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FB2026_01
,
released March 12, 2026
This report describes Charcot-Marie-Tooth disease_GDAP1, which includes several subtypes of Charcot-Marie-Tooth disease (MIM:214400, MIM:608340, MIM:607706, MIM:607831). The human gene implicated in this disease is GDAP1, which is an integral membrane protein of the outer mitochondrial membrane and is found at high levels in neuronal cells. Most GDAP1-related forms of CMT are inherited as an autosomal recessives; one form shows milder dominant phenotypes. There is a single fly ortholog, Dmel\Gdap1, for which RNAi-targeting constructs and alleles caused by insertional mutagenesis have been generated. Dmel\Gdap1 has a second high-scoring human ortholog, GDAP1L1.
A tagged wild-type UAS construct of the human gene, Hsap\GDAP1, has been introduced into flies. Heterologous rescue (functional complementation) of some aspects of RNAi-induced phenotypes of Dmel\Gdap1 has been demonstrated.
Both overexpression of the fly Dmel\Gdap1 gene using GAL4\UAS constructs and reduction in expression using GAL4\UAS-RNAi result in neuroanatomy defective and mitochondrial phenotypes. A single genetic interaction of Dmel\Gdap1 has been reported (with the fly ortholog of the gene implicated in Charcot-Marie-Tooth disease, type 2A2); see the gene report for Gdap1.
[updated Apr. 2017 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]
See description of different CMT classification types, above.
The human gene implicated in these Charcot-Marie-Tooth disease subtypes is GDAP1. Most GDAP1-related forms of CMT are inherited as an autosomal recessives; one form shows milder dominant phenotypes. [from MIM:606598, MIM:607831; 2105.12.18]
GDAP1 is an integral membrane protein of the outer mitochondrial membrane; it is expressed in the central and peripheral nervous system (Niemann et al., 2005; pubmed:16172208). The C-terminal transmembrane domains are necessary for correct localization in mitochondria; 5 disease-causing missense mutations assayed did not alter mitochondrial localization (Pedrola et al. 2005; pubmed:15772096). [from MIM:606598; 2015.12.17]
Many to one: 2 human to 1 Drosophila; the second orthologous human gene is GDAP1L1.
Ortholog of human GDAP1 and GDAP1L1 (1 Drosphila to 2 human). Dmel\Gdap1 shares 29% identity and 47% similarity with human GDAP1; it shares 26% identity and 42% similarity with human GDAP1L1.