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- Title
Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy.
- Authors
Nicot, Anne-Sophie; Toussaint, Anne; Tosch, Valérie; Kretz, Christine; Wallgren-Pettersson, Carina; Iwarsson, Erik; Kingston, Helen; Garnier, Jean-Marie; Biancalana, Valérie; Oldfors, Anders; Mandel, Jean-Louis; Laporte, Jocelyn
- Abstract
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.
- Publication
Nature genetics, 2007, Vol 39, Issue 9, p1134
- ISSN
1061-4036
- Publication type
Journal Article
- DOI
10.1038/ng2086