Résumé :
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Generation of skeletal muscles with forms adapted to their function is essential for normal movement, and involves developmental mechanisms such as those regulating muscle diversification and migration. Understanding these developmental processes might provide the bases to identify potential causes of human myopathies affecting specific groups of muscles, among which the most common is Facioscapulohumeral muscular dystrophy (FSHD), a hereditary pathology affecting groups of muscles in the face and shoulder. Despite the identification in the early 1990s of its causal chromosomal abnormality - the reduction in size of an array of macrosatellite repeats, D4Z4, on chromosome 4, the molecular mechanisms leading to FSHD pathogenesis are still incompletely understood. We report the unexpected finding that mice with reduced expression of the Planar Cell Polarity (PCP) gene FAT1, a gene regulating collective and polarized cell migration during development, reproduce the highly selective muscular and non-muscular aspects of the clinical picture of FSHD. During development, Fat1-deficiency perturbs migration polarity, consequently altering the shape of specific groups of scapular belt muscles. At postnatal stages, FAT1 mutant mice showed selective reduction of shoulder muscle mass followed by more widespread muscular dystrophy. Moreover FAT1 mutant mice also show non-muscle defects characteristic of FSHD such as retinal vasculopathy. Together, these phenotypes are reminiscent of the clinical phenotype of patients with FSHD. Interestingly, we observed reduced levels of FAT1 RNA in human FSHD muscle, but not brain, suggesting that the tissue-specific lowering of FAT1 expression may play a major role in triggering the disease. Evidence for such a direct role is supported by the finding that this reduction of FAT1 expression is genetically or epigenetically encoded. Strikingly, we found two ways by which silencing of FAT1 expression was associated with FSHD. First, in two FSHD1 samples carrying a pathogenic D4Z4 contraction, we observed a strong increase in chromatin marks associated with silencing, both at promoter and enhancer level. Second, in three additional FSHD cases with a non-pathogenic D4Z4 array, we discovered deletions of an internal intronic enhancer. Thus, even in the absence of D4Z4 contractions, tissue-specific lowering of expression of this developmental gene is a potential causal mechanism for FSHD.
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