Defects in amphiphysin 2 (BIN1) and triads in several forms of centronuclear myopathies
| Autor: | Karim Hnia, Uluç Yiş, Thierry Maisonobe, Belinda S. Cowling, Ichizo Nishino, Anne Toussaint, Anders Oldfors, Tanya Stojkovic, Andoni Echaniz-Laguna, Vincent Laugel, Jean-Louis Mandel, Jocelyn Laporte, Carina Wallgren-Pettersson, Michel Mohr, Yannick Schwab |
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| Rok vydání: | 2010 |
| Předmět: |
Adult
Male Adolescent Myotubularin Biology Pathology and Forensic Medicine T-tubule Dynamin II Young Adult Cellular and Molecular Neuroscience Microscopy Electron Transmission medicine Humans Centronuclear myopathy Child Muscle Skeletal Adaptor Proteins Signal Transducing Genetics Tumor Suppressor Proteins Brain Infant Nuclear Proteins Skeletal muscle Triad (anatomy) Protein Tyrosine Phosphatases Non-Receptor medicine.disease Congenital myopathy DNM2 medicine.anatomical_structure Mutation Amphiphysin Female Neurology (clinical) Myopathies Structural Congenital |
| Zdroj: | Acta Neuropathologica. 121:253-266 |
| ISSN: | 1432-0533 0001-6322 |
| DOI: | 10.1007/s00401-010-0754-2 |
| Popis: | 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 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. |
| Databáze: | OpenAIRE |
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