TRANSLATIONAL IMPACT
Clinical issue

Charcot-Marie-Tooth (CMT) diseases are hereditary sensory neuropathies, which affect up to 1 in 2500 individuals. They are characterised by distal muscle weakness and impaired sensation. A related set of peripheral nervous system disorders are the hereditary motor neuronopathies (HMNs), which lead to muscle wasting and death in severe cases. These diseases are difficult to model owing to phenotypic variance and the lethality of known mutations in mice. Recently, mutations in a single gene, encoding the enzyme glycyl-tRNA synthetase (GARS), were found in familial cases of both CMT and severe infantile HMN. GARS function is ubiquitously important for protein translation, where it is necessary to load glycine into proteins, but it is not clear why mutations in the GARS gene result in neurological disease. New evidence shows that the activity of GARS and other amino acid transport enzymes is present in nerve terminal ends, away from the cell body where such activities were thought to take place. Furthermore, several recent papers show that mutations in other tRNA synthetases cause neurological effects. However, the purpose of tRNA synthetase in neuron terminals is unknown and it is possible that their undiscovered functions may contribute to neuropathy.

Results

We describe a new mouse model with a dominant mutation in the Gars gene, which displays a spectrum of disorders reminiscent of disease in humans, particularly the CMTs. The mutation has sensory effects, which include the loss of electrical conductance in certain nerves and muscle abnormalities. Although heterozygous mice have a relatively mild phenotype, these animals have defects at the neuromuscular junction. Intriguingly, phenotypes vary depending on the genetic background, concordant with a recent genetic study, which identified that a single regulatory locus controls expression of many of the tRNA synthetases in the mouse. Very few homozygous mice survive to birth and all die within 17 days of birth. Still, this is the first report of successful breeding of homozygous animals with this mutation, and the unique access to material from homozygous animals allows for comparison of enzyme levels and activities between wild-type, heterozygous and homozygous animals. The authors’ findings suggest that, in addition to its role in neuropathy, the GARS enzyme may be particularly important during development.

Implications and future directions

This new mouse model shows many similarities to human mutations in GARS, including phenotype variability, which in this study is influenced by the unique genetic background of two different inbred mouse lines. This indicates that other genes in the genome can modulate the GARS phenotype and that the products of these genes may represent accessible targets for therapeutics. The production of homozygous mice for study will enable the characterisation of the GARS enzyme defects that contribute to human diseases such as CMT and HMN, and the role of this enzyme during development and aging. Furthermore, this model should provide insight into the contribution of other tRNA synthetase defects on nervous system pathology.