Glutamyl-tRNA synthetase 2 (encoded by EARS2) is a mitochondrial aminoacyl-tRNA synthetase required to translate the 13 subunits of the electron transport chain encoded by the mitochondrial DNA. Pathogenic EARS2 variants cause combined oxidative phosphorylation deficiency, subtype 12 (COXPD12), an autosomal recessive disorder involving lactic acidosis, intellectual disability, and other features of mitochondrial compromise. Patients with EARS2 deficiency present with variable phenotypes ranging from neonatal lethality to a mitigated disease with clinical improvement in early childhood. Here, we report a neonate homozygous for a rare pathogenic variant in EARS2 (c.949G>T; p.G317C). Metabolomics in primary fibroblasts from this patient revealed expected abnormalities in TCA cycle metabolites, as well as numerous changes in purine, pyrimidine, and fatty acid metabolism. To examine genotype-phenotype correlations in COXPD12, we compared the metabolic impact of reconstituting these fibroblasts with wild-type EARS2 versus four additional EARS2 variants from COXPD12 patients with varying clinical severity. Metabolomics identified a group of signature metabolites, mostly from the TCA cycle and amino acid metabolism, that discriminate between EARS2 variants causing relatively mild and severe COXPD12. Taken together, these findings indicate that metabolomics in patient-derived fibroblasts may help establish genotype-phenotype correlations in EARS2 deficiency and likely other mitochondrial disorders.

中文翻译：

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线粒体谷氨酰-tRNA合成酶EARS2中致病变异的代谢影响

谷氨酰-tRNA 合成酶 2（由EARS2编码）是一种线粒体氨酰-tRNA 合成酶，需要翻译线粒体 DNA 编码的电子传递链的 13 个亚基。致病性EARS2变异导致联合氧化磷酸化缺乏症，亚型 12 (COXPD12)，一种常染色体隐性遗传疾病，涉及乳酸酸中毒、智力障碍和线粒体损害的其他特征。EARS2 缺乏症患者表现出不同的表型，从新生儿致死率到儿童早期临床改善的疾病减轻。在这里，我们报告了EARS2中罕见致病性变异的新生儿纯合子(c.949G>T；p.G317C)。该患者原代成纤维细胞的代谢组学显示预期的 TCA 循环代谢物异常，以及嘌呤、嘧啶和脂肪酸代谢的许多变化。为了检查 COXPD12 中的基因型-表型相关性，我们比较了用野生型EARS2重建这些成纤维细胞与来自临床严重程度不同的 COXPD12 患者的另外四种EARS2变体的代谢影响。代谢组学鉴定了一组标志性代谢物，主要来自 TCA 循环和氨基酸代谢，可区分EARS2导致相对轻微和严重的 COXPD12 的变体。总之，这些发现表明患者来源的成纤维细胞中的代谢组学可能有助于建立EARS2缺陷和可能的其他线粒体疾病的基因型-表型相关性。