Dynamin-2 mutations associated with centronuclear myopathy are hypermorphic and lead to T-tubule fragmentation
Journal
Human Molecular Genetics
Journal Volume
24
Journal Issue
19
Pages
5542-5554
Date Issued
2015
Author(s)
Abstract
Skeletal muscle requires adequate membrane trafficking and remodeling to maintain its normal structure and functions. Consequently, many human myopathies are caused by mutations in membrane trafficking machinery. The large GTPase dynamin-2 (Dyn2) is best known for catalyzing membrane fission during clathrin-mediated endocytosis (CME), which is critical for cell signaling and survival. Despite its ubiquitous expression, mutations of Dyn2 are associated with two tissue-specific congenital disorders: centronuclear myopathy (CNM) and Charcot-Marie-Tooth (CMT) neuropathy. Several disease models for CNM-Dyn2 have been established to study its pathogenic mechanism; yet the cellular and biochemical effects of these mutations are still not fully understood. Here we comprehensively compared the biochemical activities of disease-associated Dyn2 mutations and found that CNM-Dyn2 mutants are hypermorphic with enhanced membrane fission activity, whereas CMT-Dyn2 is hypomorphic. More importantly, we found that the expression of CNM-Dyn2 mutants does not impair CME in myoblast, but leads to T-tubule fragmentation in both C2C12-derived myotubes and Drosophila body wall muscle. Our results demonstrate that CNM-Dyn2 mutants are gain-of-function mutations, and their primary effect in muscle is T-tubule disorganization, which explains the susceptibility of muscle to Dyn2 hyperactivity. ? The Author 2015. Published by Oxford University Press. All rights reserved.
SDGs
Other Subjects
caveolin 3; dynamin II; mutant protein; clathrin; DNM2 protein, Drosophila; DNM2 protein, mouse; Drosophila protein; dynamin II; animal cell; animal experiment; animal model; animal tissue; Article; centronuclear myopathy; controlled study; endocytosis; gain of function mutation; gene mutation; hypermorphic mutation; insect cell; locomotion; muscle disease; myoblast; myotube; nonhuman; priority journal; protein expression; sarcomere; SF9 cell line; transgenic Drosophila; transverse tubular system; transverse tubular system fragmentation; animal; cell line; cytology; Drosophila; genetics; hereditary motor sensory neuropathy; human; metabolism; mouse; mutation; myopathy; pathology; skeletal muscle; Animals; Cell Line; Charcot-Marie-Tooth Disease; Clathrin; Drosophila; Drosophila Proteins; Dynamin II; Endocytosis; Humans; Mice; Muscle, Skeletal; Mutation; Myopathies, Structural, Congenital
Publisher
Oxford University Press
Type
journal article