C.O.1 Identification of a new gene mutated in autosomal recessive centronuclear myopathy, and functional links with the dominant form (original) (raw)
Centronuclear (myotubular) myopathies (CNM) are characterized by muscle weakness and abnormal centralisation of nuclei in muscle fibres which is not secondary to excessive regeneration. The severe neonatal X-linked form (myotubular myopathy, XLMTM) is due to mutations in the phosphoinositide phosphatase myotubularin (MTM1), while mutations in dynamin 2 (DNM2) have been found in some autosomal dominant cases. By direct sequencing of functional candidate genes, we identified homozygous mutations of the amphiphysin 2 gene (also called BIN1, a putative tumor suppressor) 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. Our results suggest that mutations in amphiphysin 2 cause recessive centronuclear myopathy by interfering with membrane remodeling, and that the functional interaction between amphiphysin 2 and dynamin 2 is necessary for normal muscle function.