BACKGROUND Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N). OBJECTIVE To identify pathogenic mutation in the Korean patients with CMT and distal hereditary motor neuronopathy (dHMN). METHODS We screened AARS1 mutations in 373 unrelated CMT families including 318 axonal CMT, 36 dHMN, and 19 intermediate CMT (Int-CMT) who were negative for 17p12 (PMP22) duplication or deletion using whole exome sequencing and targeted sequencing of CMT-related genes. RESULTS This study identified an early onset Int-CMT family harboring an AARS1 p.Arg329His mutation which was previously reported as pathogenic in French and Australian families. The mutation was located in the highly conserved tRNA binding domain and several in silico analyses suggested pathogenic prediction of the mutations. The patients harboring p.Arg329His showed clinically similar phenotypes of the early onset and electrophysiological intermediate type as those in Australian patients with same mutation. We also found a novel c.2564A>G (p.Gln855Arg) in a CMT2 patient, but its' pathogenic role was uncertain (variant of uncertain significance). CONCLUSION This study suggests that the frequency of the AARS1 mutations appears to be quite low in Korean CMT. This is the first report of the AARS1 mutation in Korean CMT patients and will be helpful for the exact molecular diagnosis and treatment of Int-CMT patients.

中文翻译：

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患有中级Charcot-Marie-Tooth神经病的家庭中的Alanyl-tRNA合成酶1（AARS1）基因突变。

背景技术丙氨酰-tRNA合成酶1（AARS1）基因编码普遍表达的II类酶，该酶催化丙氨酸与同源tRNA的连接。AARS1突变通常是导致常染色体显性遗传2N型夏科特-玛丽-牙齿疾病（CMT2N）的原因。目的确定韩国CMT和远端遗传性运动神经病（dHMN）患者的致病突变。方法我们使用CMT相关基因的全外显子组测序和靶向测序筛选了373个无关CMT家族的ARSR突变，包括318个轴突CMT，36个dHMN和19个中间CMT（Int-CMT），它们对17p12（PMP22）复制或缺失呈阴性。 。结果本研究确定了一个早期发作的Int-CMT家族，该家族携带AARS1 p.Arg329His突变，该突变先前在法国和澳大利亚家族中被报告为致病性。该突变位于高度保守的tRNA结合域中，一些计算机分析表明该突变的病原性预测。携带p.Arg329His的患者表现出的临床早期表现型和电生理学中型与临床上具有相同突变的澳大利亚患者相似。我们还在CMT2患者中发现了一个新的c.2564A> G（p.Gln855Arg），但其致病作用尚不确定（不确定意义的变量）。结论这项研究表明，AARS1突变的频率在韩国CMT中似乎很低。这是韩国CMT患者中ARS1突变的首次报道，将有助于Int-CMT患者的确切分子诊断和治疗。