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FB2026_02
,
released June 18, 2026
This report describes Charcot-Marie-Tooth disease, type 2D (CMT2D), which is a subtype of Charcot-Marie-Tooth disease; CMT2D exhibits autosomal dominant inheritance. The human gene implicated in this disease is GARS1, which encodes glycyl-tRNA synthetase. There is a single fly ortholog, GlyRS, for which classical amorphic and loss-of-function alleles, alleles equivalent to missense mutations associated with CMT2D, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. GARS1 has also been implicated as the causative gene is a second, similar disease, distal hereditary motor neuronopathy type VA (HMN5A; MIM:600794; FBhh0000524); collectively, these two diseases are described as GARS1-associated axonal neuropathy.
Multiple different UAS constructs of the human Hsap\GARS1 gene have been introduced into flies, including wild-type and genes carrying mutational lesions implicated in CMT2D. Heterologous rescue (functional complementation) has been demonstrated, assaying the neuroanatomy-defective phenotype of Dmel\GlyRS mutant clones. UAS-mutant alleles of Hsap\GARS1 produce lethal, locomotor-defective or other behavior-defective phenotypes, depending upon the GAL4 driver used.
Variant(s) implicated in human disease tested (as transgenic human gene, GARS1): the variant forms G294R (G240R) and E125G (E71G) of the human gene have been introduced into flies; E125G (E71G) is also associated with HMN5A. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): G326R in the fly GlyRS gene [corresponds to G294R (G240R) in the human GARS1 gene]. Additional variants implicated in HMN5A have also been tested (see FBhh0000524).
When expressed in somatic clones, a lethal amorphic allele of Dmel\GlyRS produces neuroanatomy-defective phenotypes. UAS-loss-of-function and UAS-RNAi alleles of the fly GlyRS gene typically result in semi-lethal or locomotor-behavior-defective phenotypes, depending upon the GAL4 driver used. Phenotypic assays using an allele of the fly gene equivalent to a missense mutation associated with CMT2D have allowed characterization of genetic interactions. Physical interactions of the Dmel\GlyRS protein product have been described and can be found in the FlyBase report for GlyRS.
[updated Apr. 2018 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, AXONAL, TYPE 2D; CMT2D](https://omim.org/entry/601472)
[GLYCYL-tRNA SYNTHETASE 1; GARS1](https://omim.org/entry/600287)
See description of different CMT classification types, above.
CMT2D exhibits an autosomal dominant pattern of transmission; it has been shown to be caused by mutations in the GARS gene. [from MIM:601472, 2015.12.15]
The GARS gene encodes glycyl-tRNA synthetase, an essential enzyme that is responsible for charging tRNA molecules with glycine via an aminoacylation reaction (summary by Griffin et al., 2014, pubmed:25168514). [from MIM:600287, 2015.12.15]
One to one: 1 human to 1 Drosophila.
Ortholog of human GARS (1 Drosophila to 1 human). Dmel\GlyRS shares 60% identity and 75% similarity with human GARS.