Indexed on: 23 Jul '09Published on: 23 Jul '09Published in: Human Mutation
Dynamin 2 (DNM2) is a large GTPase involved in the release of nascent vesicles during endocytosis and intracellular membrane trafficking. Distinct DNM2 mutations, affecting the middle domain (MD) and the Pleckstrin homology domain (PH), have been identified in autosomal dominant centronuclear myopathy (CNM) and in the intermediate and axonal forms of the Charcot-Marie-Tooth peripheral neuropathy (CMT). We report here the first CNM mutation (c.1948G>A, p.E650 K) in the DNM2 GTPase effector domain (GED), leading to a slowly progressive moderate myopathy. COS7 cells transfected with DNM2 constructs harboring a disease-associated mutation in MD, PH, or GED show a reduced uptake of transferrin and low-density lipoprotein (LDL) complex, two markers of clathrin-mediated receptor endocytosis. A decrease in clathrin-mediated endocytosis was also identified in skin fibroblasts from one CNM patient. We studied the impact of DNM2 mutant overexpression on epidermal growth factor (EGF)-induced extracellular signal-regulated kinase 1 (ERK1) and ERK2 activation, known to be an endocytosis- and DNM2-dependent process. Activation of ERK1/2 was impaired for all the transfected mutants in COS7 cells, but not in CNM fibroblasts. Our results indicate that impairment of clathrin-mediated endocytosis may play a role in the pathophysiological mechanisms leading to DNM2-related diseases, but the tissue-specific impact of DNM2 mutations in both diseases remains unclear.