Mutations in histidyl‐tRNA synthetase (HARS1), an enzyme that charges transfer RNA with the amino acid histidine in the cytoplasm, have only been associated to date with autosomal recessive Usher syndrome type III and autosomal dominant Charcot–Marie–Tooth disease type 2W. Using massive parallel sequencing, we identified bi‐allelic HARS1 variants in a child (c.616G>T, p.Asp206Tyr and c.730delG, p.Val244Cysfs*6) and in two sisters (c.1393A>C, p.Ile465Leu and c.910_912dupTTG, p.Leu305dup), all characterized by a multisystem ataxic syndrome. All mutations are rare, segregate with the disease, and are predicted to have a significant effect on protein function. Functional studies helped to substantiate their disease‐related roles. Indeed, yeast complementation assays showing that one out of two mutations in each patient is loss‐of‐function, and the reduction of messenger RNA and protein levels and enzymatic activity in patient's skin‐derived fibroblasts, together support the pathogenicity of the identified HARS1 variants in the patient phenotypes. Thus, our efforts expand the allelic and clinical spectrum of HARS1‐related disease.

中文翻译：

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HARS1 中的双等位基因突变严重损害了组氨酰 tRNA 合成酶的表达和酶活性，从而导致了一种新型的多系统共济失调综合征。

组氨酰 tRNA 合成酶 (HARS1) 的突变是一种用细胞质中的氨基酸组氨酸为 RNA 充电的酶，迄今为止仅与常染色体隐性亚瑟综合征 III 型和常染色体显性夏科-玛丽-牙病 2W 型相关。使用大规模并行测序，我们确定了双等位基因HARS1一个孩子的变异（c.616G>T，p.Asp206Tyr 和 c.730delG，p.Val244Cysfs*6）和两个姐妹（c.1393A>C，p.Ile465Leu 和 c.910_912dupTTG，p.Leu305dup）以多系统共济失调综合征为特征。所有突变都是罕见的，与疾病隔离，预计会对蛋白质功能产生显着影响。功能研究有助于证实它们与疾病相关的作用。事实上，酵母互补分析表明，每名患者的两个突变中有一个是功能丧失，以及患者皮肤来源的成纤维细胞中信使 RNA 和蛋白质水平以及酶活性的降低，共同支持了已鉴定的HARS1变异的致病性在患者表型中。因此，我们的努力扩大了 HARS1 相关疾病的等位基因和临床谱。