CMT 2D: An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes pe

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Dis Model Mech. 2009 May 26.

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.

Achilli F, Bros-Facer V, HP, Banks GT, Alqatari M, Chia R, Tucci V,

Groves M, Nickols CD, Seburn KL, Kendall R, Cader MZ, Talbot K, van Minnen J,

Burgess RW, Brandner S, JE, Koltzenburg M, Greensmith L, Nolan PM, Fisher

EM. Department of Neurodegenerative Disease.

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.