RESUMO
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.
Assuntos
Dinamina II/genética , Genes Dominantes , Estudos de Associação Genética , Mutação , Miopatias Congênitas Estruturais/genética , Sequência de Aminoácidos , Dinamina II/química , Humanos , Dados de Sequência Molecular , Miopatias Congênitas Estruturais/diagnóstico , Polimorfismo Genético , Alinhamento de SequênciaRESUMO
Mutations in dynamin 2 (DNM2), an ubiquitously-expressed large GTPase, cause autosomal dominant centronuclear myopathy (DNM2-CNM) and AD Charcot-Marie-Tooth disease type 2B (DNM2-CMT2B). We report a series of 5 patients from the same family who all presented with dominant centronuclear myopathy, mild cognitive impairment, mild axonal peripheral nerve involvement, and the novel E368Q mutation in the DNM2 gene. This study suggests that the phenotypes of dynamin 2 related centronuclear myopathy and Charcot-Marie-Tooth disease overlap and that DNM2 mutations may alter cerebral function. This report extends the clinical knowledge of DNM2-centronuclear myopathy and shows that the role of DNM2 mutations in the central nervous system should be further studied.