Résumé :
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Myotonic dystrophy (DM) is the most common muscular dystrophy in adults and comprises two genetically distinct forms, both of which are caused by expansions of microsatellite repeats. The expansion of a CTG repeat in the 3'-UTR of the DMPK gene leads to myotonic dystrophy type 1 (DM1) and its congenital form (CDM). The expansion of a CCTG repeat in the ZNF9 gene causes myotonic dystrophy type 2 (DM2). Expression of abnormal transcripts containing expanded CUG or CCUG repeats interferes with the splicing of other mRNAs, through sequestering of splicing factor muscleblind (MBNL1).We found that alternative splicing of the BIN1 mRNA is altered in CDM, DM1 and DM2 skeletal muscle tissues. Amphiphysin II (BIN1) belongs to the superfamily of BAR proteins, and is involved in diverse cellular functions, including endocytosis, intracellular transport, and synaptic vesicle recycling. In muscle, BIN1 plays an important role in tubular invaginations of the plasma membrane and is required for biogenesis of T-tubules, which are specialized skeletal muscle membrane structures essential for excitation-contraction (EC) coupling. Mutations in the BIN1 gene cause centronuclear myopathy (CNM) that shares some histopathological features with DM, and both diseases are characterized by muscle weakness. Our study shows that MBNL1 binds to the BIN1 pre-mRNA and regulates its alternative splicing. Next, BIN1 splicing mis-regulation results in the expression of an inactive form of BIN1 deprived of phosphoinositide-binding and membrane-tubuling activities. Consistent with a loss-of-function of BIN1, muscle T-tubules are altered in DM patients and BIN1 structures are restored upon expression of the normal splicing form of BIN1 in DM muscle cells. Finally, reproducing BIN1 splicing alteration in mice is sufficient to promote T-tubule alterations ans muscle weakness.We propose a model where the alteration of BIN1 alternative splicing regulation leads to muscle weakness, a predominant pathological feature of DM.
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