Résumé :
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Facioscapulohumeral muscular dystrophy (FSHD) is the third most important myopathy. Currently, no therapeutic treatment is available for FSHD. Unlike the majority of genetic diseases, FSHD is not caused by mutation in a protein-coding gene. Instead, FSHD is the result of a complex epigenetic cascade activated by deletion of a 3.3 kb subtelomeric repeat (D4Z4) located on chromosome 4q35. D4Z4 appears to regulate chromatin structure at 4q35 and its partial deletion causes de-repression of several 4q35 genes. Notably, we found that FSHD is caused by over-expression of the 4q35 gene FRG1 and we generated the first animal model of the disease. Several evidences suggest a differentiation defect in FSHD. First, global gene expression profiling of muscle biopsies obtained from FSHD, normal as well as other muscular dystrophies showed that among the genes altered in an FSHD-specific and highly significant manner, many are involved in myogenesis, cellular differentiation, and cell-cycle control, suggesting that a partial block in the normal differentiation program occurs in FSHD muscle. Second, primary myoblasts derived from FSHD patients were reported to manifest increased susceptibility to oxidative stress, morphological aberrations and early cell cycle arrest suggestive of a defect in early myogenesis. Third, mesoangioblasts (a new class of adult stem cells of mesodermal origin) derived from FSHD patients have been shown to display impaired differentiation capabilities. To determine if these phenotypes are mediated by FRG1, we compared the differentiation capability of naïve C2C12 muscle cells, control stable cell lines containing the empty vector and stable C2C12 cells over-expressing FRG1. Interestingly, very few and very small myotubes were present in FRG1 over-expressing cells. Moreover, several myogenic markers were down-regulated in FRG1 over-expressing cells by real-time RT-PCR. Collectively, our preliminary results reveal that FRG1 over-expression inhibits muscle differentiation. The molecular mechanism responsible for FRG1 inhibition of muscle differentiation is under investigation.
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