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A novel mutation in the DNM2 gene impairs dynamin 2 localization in skeletal muscle of a patient with late onset centronuclear myopathy

2013; Elsevier BV; Volume: 23; Issue: 3 Linguagem: Inglês

10.1016/j.nmd.2012.12.007

1873-2364

Biruta Kierdaszuk, Mariusz Berdyński, Justyna Karolczak, Maria Jolanta Rędowicz, Cezary Żekanowski, Anna Kamińska,

Microtubule and mitosis dynamics

Centronuclear myopathies constitute a group of heterogeneous congenital myopathies characterized by the presence of abnormal, centrally located nuclei within muscle fibers. Centronuclear myopathies can be caused by mutations of several different genes, including DNM2, encoding dynamin 2 (DNM2) a large GTPase involved in membrane trafficking and endocytosis. We report a 52-year old female with slowly progressive muscle weakness, and a family history of the disease. Clinical, morphological, biochemical and genetic analyses of the proband and her family members were performed, including analyses of the proband's muscle biopsy. A novel D614N mutation, located in the C-terminal region pleckstrin-homology (PH) domain of DNM2 was identified in the proband and four family members, who exhibited similar symptoms. The mutation was associated with profound changes in the localization of DNM2 in muscle fibers without significant changes in protein expression. Mutated DNM2 and proteins involved in the membrane trafficking or membrane compartments maintenance were dislocalized within the myofiber, and concentrated at centrally located nuclei. This novel causative mutation (D614N) within the DNM2 gene in a large Polish centronuclear myopathy family with a late age of overt clinical manifestation caused profound changes in DNM2 localization and impaired proper organization of myofibers, and skeletal muscle functioning.