Abstract
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.
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Abbreviations
- ADCNM:
-
Autosomal dominant centronuclear myopathy
- ARCNM:
-
Autosomal recessive centronuclear myopathy
- BAR:
-
Bin/Amphiphysin/Rvs167
- CNM:
-
Centronuclear myopathy
- KO:
-
Knockout
- NADH-TR:
-
Nicotinamide adenine dinucleotide tetrazolium reductase
- OMIM:
-
Online mendelian inheritance in man
- PIs:
-
Phosphoinositides
- SR:
-
Sarcoplasmic reticulum
- XLMTM:
-
X-linked myotubular myopathy
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Acknowledgments
We thank Christine Kretz and the IGBMC imaging center for technical assistance. This work was supported by grants from Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), University of Strasbourg, Collège de France, Association Française contre les Myopathies (AFM), Fondation Recherche Médicale (FRM DEQ20071210538), Agence Nationale de la Recherche (ANR-06-MRAR 023, ANR-07-BLAN-0065-03, ANR-08-GENOPAT-005), and the E-rare program.
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Toussaint, A., Cowling, B.S., Hnia, K. et al. Defects in amphiphysin 2 (BIN1) and triads in several forms of centronuclear myopathies. Acta Neuropathol 121, 253–266 (2011). https://doi.org/10.1007/s00401-010-0754-2
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DOI: https://doi.org/10.1007/s00401-010-0754-2