A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo.
A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo.
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DOI：
10.1002/humu.22210
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发表时间：
2013-01
期刊：
影响因子：
3.9
通讯作者：
Antonellis, Anthony
中科院分区：
文献类型：
--
作者：
Vester, Aimee;Velez-Ruiz, Gisselle;McLaughlin, Heather M.;Lupski, James R.;Talbot, Kevin;Vance, Jeffery M.;Zuechner, Stephan;Roda, Ricardo H.;Fischbeck, Kenneth H.;Biesecker, Leslie G.;Nicholson, Garth;Beg, Asim A.;Antonellis, Anthony
氨酰-tRNA合成酶（ARS）是广泛表达的负责将氨基酸连接到同源tRNA分子的酶。编码ARS的四个基因的突变与伴有轴突病理的遗传性周围神经病有关，这表明所有ARS基因都是相关表型患者疾病的相关候选基因。在这里，我们提出的结果，从突变筛选组氨酰-tRNA合成酶（HARS）基因在一个大的队列患者周围神经病变。这些努力揭示了一种罕见的错义变体（p.Arg137Gln），它位于一个高度保守的氨基酸，在酵母互补试验中评估时代表一个功能丧失的等位基因，并且在蠕虫模型中表达时对神经元有毒。除了周围神经病变患者外，通过全基因组外显子组测序在3个个体中检测到p.Arg137Gln HARS。这些结果表明，HARS是与轴突周围神经病变相关的第五个ARS位点。识别ARS等位基因在人群中的影响，并评估他们在神经退行性表型的作用进行了讨论。
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 (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.
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