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.