title: An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model.
abstract: Of the many inherited Charcot-Marie-Tooth peripheral neuropathies, type 2D (CMT2D) is caused by dominant point mutations in the gene GARS, encoding glycyl tRNA synthetase (GlyRS). Here we report a dominant mutation in Gars that causes neuropathy in the mouse. Importantly, both sensory and motor axons are affected, and the dominant phenotype is not caused by a loss of the GlyRS aminoacylation function. Mutant mice have abnormal neuromuscular junction morphology and impaired transmission, reduced nerve conduction velocities, and a loss of large-diameter peripheral axons, without defects in myelination. The mutant GlyRS enzyme retains aminoacylation activity, and a loss-of-function allele, generated by a gene-trap insertion, shows no dominant phenotype in mice. These results indicate that the CMT2D phenotype is caused not by reduction of the canonical GlyRS activity and insufficiencies in protein synthesis, but instead by novel pathogenic roles for the mutant GlyRS that specifically affect peripheral neurons.
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Seburn
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Nangle
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Cox
authors.forename: Paul
authors.initials: P
authors.lastname: Schimmel
authors.forename: Robert W
authors.initials: RW
authors.lastname: Burgess
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D001483:Base Sequence; D002607:Charcot-Marie-Tooth Disease / Q000145:classification / Q000201:enzymology / Q000235:genetics*; D002874:Chromosome Mapping; D004195:Disease Models, Animal; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D006032:Glycine-tRNA Ligase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009469:Neuromuscular Junction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D017386:Sequence Homology, Amino Acid
chemical_list: D006032:Glycine-tRNA Ligase