Journal
NEURON
Volume 51, Issue 6, Pages 715-726Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2006.08.027
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Funding
- NIGMS NIH HHS [GM23562, GM15539] Funding Source: Medline
- NINDS NIH HHS [U01-NS041215, NS054154] Funding Source: Medline
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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.
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