Defects in amphiphysin 2 (BIN1) and triads in several forms of centronuclear myopathies

Myotubular myopathy and centronuclear myopathies (CNM) are congenital myopathies characterized by generalized muscle weakness and mislocalization of muscle fiber nuclei. Genetically distinct forms exist, and mutations in BIN1 were recently identified in autosomal recessive cases (ARCNM). Amphiphysins have been implicated in membrane remodeling in brain and skeletal muscle. Our objective was to decipher the pathogenetic mechanisms underlying different forms of CNM, with a focus on ARCNM cases. In this study, we compare the histopathological features from patients with X-linked, autosomal recessive, and dominant forms, respectively, mutated in myotubularin (MTM1), amphiphysin 2 (BIN1), and dynamin 2 (DNM2). We further characterize the ultrastructural defects in ARCNM muscles. We demonstrate that the two BIN1 isoforms expressed in skeletal A. Toussaint  B. S. Cowling  K. Hnia  J.-L. Mandel  J. Laporte (&) Department of Neurobiology and Genetics, Institut de Ge´ne´tique et de Biologie Mole´culaire et Cellulaire (IGBMC), 1 rue Laurent Fries, BP10142, 67404 Illkirch, France e-mail: jocelyn@igbmc.fr A. Toussaint  B. S. Cowling  K. Hnia  Y. Schwab  J.-L. Mandel  J. Laporte INSERM, U964, 67404 Illkirch, France A. Toussaint  B. S. Cowling  K. Hnia  Y. Schwab  J.-L. Mandel  J. Laporte CNRS, UMR7104, 67404 Illkirch, France A. Toussaint  B. S. Cowling  K. Hnia  J.-L. Mandel  J. Laporte Universite´ de Strasbourg, 67404 Illkirch, France A. Toussaint  B. S. Cowling  K. Hnia  J.-L. Mandel  J. Laporte Chaire de Ge´ne´tique Humaine, Colle`ge de France, 67404 Illkirch, France M. Mohr Service d’Anatomie Pathologique, Centre Hospitalier Universitaire (CHU) Hautepierre, 67091 Strasbourg, France A. Oldfors Department of Pathology, Institute of Biomedicine, University of Gothenburg, 41345 Gothenburg, Sweden Y. Schwab Imaging Platform, Institut de Ge´ne´tique et de Biologie Mole´culaire et Cellulaire (IGBMC), 67404 Illkirch, France U. Yis Division of Child Neurology, Gaziantep Children’s Hospital, 27400 Gaziantep, Turkey T. Maisonobe Service de Neuropathologie, Groupe Hospitalier Pitie´-Salpeˆtrie`re, AP-HP, 75013 Paris, France T. Maisonobe Fe´de´ration de Neurophysiologie Clinique, Groupe Hospitalier Pitie´-Salpeˆtrie`re, AP-HP, 75013 Paris, France T. Stojkovic Unite´ de Morphologie Neuromusculaire, Institut de Myologie, Groupe Hospitalier Pitie´-Salpeˆtrie`re, AP-HP, 75013 Paris, France T. Stojkovic Centre de Re´fe´rence Neuromusculaire Paris-Est, Institut de Myologie, Groupe Hospitalier Pitie´-Salpeˆtrie`re, AP-HP, 75013 Paris, France C. Wallgren-Pettersson Department Medical Genetics, The Haartman Institute, University of Helsinki, 00290 Helsinki, Finland 123 Acta Neuropathol (2011) 121:253–266 DOI 10.1007/s00401-010-0754-2 muscle possess the phosphoinositide-binding domain and are specifically targeted to the triads close to the DHPR– RYR1 complex. Cardiac isoforms do not contain this domain, suggesting that splicing of BIN1 regulates its specific function in skeletal muscle. Immunofluorescence analyses of muscles from patients with BIN1 mutations reveal aberrations of BIN1 localization and triad organization. These defects are also observed in X-linked and autosomal dominant forms of CNM and in Mtm1 knockout mice. In addition to previously reported implications of BIN1 in cancer as a tumor suppressor, these findings sustain an important role for BIN1 skeletal muscle isoforms in membrane remodeling and organization of the excitation– contraction machinery. We propose that aberrant BIN1 localization and defects in triad structure are part of a common pathogenetic mechanism shared between the three forms of centronuclear myopathies.