Recombinant Mouse Glycine--tRNA ligase (Gars)

1. Gars mutations are associated with Charcot-Marie-Tooth disease type 2D. PMID: 28351971
2. Results link the aberrant GlyRS-HDAC6 interaction to Charcot-Marie-Tooth disease type 2D pathology and suggest HDAC6 as an effective therapeutic target. PMID: 29520015
3. findings link the selective pathology of Charcot-Marie-Tooth disease type 2D to the neomorphic binding activity of GlyRS(CMT2D) that antagonizes the VEGF-Nrp1 interaction, meaning the VEGF-Nrp1 signalling axis is an actionable target for treating CMT2D PMID: 26503042
4. These results suggest that this animal model of CMT using an adenovirus may provide information regarding CMT as well as a useful strategy for the treatment of neuropathic pain. PMID: 25120326
5. Results indicate that Charcot-Marie-Tooth peripheral neuropathies, type 2D (CMT2D) phenotype is caused by novel pathogenic roles for the mutant GARS that specifically affect peripheral neurons. PMID: 16982418
6. a glycyl-tRNA synthetase (GARS) mutation causes peripheral sensory and motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy PMID: 19470612
7. Gars(C201R) mutation significantly delayed disease onset in the SOD1(G93A);Gars(C201R/+) double heterozygous mutant mice and increased lifespan by 29% on the genetic background investigated PMID: 19593442

Show More

Hide All

Mice (Nmf249) heterozygous for the P278YK variant are used a model for human Charcot-Marie-Tooth 2D (CMT2D), which is caused by dominant GARS mutations. They exhibit reduced amplitudes of muscle compound action potentials and a large reduction in sciatic nerve conduction velocity in the absence of demyelination or remyelination, resulting from an age-related decrease in the number of large myelinated motor and sensory axons. The loss of myelinated axons is length-dependent, and there is a length- and time-dependent decrease in motor innervation of distal versus proximal muscles. Most of the axonal loss occurs by 1 month of age and mice that survive this period can be long-lived. At the molecular level, the P278YK mutation creates a neomorphic binding activity leading to the interaction of the variant with NRP1. This interaction competes out VEGFA binding and inhibits VEGFA-NRP1 signling which is essential for motor neuron survival. VEGFA, but not GDNF treatment significantly ameliorates the loss of motor function in mutant mice.

Cytoplasm. Mitochondrion. Cell projection, axon. Secreted. Secreted, extracellular exosome.

Class-II aminoacyl-tRNA synthetase family

KEGG: mmu:353172

STRING: 10090.ENSMUSP00000003572

UniGene: Mm.250004