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

Anne-Sophie Nicot (1) , Anne Toussaint (1) , Valérie Tosch (1) , Christine Kretz (1) , Carina Wallgren-Pettersson , Erik Iwarsson , Helen Kingston , Jean-Marie Garnier (1) , Valérie Biancalana , Anders Oldfors , Jean-Louis Mandel (1, 2) , Jocelyn Laporte (1)

1 IGBMC - Institut de génétique et biologie moléculaire et cellulaire
2 Collège de France - Chaire Génétique Humaine

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), whereas mutations in dynamin 2 (DNM2) have been found in some autosomal dominant cases. 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.

Domaines: Biologie moléculaire

Anne-Sophie Nicot, Anne Toussaint, Valérie Tosch, Christine Kretz, Carina Wallgren-Pettersson, et al.. Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy.. Nature Genetics, 2007, 39 (9), pp.1134-9. ⟨10.1038/ng2086⟩. ⟨hal-00189145⟩