An Active Dominant Mutation of Glycyl-tRNA Synthetase Causes Neuropathy in a Charcot-Marie-Tooth 2D Mouse Model

• Published in: Neuron (Cambridge, Mass.) Vol. 51; no. 6; pp. 715 - 726
• Main Authors: Seburn, Kevin L., Nangle, Leslie A., Cox, Gregory A., Schimmel, Paul, Burgess, Robert W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21-09-2006; Elsevier Limited
• Subjects: Amino Acid Sequence; Amino acids; Animals; Axons - metabolism; Axons - pathology; Axons - ultrastructure; Base Sequence; Charcot-Marie-Tooth Disease - classification; Charcot-Marie-Tooth Disease - enzymology; Charcot-Marie-Tooth Disease - genetics; Chromosome Mapping; Chromosomes; Disease Models, Animal; Enzymes; Female; Genes; Genes, Dominant - genetics; Genomes; Genotype & phenotype; Glycine-tRNA Ligase - genetics; Glycine-tRNA Ligase - metabolism; Humans; HUMDISEASE; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Microscopy, Electron, Transmission; Molecular Sequence Data; MOLNEURO; Mutagenesis; Mutation; Mutation - genetics; Neuromuscular Junction - metabolism; Neuromuscular Junction - pathology; Neuromuscular Junction - physiopathology; Neurons; Neurosciences; Peripheral Nervous System Diseases - enzymology; Peripheral Nervous System Diseases - genetics; Peripheral Nervous System Diseases - pathology; Proteins; RNA; Sciatic Nerve - metabolism; Sciatic Nerve - pathology; Sciatic Nerve - ultrastructure; Sequence Homology, Amino Acid; RNA; HUMDISEASE; MOLNEURO
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2006.08.027

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.