Letter abstract
Nature Genetics 39, 1134 - 1139 (2007)
Published online: 5 August 2007 | doi:10.1038/ng2086
Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy
Anne-Sophie Nicot1,7, Anne Toussaint1,7, Valérie Tosch1, Christine Kretz1, Carina Wallgren-Pettersson2, Erik Iwarsson3, Helen Kingston4, Jean-Marie Garnier1, Valérie Biancalana5, Anders Oldfors6, Jean-Louis Mandel1,5 & Jocelyn Laporte1
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 cases2. 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.
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of Molecular Pathology, F-67400 Illkirch, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U596, F-67400 Illkirch, France; the Centre National de la Recherche Scientifique (CNRS), UMR7104, F-67400 Illkirch, France; Université Louis Pasteur, F-67000 Strasbourg, France; and Collège de France, Chaire de Génétique Humaine, F-67400 Illkirch, France.
- Department of Medical Genetics, University of Helsinki, and The Folkhälsan Institute of Genetics, Biomedicum, FIN-00014 Helsinki, Finland.
- Clinical Genetics Unit, Department of Molecular Medicine and Surgery, Karolinska University Hospital, S-171 76 Stockholm, Sweden.
- Academic Unit of Medical Genetics and Regional Genetic Service, Central Manchester and Manchester Children's University Hospitals, Manchester M13 OJH, UK.
- Laboratoire de Diagnostic Génétique, CHRU–Faculté de Médecine et Laboratoire de Génétique Médicale EA3949, Université Louis Pasteur, Strasbourg F-67085, France.
- Department of Pathology, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden.
- These authors contributed equally to this work.
Correspondence to: Jocelyn Laporte1 e-mail: mtm@igbmc.u-strasbg.fr
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RESEARCH
Mutations in dynamin 2 cause dominant centronuclear myopathyNature Genetics Brief Communication (01 Nov 2005)
Crystal structure of the amphiphysin-2 SH3 domain and its role in the prevention of dynamin ring formationThe EMBO Journal Article (15 Sep 1998)
Regulation of Bin1 SH3 domain binding by phosphoinositidesThe EMBO Journal Article (10 Nov 2004)
Two distinct interaction motifs in amphiphysin bind two independent sites on the clathrin terminal domain β-propellerNature Structural & Molecular Biology Article (01 Mar 2004)
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