The large
GTPase dynamin 2 is a key player in membrane and cytoskeletal dynamics mutated in
centronuclear myopathy (CNM) and Charcot-Marie Tooth (CMT) neuropathy, two discrete dominant neuromuscular disorders affecting skeletal muscle and peripheral nerves respectively. The molecular basis for the tissue-specific phenotypes observed and the physiopathological mechanisms linked to
dynamin 2 mutations are not well established. In this study, we have analyzed the impact of CNM and CMT implicated
dynamin 2 mutants using ectopic expression of four CNM and two CMT mutations, and patient fibroblasts harboring two
dynamin 2 CNM mutations in established cellular processes of
dynamin 2 action. Wild type and CMT mutants were seen in association with microtubules whereas CNM mutants lacked microtubules association and did not disrupt interphase microtubules dynamics. Most
dynamin 2 mutants partially decreased
clathrin-mediated endocytosis when ectopically expressed in cultured cells; however, experiments in patient fibroblasts suggested that endocytosis is overall not defective. Furthermore, CNM mutants were seen in association with enlarged
clathrin stained structures whereas the CMT mutant constructs were associated with
clathrin structures that appeared clustered, similar to the structures observed in Dnm1 and Dnm2 double knock-out cells. Other roles of
dynamin 2 including its interaction with BIN1 (
amphiphysin 2), and its function in Golgi maintenance and centrosome cohesion were not significantly altered. Taken together, these mild functional defects are suggestive of differences between CMT and CNM disease-causing
dynamin 2 mutants and suggest that a slight impairment in
clathrin-mediated pathways may accumulate over time to foster the respective human diseases.