Résumé :
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Centronuclear (myotubular) myopathies (CNM) are characterized by muscle weakness and abnormal centralisation of nuclei in muscle fibres, which does not appear secondary to regeneration. The severe neonatal X-linked form (myotubular myopathy, XLCNM) is due to mutations in the phosphoinositides phosphatase myotubularin (MTM1), while mutations in the large GTPase dynamin 2 (DNM2) have been found in some autosomal dominant cases. We have demonstrated that MTM1 dephosphorylates the endosomal phosphoinositides PtdIns(3)P and PtdIns(3,5)P2. By direct sequencing of functional candidate genes, we identified homozygous mutations of the amphiphysin 2 gene (also called BIN1) in three families with autosomal recessive inheritance. 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. On the contrary, dynamin 2 mutants are correctly recruited by amphiphysin 2. Our results suggest that mutations in amphiphysin 2 cause centronuclear myopathy by interfering with membrane remodeling, and that the functional interaction between amphiphysin 2 and dynamin 2 is necessary but not sufficient for normal muscle function and positioning of nuclei. Current work aims to understand how mutations in different genes that are associated with centronuclear myopathies are involved in nuclear positioning and lead to the muscle weakness.
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