Abstract |
Mutations in amphiphysin-2/BIN1, dynamin 2, and myotubularin are associated with centronuclear myopathy (CNM), a muscle disorder characterized by myofibers with atypical central nuclear positioning and abnormal triads. Mis-splicing of amphiphysin-2/BIN1 is also associated with myotonic dystrophy that shares histopathological hallmarks with CNM. How amphiphysin-2 orchestrates nuclear positioning and triad organization and how CNM-associated mutations lead to muscle dysfunction remains elusive. We find that N-WASP interacts with amphiphysin-2 in myofibers and that this interaction and N-WASP distribution are disrupted by amphiphysin-2 CNM mutations. We establish that N-WASP functions downstream of amphiphysin-2 to drive peripheral nuclear positioning and triad organization during myofiber formation. Peripheral nuclear positioning requires microtubule/Map7/Kif5b-dependent distribution of nuclei along the myofiber and is driven by actin and nesprins. In adult myofibers, N-WASP and amphiphysin-2 are only involved in the maintenance of triad organization but not in the maintenance of peripheral nuclear positioning. Importantly, we confirmed that N-WASP distribution is disrupted in CNM and myotonic dystrophy patients. Our results support a role for N-WASP in amphiphysin-2-dependent nuclear positioning and triad organization and in CNM and myotonic dystrophy pathophysiology.
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Authors | Sestina Falcone, William Roman, Karim Hnia, Vincent Gache, Nathalie Didier, Jeanne Lainé, Frederic Auradé, Isabelle Marty, Ichizo Nishino, Nicolas Charlet-Berguerand, Norma Beatriz Romero, Giovanna Marazzi, David Sassoon, Jocelyn Laporte, Edgar R Gomes |
Journal | EMBO molecular medicine
(EMBO Mol Med)
Vol. 6
Issue 11
Pg. 1455-75
(Nov 2014)
ISSN: 1757-4684 [Electronic] England |
PMID | 25262827
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2014 The Authors. Published under the terms of the CC BY 4.0 license. |
Chemical References |
- Adaptor Proteins, Signal Transducing
- BIN1 protein, human
- Mutant Proteins
- Nuclear Proteins
- Tumor Suppressor Proteins
- WASL protein, human
- Wiskott-Aldrich Syndrome Protein, Neuronal
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Topics |
- Adaptor Proteins, Signal Transducing
(genetics, metabolism)
- Adult
- Humans
- Muscle Fibers, Skeletal
(metabolism)
- Muscle, Skeletal
(physiopathology)
- Mutant Proteins
(genetics, metabolism)
- Myopathies, Structural, Congenital
(physiopathology)
- Nuclear Proteins
(genetics, metabolism)
- Tumor Suppressor Proteins
(genetics, metabolism)
- Wiskott-Aldrich Syndrome Protein, Neuronal
(metabolism)
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