CMT 2D: Active Dominant Mutation of Glycyl-tRNA Synthetase Causes Neuropathy in

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Neuron. 2006 Sep 21;51(6):715-26.

An Active Dominant Mutation of Glycyl-tRNA Synthetase Causes

Neuropathy in a Charcot-Marie-Tooth 2D Mouse Model.

Seburn KL, Nangle LA, GA, Schimmel P, Burgess RW.

The Laboratory, 600 Main Street, Bar Harbor, Maine 04609.

Of the many inherited Charcot-Marie-Tooth peripheral neuropathies,

type 2D (CMT2D) is caused by dominant point mutations in the gene

GARS, encoding glycyl tRNA synthetase (GlyRS).

Here we report a dominant mutation in Gars that causes neuropathy in

the mouse. Importantly, both sensory and motor axons are affected,

and the dominant phenotype is not caused by a loss of the GlyRS

aminoacylation function.

Mutant mice have abnormal neuromuscular junction morphology and

impaired transmission, reduced nerve conduction velocities, and a

loss of large-diameter peripheral axons, without defects in

myelination.

The mutant GlyRS enzyme retains aminoacylation activity, and a loss-

of-function allele, generated by a gene-trap insertion, shows no

dominant phenotype in mice.

These results indicate that the CMT2D phenotype is caused not by

reduction of the canonical GlyRS activity and insufficiencies in

protein synthesis, but instead by novel pathogenic roles for the

mutant GlyRS that specifically affect peripheral neurons.