title: An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy.
abstract: Mutations in the enzyme glycyl-tRNA synthetase (GARS) cause motor and sensory axon loss in the peripheral nervous system in humans, described clinically as Charcot-Marie-Tooth type 2D or distal spinal muscular atrophy type V. Here, we characterise a new mouse mutant, Gars(C201R), with a point mutation that leads to a non-conservative substitution within GARS. Heterozygous mice with a C3H genetic background have loss of grip strength, decreased motor flexibility and disruption of fine motor control; this relatively mild phenotype is more severe on a C57BL/6 background. Homozygous mutants have a highly deleterious set of features, including movement difficulties and death before weaning. Heterozygous animals have a reduction in axon diameter in peripheral nerves, slowing of nerve conduction and an alteration in the recovery cycle of myelinated axons, as well as innervation defects. An assessment of GARS levels showed increased protein in 15-day-old mice compared with controls; however, this increase was not observed in 3-month-old animals, indicating that GARS function may be more crucial in younger animals. We found that enzyme activity was not reduced detectably in heterozygotes at any age, but was diminished greatly in homozygous mice compared with controls; thus, homozygous animals may suffer from a partial loss of function. The Gars(C201R) mutation described here is a contribution to our understanding of the mechanism by which mutations in tRNA synthetases, which are fundamentally important, ubiquitously expressed enzymes, cause axonopathy in specific sets of neurons.
authors.affiliation: Department of Neurodegenerative Disease, Institute of Neurology, University College London, London WC1N 3BG, UK.
authors.forename: Francesca
authors.initials: F
authors.lastname: Achilli
authors.forename: Virginie
authors.initials: V
authors.lastname: Bros-Facer
authors.forename: Hazel P
authors.initials: HP
authors.lastname: Williams
authors.forename: Gareth T
authors.initials: GT
authors.lastname: Banks
authors.forename: Mona
authors.initials: M
authors.lastname: AlQatari
authors.forename: Ruth
authors.initials: R
authors.lastname: Chia
authors.forename: Valter
authors.initials: V
authors.lastname: Tucci
authors.forename: Michael
authors.initials: M
authors.lastname: Groves
authors.forename: Carole D
authors.initials: CD
authors.lastname: Nickols
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Seburn
authors.forename: Rachel
authors.initials: R
authors.lastname: Kendall
authors.forename: Muhammed Z
authors.initials: MZ
authors.lastname: Cader
authors.forename: Kevin
authors.initials: K
authors.lastname: Talbot
authors.forename: Jan
authors.initials: J
authors.lastname: van Minnen
authors.forename: Robert W
authors.initials: RW
authors.lastname: Burgess
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandner
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Martin
authors.forename: Martin
authors.initials: M
authors.lastname: Koltzenburg
authors.forename: Linda
authors.initials: L
authors.lastname: Greensmith
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Nolan
authors.forename: Elizabeth M C
authors.initials: EM
authors.lastname: Fisher
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D004195:Disease Models, Animal; D005038:Ethylnitrosourea / Q000494:pharmacology; D005260:Female; D006032:Glycine-tRNA Ligase / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000473:pathology*; D009154:Mutation; D010641:Phenotype; D011984:Sensory Receptor Cells / Q000473:pathology*; D017386:Sequence Homology, Amino Acid
chemical_list: D006032:Glycine-tRNA Ligase; D005038:Ethylnitrosourea