Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Hum Mutat. 2013 Jan;34(1):191-9. doi: 10.1002/humu.22210. Epub 2012 Oct 11.
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.
氨酰-tRNA 合成酶（ARSs）是广泛表达的酶，负责将氨基酸连接到相应的 tRNA 分子上。四个编码 ARS 的基因的突变与具有轴突病理学的遗传性周围神经病有关，这表明所有 ARS 基因都是具有相关表型的患者疾病的相关候选基因。在这里，我们报告了对一组大的周围神经病患者的组氨酸-tRNA 合成酶（HARS）基因进行突变筛选的结果。这些努力发现了一种罕见的错义变体（c.410G>A/p.Arg137Gln），该变体位于高度保守的氨基酸上，当在酵母互补测定中进行评估时代表失活等位基因，并且在蠕虫模型中表达时对神经元有毒。除了患有周围神经病的患者外，通过全基因组外显子组测序在另外三个人中检测到 p.Arg137Gln HARS。这些发现表明 HARS 是与轴突周围神经病相关的第五个 ARS 基因座。讨论了在人类群体中识别 ARS 等位基因并评估它们在神经退行性表型中的作用的意义。
