The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein

Kowaljow, Valeria; Marcowycz, Aline; Ansseau, Eugénie; Conde, Cecı́lia; Sauvage, Sébastien; Mattéotti, Christel; Arias, Cristina; Corona, E.D.; Núñez, Nicolás Gonzalo; Léo, Oberdan; Wattiez, Ruddy; Figlewicz, Denise A.; Laoudj-Chenivesse, Dalila; Belayew, Alexandra; Coppée, Frédérique; Rosa, Alberto L.

doi:10.1016/j.nmd.2007.04.002

Cited by 290 publications

(339 citation statements)

References 42 publications

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“…It will be crucial to identify 4qA161-specific sequence polymorphisms and show their effect on the binding of proteins to the D4Z4 repeat or on the production of transcripts from the D4Z4 repeat. Expression of two different transcripts from D4Z4 was reported previously [45,46] . While the first transcript is transcribed from internal repeat units, the second transcript is transcribed from the distal D4Z4 repeat unit.…”

Section: Fshd1 and Fshd2 Share A Common Epigenetic Disease Mechanismmentioning

confidence: 66%

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: Fshd1 and Fshd2 Share A Common Epigenetic Disease Mechanismmentioning

confidence: 66%

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

et al. 2009

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“…7 Many studies have, therefore, used primary myogenic cell cultures derived from FSHD subject biopsies to examine potential pathogenic mechanisms and therapeutic strategies. [8][9][10][11][12][13][14][15] Such studies have suggested several possible FSHD-specific phenotypes, including increased sensitivity to oxidative stress 14,16 and altered gene expression, [17][18][19][20] as well as expression of the long form of DUX4. 5,6 These findings have, however, sometimes not been consistent among laboratories.…”

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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“…The de-repression of this transcription factor results in significant cell toxicity. It is accumulated into the nucleus where it is involved in emerin relocalization and caspase 3 and/or 7 induction, resulting in increased cell death [7]. Moreover, its expression is correlated with lower MyoD expression levels, preventing normal cell signaling, and contributing to the final FSHD phenotype [8].…”

Section: Facioscapulohumeral Muscular Dystrophy (Fshd) Is a Neuromuscmentioning

confidence: 99%

The activatory long non-coding RNA DBE-T reveals the epigenetic etiology of facioscapulohumeral muscular dystrophy

Vizoso

Esteller

2012

Cell Res

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The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein

Cited by 290 publications

References 42 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

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

The activatory long non-coding RNA DBE-T reveals the epigenetic etiology of facioscapulohumeral muscular dystrophy

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