CMT Type 2D, dSMA-V, tRNA and peripheral axons

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J Neurosci. 2006 Oct 11;26(41):10397-10406.

Functional Analyses of Glycyl-tRNA Synthetase Mutations Suggest a

Key Role for tRNA-Charging Enzymes in Peripheral Axons.

Antonellis A, Lee-Lin SQ, Wasterlain A, Leo P, Quezado M, Goldfarb

LG, Myung K, Burgess S, Fischbeck KH, Green ED.

Genome Technology Branch, Genetic Disease Research Branch, and

Genetics and Molecular Biology Branch, National Human Genome

Research Institute, Laboratory of Pathology, National Cancer

Institute, Clinical Neurogenetics Unit and Neurogenetics Branch,

National Institute of Neurological Disorders and Stroke, National

Institutes of Health, Bethesda, land 20892.

Charcot-Marie-Tooth disease type 2D (CMT2D) and distal spinal

muscular atrophy type V (dSMA-V) are axonal neuropathies

characterized by a phenotype that is more severe in the upper

extremities. We previously implicated mutations in the gene encoding

glycyl-tRNA synthetase (GARS) as the cause of CMT2D and dSMA-V.

GARS is a member of the family of aminoacyl-tRNA synthetases

responsible for charging tRNA with cognate amino acids; GARS ligates

glycine to tRNA(Gly). Here, we present functional analyses of

disease-associated GARS mutations and show that there are not any

significant mutation-associated changes in GARS expression levels;

that the majority of identified GARS mutations modeled in yeast

severely impair viability; and that, in most cases, mutant GARS

protein mislocalizes in neuronal cells. Indeed, four of the five

mutations studied show loss-of-function features in at least one

assay, suggesting that tRNA-charging deficits play a role in disease

pathogenesis. Finally, we detected endogenous GARS-associated

granules in the neurite projections of cultured neurons and in the

peripheral nerve axons of normal human tissue. These data are

particularly important in light of the recent identification of CMT-

associated mutations in another tRNA synthetase gene [YARS (tyrosyl-

tRNA synthetase gene)]. Together, these findings suggest that tRNA-

charging enzymes play a key role in maintaining peripheral axons.