Achilli, F;
Bros-Facer, V;
Williams, HP;
Banks, GT;
AlQatari, M;
Chia, R;
Tucci, V;
... Fisher, EMC; + view all
(2009)
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.
Disease Models & Mechanisms
, 2
(7-8)
359 - 373.
10.1242/dmm.002527.
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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.
| Type: | Article |
|---|---|
| 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 |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1242/dmm.002527 |
| Publisher version: | http://dx.doi.org/10.1242/dmm.002527 |
| Language: | English |
| Additional information: | The article is published under under a Creative Commons Attribution (CC-BY) Licence (the terms of which are set out at http://creativecommons.org/licenses/by/3.0/legalcode). Authors retain ownership of the copyright for their article, but undertake to allow anyone to download, reuse, reprint, modify, distribute, and/or copy articles, including for commercial purposes, provided that the original authors and source are cited. No permission is required from the authors or the publisher under the CC-BY license. The full guidance that applies to this licence can be found at http://creativecommons.org/licenses/by/3.0/legalcode |
| Keywords: | Spinal muscular-atrophy, crystal-structure, gene mutation, disease, neurodegeneration, translation, expression, protocol, domains, neuron |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/137323 |
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