing the expression of the toxic DUX4 transcription factor encoded within the terminal D4Z4 repeat in skeletal muscles. FSHD2 associated with approximately 2–3% of the FSHD patients results from haploinsufficiency of the SMCHD1 gene in individuals carrying a permissive 4qA allele and marked hypomethylation of 4q and 10q D4Z4, which leads to the derepression of DUX4 hence DUX4 appears to be a key player in both types of FSHD. Currently, there is no reliable treatment for this condition, therefore for the successful development of new treatments, an integration of clinical and pathogenetic information is vital. Key Concepts FSHD is the third most common inherited muscular dystrophy characterised by a typical phenotype and involvement of specific groups of muscles. FSHD is characterised by a highly variable penetrance and clinical severity. In most cases, FSHD involves shortening of a repetitive macrosatellite array. The D4Z4 macrosatellite linked to FSHD encodes the DUX4 transcription factor. A small proportion of FSHD patients carry mutation in the SMCHD1 gene. Epigenetic changes in FSHD are closely associated with molecular features. FSHD is a unique disease with complex genetic and epigenetic aetiology and the underlying biological mechanisms are still not fully deciphered. There is no reliable treatment for the disease.

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DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53‐dependent myopathy in vivo

Wallace

Garwick

Mei

et al. 2010

Annals of Neurology

220

262

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Objective Facioscapulohumeral muscular dystrophy (FSHD) is associated with D4Z4 repeat contraction on human chromosome 4q35. This genetic lesion does not result in complete loss or mutation of any gene. Consequently, the pathogenic mechanisms underlying FSHD have been difficult to discern. In leading FSHD pathogenesis models, D4Z4 contractions are proposed to cause epigenetic changes, which ultimately increase expression of genes with myopathic potential. Although no gene has been conclusively linked to FSHD development, recent evidence supports a role for the D4Z4-encoded DUX4 gene in FSHD. In this study, our objective was to test the in vivo myopathic potential of DUX4. Methods We delivered DUX4 to zebrafish and mouse muscle by transposon-mediated transgenesis and adeno-associated viral vectors, respectively. Results Overexpression of DUX4, which encodes a transcription factor, caused abnormalities associated with muscular dystrophy in zebrafish and mice. This toxicity required DNA binding, because a DUX4 DNA binding domain mutant produced no abnormalities. Importantly, we found the myopathic effects of DUX4 were p53 dependent, as p53 inhibition mitigated DUX4 toxicity in vitro, and muscles from p53 null mice were resistant to DUX4-induced damage. Interpretation Our work demonstrates the myopathic potential of DUX4 in animal muscle. Considering previous studies showed DUX4 was elevated in FSHD patient muscles, our data support the hypothesis that DUX4 overexpression contributes to FSHD development. Moreover, we provide a p53-dependent mechanism for DUX4 toxicity that is consistent with previous studies showing p53 pathway activation in FSHD muscles. Our work justifies further investigation of DUX4 and the p53 pathway in FSHD pathogenesis.

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Hypomethylation is restricted to the D4Z4 repeat array in phenotypic FSHD

Abstract: Our data suggest that in phenotypic FSHD hypomethylation is restricted to D4Z4 and that phenotypic FSHD and ICF do not share a defect in the same molecular pathway.

Cited by 70 publications

References 27 publications

Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD

Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD

Facioscapulohumeral Muscular Dystrophy: Genetics

DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53‐dependent myopathy in vivo

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