Mutation of the human mitochondrial phenylalanine-tRNA synthetase causes infantile-onset epilepsy and cytochrome c oxidase deficiency
Mutation of the human mitochondrial phenylalanine-tRNA synthetase causes infantile-onset epilepsy and cytochrome c oxidase deficiency
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DOI：
10.1016/j.bbadis.2013.10.008
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发表时间：
2014-01-01
影响因子：
6.2
通讯作者：
Chrzanowska-Lightowlers, Zofia M. A.
中科院分区：
文献类型：
--
作者：
Almalki, Abdulraheem;Alston, Charlotte L.;Chrzanowska-Lightowlers, Zofia M. A.
线粒体氨酰-tRNA 合成酶 (aaRS) 是蛋白质合成中必需的酶，因为它们为 tRNA 提供同源氨基酸。编码线粒体 aaRS 的基因突变与多种人类线粒体疾病有关。在此，我们报告了一名早发性癫痫和孤立性肌肉复合体 IV 缺陷患者中 FARS2（编码线粒体苯丙氨酰-tRNA 合成酶的基因）致病性突变（部分基因组缺失和高度保守的 p.Asp325Tyr 错义变体）的鉴定。该生化缺陷在成肌细胞中表达，但在成纤维细胞中不表达，并且与 COXI 和 COXII 蛋白稳态水平降低以及 mt-tRNAPhe 转录物稳态水平降低相关。对重组突变体 p.Asp325Tyr FARS2 蛋白的功能分析显示，其无法结合 ATP，因此使用细菌 tRNA 或人 mt-tRNAPhe 作为底物无法检测到氨酰化活性。野生型 FARS2 细胞的慢病毒转导恢复了复合物 IV 蛋白水平，证实 pAsp325Tyr 突变具有致病性，由于 mt-tRNAPhe 的氨酰化缺陷导致呼吸链缺陷和神经功能缺损。 (C) 2013 作者。由 Elsevier B.V. 出版。保留所有权利。
Mitochondrial aminoacyl-tRNA synthetases (aaRSs) are essential enzymes in protein synthesis since they charge tRNAs with their cognate amino acids. Mutations in the genes encoding mitochondrial aaRSs have been associated with a wide spectrum of human mitochondrial diseases. Here we report the identification of pathogenic mutations (a partial genomic deletion and a highly conserved p. Asp325Tyr missense variant) in FARS2, the gene encoding mitochondrial phenylalanyl-tRNA synthetase, in a patient with early-onset epilepsy and isolated complex IV deficiency in muscle. The biochemical defect was expressed in myoblasts but not in fibroblasts and associated with decreased steady state levels of COXI and COXII protein and reduced steady state levels of the mt-tRNAPhe transcript. Functional analysis of the recombinant mutant p.Asp325Tyr FARS2 protein showed an inability to bind ATP and consequently undetectable aminoacylation activity using either bacterial tRNA or human mt-tRNAPhe as substrates. Lentiviral transduction of cells with wildtype FARS2 restored complex IV protein levels, confirming that the pAsp325Tyr mutation is pathogenic, causing respiratory chain deficiency and neurological deficits on account of defective aminoacylation of mt-tRNAPhe. (C) 2013 The Authors. Published by Elsevier B.V. All rights reserved.