Differential DNA methylation of the
            <i>D4Z4</i>
            repeat in patients with FSHD and asymptomatic carriers

Gaillard, Marie-Cécile; Roche, Stéphane; Dion, Camille; Tasmadjian, Armand; Bouget, Gwenaëlle; Salort‐Campana, Emmanuelle; Vovan, Catherine; Chaix, C; Broucqsault, Natacha; Morere, Julia; Puppo, Francesca; Bartoli, Marc; Lévy, Nicolas; Bernard, R.; Attarian, Shahram; Nguyen, Karine; Magdinier, Frédérique

doi:10.1212/wnl.0000000000000708

Cited by 84 publications

(111 citation statements)

References 34 publications

(40 reference statements)

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“…[5][6][7] A number of articles have looked at the relationship of D4Z4 methylation levels to penetrance of disease expression, with decreased methylation in patients expressing disease. 8,9 A linear relationship exists between the number of residual D4Z4 repeats and estimates of methylation in the D4Z4 region. 9 So for most patients with FSHD1, the repeat contraction is sufficient to decrease methylation and cause disease.…”

Section: Discussionmentioning

confidence: 99%

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Milder phenotype in facioscapulohumeral dystrophy with 7–10 residual D4Z4 repeats

et al. 2015

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Objective: To examine the relationship of clinical and genetic features of patients with facioscapulohumeral muscular dystrophy (FSHD) with 7-10 residual D4Z4 repeats in a large genetically defined FSHD1 cohort.Methods: We performed a prospective cross-sectional observational study of 74 clinically affected patients with FSHD1. Measures of clinical severity were compared between patients with 1-6 D4Z4 repeats and 7-10 repeats, and included D4Z4 CpG methylation, age at diagnosis, age-adjusted clinical severity score, a muscle pathology grade of quadriceps biopsies (0 5 normal, 12 5 severe dystrophic changes), quantitative myometry of biopsied muscles, global manual muscle testing scores, and frequency of wheelchair use.Results: Twenty-eight (37.8%) participants had 7-10 D4Z4 repeats, and compared to participants with 1-6 repeats, were diagnosed 6.6 years older (p 5 0.17); had lower CpG methylation than would be predicted by D4Z4 repeat size (p 5 0.04); had age-adjusted clinical severity 39.8 points lower (p 5 0.004); had muscle pathology grades that were 2.4 points less severe (p , 0.0001); had quantitative myometry 28.3% predicted of normal higher (p 5 0.002); had global manual muscle testing scores 0.6 higher (p 5 0.005); and did not require wheelchairs. Facioscapulohumeral muscular dystrophy (FSHD) is a common muscular dystrophy due in its most prevalent form (FSHD1) to deletions in the D4Z4 macrosatellite repeat region on chromosome 4q35.1,2 While normal individuals have .10 repeats, patients with FSHD1 have between 1 and 10 repeats. The current model for disease proposes FSHD is an epigenetic disease: deletions lead to decreased CpG methylation and opening of chromatin structure. 3The open chromatin structure in combination with a polyadenylation signal polymorphism allow the transcription of a normally repressed gene located within the D4Z4 repeat, DUX4, which causes disease by a toxic gain of function. 4Patients with the smallest number of repeats demonstrate a more severe phenotype, including earlier wheelchair use and increased frequency of extramuscular manifestations (retinal vasculopathy and hearing loss).5-7 A number of articles have looked at the relationship of D4Z4 methylation levels to penetrance of disease expression, with decreased methylation in patients expressing disease. 8,9 A linear relationship exists between the number of residual D4Z4 repeats and estimates of methylation in the D4Z4 region.9 So for most patients with FSHD1, the repeat contraction is sufficient to decrease methylation and cause disease. Symptomatically affected patients with 7-10 repeats, unlike patients with 1-6 repeats, have divergent methylation values

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Section: Discussionmentioning

confidence: 99%

“…8,9 A linear relationship exists between the number of residual D4Z4 repeats and estimates of methylation in the D4Z4 region.…”

mentioning

confidence: 99%

Milder phenotype in facioscapulohumeral dystrophy with 7–10 residual D4Z4 repeats

et al. 2015

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“…One hypothesis to explain how the contraction of D4Z4 leads to deregulation of nearby genes in FSHD (van Geel et al 1999;Jiang et al 2003;Celegato et al 2006;Caruso et al 2013) on 4q is via chromosomal looping and/or epigenetic modifications Gaillard et al 2014;Jones et al 2014). The number of D4Z4 repeats might influence the ability of repressor or enhancer binding sequences within the repeats to loop and form contacts with other genes in the 4q region and thereby influence transcription (Pirozhkova et al 2008;Tsumagari et al 2008;Bodega et al 2009;Ottaviani et al 2009).…”

