This report describes centronuclear myopathy 1 (CNM1), which is a subtype of centronuclear myopathy; CNM1 exhibits autosomal dominant inheritance. The human gene implicated in this disease is Dynamin 2, DNM2, which 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 forms of Charcot-Marie-Tooth disease (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 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 forms R465W, A618T, and S619L of the human gene have been introduced into flies. A variant implicated in Charcot-Marie-Tooth disease (FBhh0000973) has 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]
Centronuclear myopathy is a congenital myopathy characterized by slowly progressive muscular weakness and wasting; the disorder involves mainly limb girdle, trunk, and neck muscles but may also affect distal muscles; ptosis (drooping eyelid) and limitation of eye movements may occur. Age of onset varies, from childhood to young adulthood. (Bitoun et al., 2005, pubmed:16227997). [from MIM:160150; 2015.12.16]
[MYOPATHY, CENTRONUCLEAR, 1; CNM1](https://omim.org/entry/160150)
[MYOTUBULARIN-RELATED PROTEIN 14; MTMR14](https://omim.org/entry/611089)
[DYNAMIN 2; DNM2](https://omim.org/entry/602378)
See general description of symptoms of centronuclear myopathy, above.
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.
Centronuclear myopathy 1 (CNM1) is inherited as an autosomal dominant and is usually caused by heterozygous mutation in the gene encoding Dynamin-2 (DNM2). Age of onset ranges from childhood to early adulthood.[from MIM:160150; 2015.12.17]
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] The most common mutations in CNM1 are in the middle (MID) domain (required for tetramer formation), followed by the pleckstrin homology (PH) domain and the PH-GED linker; mutations in the GTPase effector (GED) domain are rare (Bohm et al., 2012; pubmed:22396310). [from MIM:160150; 2015.12.17]
Many to one: 3 human to 1 Drosophila; additional orthologous human genes are DNM1 and DNM3.
Ortholog of human DNM1, DNM2, and DNM3 (1 Drosphila to 3 human). Dmel\shi shares 66% identity and 78% similarity with each of the 3 human genes.
