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The Journal of Neuroscience, October 11, 2006, 26(41):10397-10406; doi:10.1523/JNEUROSCI.1671-06.2006

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Neurobiology of Disease
Functional Analyses of Glycyl-tRNA Synthetase Mutations Suggest a Key Role for tRNA-Charging Enzymes in Peripheral Axons

Anthony Antonellis,¹ Shih-Queen Lee-Lin,¹ Amy Wasterlain,¹ Paul Leo,² Martha Quezado,⁴ Lev G. Goldfarb,⁵ Kyungjae Myung,³ Shawn Burgess,¹ Kenneth H. Fischbeck,⁶ and Eric D. Green¹

¹Genome Technology Branch, ²Genetic Disease Research Branch, and ³Genetics and Molecular Biology Branch, National Human Genome Research Institute, ⁴Laboratory of Pathology, National Cancer Institute, ⁵Clinical Neurogenetics Unit and ⁶Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892

Correspondence should be addressed to Dr. Eric D. Green, National Human Genome Research Institute, National Institutes of Health, 50 South Drive, Building 50, Room 5222, Bethesda, MD 20892. Email: egreen{at}nhgri.nih.gov

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.

Key words: Charcot–Marie–Tooth disease; spinal muscular atrophy; peripheral neuropathy; axonopathy; tRNA synthetase; axonal translation

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Received April 19, 2006; revised July 29, 2006; accepted Aug. 14, 2006.

Correspondence should be addressed to Dr. Eric D. Green, National Human Genome Research Institute, National Institutes of Health, 50 South Drive, Building 50, Room 5222, Bethesda, MD 20892. Email: egreen{at}nhgri.nih.gov

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