This report describes neuronopathy, distal hereditary motor, autosomal dominant 5 (HMND5). 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, 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, Charcot-Marie-Tooth disease, type 2D (CMT2D; MIM:601472; FBhh0000086); 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 HMND5. 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 G580R (G526R), L183P (L129P), E125G (E71G) of the human gene have been introduced into flies; E125G (E71G) is also associated with CMT2D. See the 'Disease-Implicated Variants' table below. Additional variants implicated in CMT2D have been tested using both the human gene and the fly gene (see FBhh0000086).
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.
[updated Feb. 2024 by FlyBase; FBrf0222196]
Distal hereditary motor neuronopathy (dHMN or HMN) is a heterogeneous group of neuromuscular disorders caused by anterior horn cell degeneration and characterized by progressive distal motor weakness and muscular atrophy of the peripheral nervous system without sensory impairment. Distal HMN is also referred to as spinal Charcot-Marie-Tooth disease (spinal CMT). Distal HMN is often referred to as a 'neuronopathy' instead of a 'neuropathy' based on the hypothesis that the primary pathologic process resides in the neuron cell body and not in the axons (Irobi et al., 2006, pubmed:16775372). [From MIM:607641, 2016.01.11]
[NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 5; HMND5](https://omim.org/entry/600794)
[GLYCYL-tRNA SYNTHETASE 1; GARS1](https://omim.org/entry/600287)
Distal hereditary motor neuropathy (or neuronopathy) is a heterogeneous group of neuromuscular disorders caused by anterior horn cell degeneration and characterized by progressive distal motor weakness and muscular atrophy of the peripheral nervous system without sensory impairment. [from MIM:182960; 2017.04.05]
Autosomal dominant distal hereditary motor neuronopathy-5 (HMND5) is caused by heterozygous mutation in the GARS1 gene. [from MIM:600794; 2024.02.20]
The primary pathologic process is hypothesized to reside in the neuron cell body and not in the axons (Irobi et al., 2006; pubmed:16775372). [from MIM:182960; 2017.04.05]
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; 2017.04.05]
One to one: 1 human to 1 Drosophila.
High-scoring ortholog of human gene GARS (1 Drosophila to 1 human). Dmel\GlyRS shares 60% identity and 75% similarity with the human gene.
