Résumé :
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Centronuclear myopathies (CNM) are characterized by muscle weakness and abnormal centralization of nuclei in muscle fibres without excessive regeneration. The severe neonatal X-linked form (myotubular myopathy, XLMTM) is due to mutations in the gene encoding the phosphoinositides phosphatase myotubularin (MTM1), while mutations in the membrane tubulating GTPase dynamin 2 (DNM2) have been found in some autosomal dominant cases. We identified homozygous mutations in the amphiphysin 2 gene (also called BIN1) in four families with autosomal recessive CNM. Two different missense mutations in the BAR (Bin1/Amphiphysin/RVS167) domain disrupt its membrane tubulation properties in transfected cells, while a partial truncation of the C-terminal SH3 domain abrogates the interaction with dynamin 2 and its recruitment to the membrane tubules. Although amphiphysin 2 is ubiquitously expressed, mutations in the gene induce a muscle phenotype. Amphiphysin 2 was shown to be located to T-tubules, and in the muscle of patients mutated in the amphiphysin 2 gene, we observed anomalies in the localization of markers of T-tubules biogenesis and organization. Thus we are investigating the role of amphiphysin 2 in the biogenesis and organization of these structures in skeletal muscle. Initial results indicate that it co-localizes with markers of the sarcotubular system in murine skeletal muscle. In parallel we are analyzing the impact of amphiphysin 2 mutations and T-tubule organization in several forms of myopathies with nuclei centralization.
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