This report describes DNM2-implicated subtypes of Charcot-Marie-Tooth disease (the two subtypes are described in one entry in OMIM): Charcot-Marie-Tooth disease, dominant intermediate B (CMTDIB or DI-CMTB) and Charcot-Marie-Tooth disease, axonal type 2M (CMT2M). The human gene implicated, Dynamin 2 (DNM2) encodes a large force-producing GTPase associated with microtubules and involved in endocytosis and intracellular membrane trafficking. DNM2 is implicated in multiple other diseases, including a form of centronuclear myopathy (see MIM:602378). There is a single fly ortholog, Dmel\shi, for which classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\shi is also the highest scoring ortholog for two additional human dynamins, DNM1 and DNM3.
Multiple different UAS constructs of the human Hsap\DNM2 gene have been introduced into flies, including wild-type DNM2 and genes carrying mutational lesions implicated in Charcot-Marie-Tooth disease and centronuclear myopathy (CNM1). Animals carrying mutant alleles of Hsap\DNM2 exhibit reduced viability, locomotor behavior defective phenotypes, muscle fiber atrophy, and exhibit cellular abnormalities in larval muscles.
Variant(s) implicated in human disease tested (as transgenic human gene, DNM2): the variant form G537C has been introduced into flies. Variants implicated in CNM1 (FBhh0000093) have also been tested in flies.
Loss-of-function mutations in the Dmel\shi gene are lethal; multiple temperature-sensitive alleles have been isolated. A UAS-heat-sensitive allele produces neuroanatomy defective, behavior defective, paralytic, chemical resistant and other phenotypes, depending upon the GAL4 driver used. Genetic and physical interactions of Dmel\shi have been described; see below and in the shi gene report.
[updated Feb. 2019 by FlyBase; FBrf0222196]
Charcot-Marie-Tooth disease (CMT) constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory peripheral neuropathies. CMT is divided into several major types: Type 1 is characterized by demyelination and by a significantly slowed motor median nerve conduction velocity (NCV). Type 2 is characterized by axonal abnormalities and a normal or slightly reduced NCV. "Intermediate" types describe CMT families with nerve conduction velocities, in different affected individuals, that overlap the division between Type 1 and Type 2. Additional types are defined on the basis inheritance patterns. [from MIM:609260 and MIM:606482; 2015.12.15]
Symptoms typically include progressive distal muscle weakness and atrophy, often associated with mild to moderate sensory loss, depressed tendon reflexes, and high-arched feet. [from Gene Reviews, http://www.ncbi.nlm.nih.gov/books/NBK1358 2015.12.15]
[CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE B; CMTDIB](https://omim.org/entry/606482)
[DYNAMIN 2; DNM2](https://omim.org/entry/602378)
A map of mutations of DNM2 implicated in CNM1 and in Charcot-Marie-Tooth (CMT) disease is shown in Bohm et al., 2012 (pubmed:22396310). Mutations of CMT most frequently affect the PH domain, with one example in the MID region; there is no overlap between the two diseases in terms of nucleotides affected.
Forms of dominant intermediate Charcot-Marie-Tooth (CMT) disease and axonal CMT that map to chromosome 19p, designated CMTDIB and CMT2M, respectively, can be caused by heterozygous mutation in the gene encoding dynamin-2 (DNM2). [from MIM:606482; 2019.02.20]
Dynamin 2 is a microtubule-associated force-producing protein involved in producing microtubule bundles and able to bind and hydrolyze GTP. Plays a role in the regulation of neuron morphology, axon growth and formation of neuronal growth cones (by similarity); in vesicular trafficking processes, in particular endocytosis; and in cytokinesis.
[Gene Cards, DNM2; 2019.02.20]
DNM2 is a ubiquitously expressed large GTPase involved in clathrin-dependent and-independent endocytosis and intracellular membrane trafficking. DNM2 interacts tightly with actin and microtubule networks and may have a role in centrosome function (summary by Durieux et al., 2010; pubmed:20858595). [from MIM:602378; 2015.12.17]
Many to one: 3 human to 1 Drosophila; additional orthologous human genes are DNM1 and DNM3.
High-scoring ortholog of human DNM1, DNM2, and DNM3 (1 Drosphila to 3 human). Dmel\shi shares 62-66% identity and 73-78% similarity with the human genes.
