title: Mild functional differences of dynamin 2 mutations associated to centronuclear myopathy and Charcot-Marie Tooth peripheral neuropathy.
abstract: 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.
authors.affiliation: Department of Translational Medecine, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
authors.forename: Olga S
authors.initials: OS
authors.lastname: Koutsopoulos
authors.forename: Catherine
authors.initials: C
authors.lastname: Koch
authors.forename: Valerie
authors.initials: V
authors.lastname: Tosch
authors.forename: Johann
authors.initials: J
authors.lastname: Böhm
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: North
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Laporte
mesh_terms: D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D034284:Dynamin I / Q000235:genetics / Q000378:metabolism; D034285:Dynamin II / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D009154:Mutation; D020914:Myopathies, Structural, Congenital / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D014168:Transferrin / Q000378:metabolism
chemical_list: D014168:Transferrin; D034284:Dynamin I; D034285:Dynamin II
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