Mutation Spectrum in the Large GTPase Dynamin 2, and Genotype-Phenotype Correlation in Autosomal Dominant Centronuclear Myopathy

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.

Institut National de la Sante et de la Recherche Medicale

Institut National de la Sante et de la Recherche Medicale

Centre National de la Recherche Scientifique

Centre National de la Recherche Scientifique

University of Strasbourg

University of Strasbourg

College de France

College de France

Association Francaise contre les Myopathies

Association Francaise Contre les Myopathies

Fondation Recherche Medicale (FRM) [DEQ20071210538]

Fondation Recherche Medicale (FRM)

Agence Nationale de la Recherche [ANR-06-MRAR-023, ANR-08-GENOPAT-005]

Agence Nationale de la Recherche

Muscular Dystrophy Association

Muscular Dystrophy Association

National Institutes of Health (NIH)

National Institutes of Health (NIH) [R01 AR044345, P50 NS040828]

Lee and Penny Anderson Family Foundation

Lee and Penny Anderson Family Foundation

Joshua Frase Foundation

Joshua Frase Foundation

ERare Program

E-Rare Program

European Community

European Community [200754]