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

“…Assay was performed as previously described (Gaillard et al 2014) with 2 μg of genomic DNA denatured for 30 min at 37°C in NaOH 0.4 N and incubated overnight in a solution of sodium bisulfite 3 M pH5 and 10 mM hydroquinone. For further details, see Supplemental Material.…”

Section: Methylation Assay By Sodium Bisulfite Sequencingmentioning

confidence: 99%

SORBS2transcription is activated by telomere position effect–over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy

et al. 2015

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DNA is organized into complex three-dimensional chromatin structures, but how this spatial organization regulates gene expression remains a central question. These DNA/chromatin looping structures can range in size from 10-20 kb (enhancers/repressors) to many megabases during intra-and inter-chromosomal interactions. Recently, the influence of telomere length on chromatin organization prior to senescence has revealed the existence of long-distance chromatin loops that dictate the expression of genes located up to 10 Mb from the telomeres (Telomere Position Effect-Over Long Distances [TPE-OLD]). Here, we demonstrate the existence of a telomere loop at the 4q35 locus involving the sorbin and SH3 domain-containing protein 2 gene, SORBS2, a skeletal muscle protein using a modification of the chromosome conformation capture method. The loop reveals a cis-acting mechanism modifying SORBS2 transcription. The expression of this gene is altered by TPE-OLD in myoblasts from patients affected with the age-associated genetic disease, facioscapulohumeral muscular dystrophy (FSHD1A, MIM 158900). SORBS2 is expressed in FSHD myoblasts with short telomeres, while not detectable in FSHD myoblasts with long telomeres or in healthy myoblasts regardless of telomere length. This indicates that TPE-OLD may modify the regulation of the 4q35 locus in a pathogenic context. Upon differentiation, both FSHD and healthy myotubes express SORBS2, suggesting that SORBS2 is normally up-regulated by maturation/differentiation of skeletal muscle and is misregulated by TPE-OLD-dependent variegation in FSHD myoblasts. These findings provide additional insights for the complexity and age-related symptoms of FSHD.

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“…Podkreśla się dużą rolę zjawisk epigenetycznych w patogenezie FSHD, którą to hipotezę dodatkowo umacnia fakt asymetrii objawów, niezwykle typowy dla tej choroby [23]. Wreszcie pozostaje wariant FSHD2 -klinicznie identyczna postać choroby, w której nie ma zmian w dłu-gości D4Z4.…”

Section: Genetykaunclassified

Facio-scapulo-humeral dystrophy (FSHD) – the latest update

2016

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StreSzczenieDystrofia twarzowo-łopatkowo-ramieniowa (FSHD) to trzecia co do częstości występowania dystrofia mięśniowa, dziedziczona autosomalnie dominująco. Pierwsze objawy zazwyczaj manifestują się w drugiej dekadzie życia, a bardzo wczesny początek (u dzieci przed 10. rokiem życia) wiąże się z ciężkim przebiegiem choroby, szybszym postępem niesprawności oraz większym ryzykiem powikłań. Praca ma na celu przedstawienie najważniejszych zagadnień dotyczących FSHD z punktu widzenia praktyki klinicznej -objawów, diagnostyki oraz opcji terapeutycznych, z uwzględnieniem wyników najnowszych badań, aktualnego piśmiennictwa oraz wytycznych opublikowanych przez Amerykańskie Towarzystwo Neurologiczne w 2015 roku. Słowa kluczowe: dystrofia twarzowo-łopatkowo-ramieniowa, niedosłuch, teleangiektazje siatkówkowe, niewydolność oddechowa, blok odnogi pęczka Hisa abStract Facio-scapulo-humeral dystrophy (FSHD) is a third most common muscular dystrophy of autosominal dominant pattern of inheritance. The onset of symptoms usually takes place in the second decade of life, whereas very early disease manifestation (in children below 10-year old) is linked to more severe clinical picture with quicker disability progression and higher risk of complications. This paper aims to present the most relevant issues in clinical practice concerning FSHD -symptoms, diagnostic process and therapeutic options, based on the latest publications, including evidence-based guidelines published by AAN in 2015.

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Differential DNA methylation of the D4Z4 repeat in patients with FSHD and asymptomatic carriers

Abstract: This study provides Class III evidence that assays for hypomethylation within the D4Z4 region accurately distinguish patients with FSHD from individuals with D4Z4 contraction without FSHD.

Cited by 84 publications

References 34 publications

Milder phenotype in facioscapulohumeral dystrophy with 7–10 residual D4Z4 repeats

Milder phenotype in facioscapulohumeral dystrophy with 7–10 residual D4Z4 repeats

SORBS2transcription is activated by telomere position effect–over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy

Facio-scapulo-humeral dystrophy (FSHD) – the latest update

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