Journal
HUMAN MUTATION
Volume 33, Issue 6, Pages 949-959Publisher
WILEY-HINDAWI
DOI: 10.1002/humu.22067
Keywords
centronuclear myopathy; congenital myopathy; Charcot-Marie-Tooth neuropathy; DNM2; AD-CNM; CMTD1B; DI-CMTB; CMT2M; hereditary motor and sensory neuropathy type II; HMSNII; MTM1; myotubular myopathy; BIN1; RYR1; endocytosis
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Funding
- Institut National de la Sante et de la Recherche Medicale
- Centre National de la Recherche Scientifique
- University of Strasbourg
- College de France
- Association Francaise contre les Myopathies
- Fondation Recherche Medicale (FRM) [DEQ20071210538]
- Agence Nationale de la Recherche [ANR-06-MRAR-023, ANR-08-GENOPAT-005]
- Muscular Dystrophy Association
- National Institutes of Health (NIH) [R01 AR044345, P50 NS040828]
- Lee and Penny Anderson Family Foundation
- Joshua Frase Foundation
- E-Rare Program
- European Community [200754]
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Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype-phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot-Marie-Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT. Hum Mutat 33: 949-959, 2012. (C) 2012 Wiley Periodicals, Inc.
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