期刊
HUMAN MUTATION
卷 34, 期 1, 页码 191-199出版社
WILEY-BLACKWELL
DOI: 10.1002/humu.22210
关键词
aminoacyl-tRNA synthetases; peripheral neuropathy; HARS; neurotoxicity
资金
- National Institute of Neurological Diseases and Stroke [NS060983, R01NS052767, U54NS065712]
- National Human Genome Research Institute (National Institutes of Health)
- National Institute of Neurological Diseases and Stroke (National Institutes of Health)
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [ZIBHG000196, ZIAHG200359, ZIAHG200330] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007544] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS052767, ZIANS002974, U54NS065712, R00NS060983] Funding Source: NIH RePORTER
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. Hum Mutat 34: 191-199, 2013. (C) 2012 Wiley Periodicals, Inc.
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