The Jackson Laboratory

Jackson Laboratory Scientists Discover Mutation Causing Charcot-Marie-Tooth-Like Disease in Mice

JAX^® NOTES Issue 504, Winter 2006

Drs. Robert Burgess, Kevin Seburn, and Gregory Cox (all at The Jackson Laboratory) and colleagues recently identified a dominantly inherited mutation that causes overt neuromuscular dysfunction and dramatically shortens lifespan in mice (Seburn et al. 2006). The mutation, designated Nmf249 because it was identified in a mutant mouse (C57BL/6J-Gars^Nmf249/J, 005013) produced at The Jackson Laboratory's Neuroscience Mutagenesis Facility in 2004, was found to be an amino acid alteration in the glycyl tRNA synthetase (Gars) gene, the mouse ortholog of the gene affected in human Charcot-Marie-Tooth type 2D (CMT2D) peripheral neuropathy.

CMTs are the most commonly inherited peripheral nerve diseases. They affect approximately 150,000 Americans and are found world-wide in all races and ethnic groups. They were discovered in 1886 by three physicians, Jean-Martin-Charcot, Pierre Marie, and Howard Henry Tooth (Charcot-Marie-Tooth Association). CMT patients slowly lose the use of their feet, legs, hands, and arms because the nerves there degenerate and the muscles weaken.

The Gars gene mutation discovered by the scientists is unusual because it does not affect the normal enzymatic function of the gene's encoded protein, glycyl tRNA synthetase. Rather, the mutation confers an additional role to the protein, a novel pathogenic role that specifically affects motor and sensory nerves.

Reference

Seburn KL, Nangle LA, Cox GA, Schimmel P, Burgess RW. 2006. An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model. Neuron 51:715-26.