1 research outputs found
Mutation spectrum in the large GTPase dynamin 2, and genotypeâphenotype 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 CNMârelated 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 spliceâsite mutation. Genotypeâphenotype 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 CharcotâMarieâTooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissueâspecific 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 33:949â959, 2012. © 2012 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92087/1/22067_ftp.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/92087/2/humu_22067_sm_SuppInfo.pd