Dynamin 2 and human diseases

Abstract

Dynamin 2 (DNM2) mutations cause autosomal dominant centronuclear myopathy, a rare form of congenital myopathy, and intermediate and axonal forms of Charcot-Marie-Tooth disease, a peripheral neuropathy. DNM2 is a large GTPase mainly involved in membrane trafficking through its function in the formation and release of nascent vesicles from biological membranes. DNM2 participates in clathrin-dependent and clathrin-independent endocytosis and intracellular membrane trafficking (from endosomes and Golgi apparatus). Recent studies have also implicated DNM2 in exocytosis. DNM2 belongs to the machinery responsible for the formation of vesicles and regulates the cytoskeleton providing intracellular vesicle transport. In addition, DNM2 tightly interacts with and is involved in the regulation of actin and microtubule networks, independent from membrane trafficking processes. We summarize here the molecular, biochemical, and functional data on DNM2 and discuss the possible pathophysiological mechanisms via which DNM2 mutations can lead to two distinct neuromuscular disorders.

Triadopathies: An Emerging Class of Skeletal Muscle Diseases

“…At least a part of the TTN protein is not translated in some patients with TTN-related CNM [48]. The pathomechanism of DNM2 mutations has been somewhat perplexing [50]. All DNM2 mutations are either dominant or de novo missense mutations, suggesting a potentially toxic gain-of-function effect produced by the mutations.…”

Dynamin 2 Mutants Linked to Centronuclear Myopathies Form Abnormally Stable Polymers

“…Other characteristics include a relative increase in the number of type I fibers, hypertrophy of these fibers, and the presence of sarcoplasmic strands distributed radially around the central nuclei. In 2005, Bitoun et al (2) reported the identification of four mutations in the DNM2 (dynamin 2) gene in patients with autosomal dominant CNM, and an additional seven mutations have since been identified (3,4). DNM2 is a ubiquitously expressed ϳ100-kDa GTPase that assembles into helical polymers around the necks of vesiculating membranes, thereby providing force for their constriction and scission (reviewed in Refs.…”

“…The DNM2 molecule consists of five functional domains: an N-terminal catalytic domain; a so-called "middle domain" implicated in dynamin-dynamin interactions; a PH domain involved in phosphoinositide binding; a GTPase effector domain, which interacts with the catalytic domain and stimulates its GTPase activity; and a C-terminal proline/arginine-rich domain, which mediates interactions of dynamin with other proteins. Most of the currently known CNM-associated dynamin mutations are located in the middle and PH domains (4,13), but others have recently been identified in the GTPase effector domain (3,14).…”

Dynamin Functions and Ligands: Classical Mechanisms Behind

“…The disease is a result of mutations of genes associated with intracellular trafficking (Szigeti and Lupski, 2009;Durieux et al, 2010). Mutations in DNM2 result in CMT.…”