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)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.
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Acknowledgements
We thank the affected individuals and their families for participation in this study. We also thank J. Wahlström for providing samples from one of the families, P. De Camilli (Yale University) for providing the BIN1-iso8 and BIN1-BAR* cDNA constructs, P. McPherson (McGill University) for providing the BIN1 SH3 domain cDNA construct, M. Argentini for peptide mass fingerprinting, G. Duval for generation of antibodies, S. Vicaire for DNA sequencing, C. Thibault for DNA microarray analysis and H. Rohde, N. Dondaine and E. Klein for experimental help. This work was supported by the Institut National de la Santé et de la Recherche Médicale, the Centre National de la Recherche Scientifique, the Collège de France, the Agence Nationale de la Recherche and the Association Française Contre les Myopathies (AFM). A.-S.N. is the recipient of an ATER from Collège de France, and A.T. is the recipient of a fellowship from AFM.
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Experiments were performed by A.-S.N., A.T., V.T., C.K., J.-M.G., V.B., A.O. and J.L. A.-S.N., A.T. and J.L. analyzed the data. C.W.-P., E.I. and H.K. contributed clinical samples and patient data. The study was designed and coordinated by J.-L.M. and J.L., and the paper was written by J.L.
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Nicot, AS., Toussaint, A., Tosch, V. et al. Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy. Nat Genet 39, 1134–1139 (2007). https://doi.org/10.1038/ng2086
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DOI: https://doi.org/10.1038/ng2086
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