Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy

Centronuclear myopathies are characterized by muscle weakness and abnormal centralization of nuclei in muscle fibers not secondary to regeneration. The severe neonatal X- linked form ( myotubular myopathy) is due to mutations in the phosphoinositide phosphatase myotubularin ( MTM1)(1), whereas mutations in dynamin 2 ( DNM2) have been found in some autosomal dominant cases(2). By direct sequencing of functional candidate genes, we identified homozygous mutations in amphiphysin 2 ( BIN1) in three families with autosomal recessive inheritance. Two missense mutations affecting the BAR ( Bin1/ amphiphysin/ RVS167) domain disrupt its membrane tubulation properties in transfected cells, and a partial truncation of the C- terminal SH3 domain abrogates the interaction with DNM2 and its recruitment to the membrane tubules. Our results suggest that mutations in BIN1 cause centronuclear myopathy by interfering with remodeling of T tubules and/ or endocytic membranes, and that the functional interaction between BIN1 and DNM2 is necessary for normal muscle function and positioning of nuclei.