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Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for ligating amino acids to cognate tRNA molecules. Mutations in four genes encoding an ARS have been implicated in inherited peripheral neuropathy with an axonal pathology, suggesting that all ARS genes are relevant candidates for disease in patients with related phenotypes. Here, we present results from a mutation screen of the histidyl-tRNA synthetase (HARS) gene in a large cohort of patients with peripheral neuropathy. These efforts revealed a rare missense variant (c.410G>A/p.Arg137Gln) that resides at a highly conserved amino acid, represents a loss-of-function allele when evaluated in yeast complementation assays, and is toxic to neurons when expressed in a worm model. In addition to the patient with peripheral neuropathy, p.Arg137Gln HARS was detected in three individuals by genome-wide exome sequencing. These findings suggest that HARS is the fifth ARS locus associated with axonal peripheral neuropathy. Implications for identifying ARS alleles in human populations and assessing them for a role in neurodegenerative phenotypes are discussed.

Original publication

DOI

10.1002/humu.22210

Type

Journal article

Journal

Hum Mutat

Publication Date

01/2013

Volume

34

Pages

191 - 199

Keywords

Amino Acid Substitution, Animals, Animals, Genetically Modified, Caenorhabditis elegans, Cohort Studies, Exome, Gene Frequency, Genetic Complementation Test, Genetic Predisposition to Disease, Genotype, Green Fluorescent Proteins, Histidine-tRNA Ligase, Humans, Microscopy, Confocal, Motor Neurons, Mutation, Peripheral Nervous System Diseases, Saccharomyces cerevisiae, Sequence Analysis, DNA