Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Genes (Basel). 2022 Dec 9;13(12):2319. doi: 10.3390/genes13122319.
Aminoacyl-tRNA synthetases (ARSs) are highly conserved essential enzymes that charge tRNA with cognate amino acids-the first step of protein synthesis. Of the 37 nuclear-encoded human ARS genes, 17 encode enzymes are exclusively targeted to the mitochondria (mt-ARSs). Mutations in nuclear mt-ARS genes are associated with rare, recessive human diseases with a broad range of clinical phenotypes. While the hypothesized disease mechanism is a loss-of-function effect, there is significant clinical heterogeneity among patients that have mutations in different mt-ARS genes and also among patients that have mutations in the same mt-ARS gene. This observation suggests that additional factors are involved in disease etiology. In this review, we present our current understanding of diseases caused by mutations in the genes encoding mt-ARSs and propose explanations for the observed clinical heterogeneity.
氨酰-tRNA 合成酶（ARSs）是高度保守的必需酶，负责将特定的氨基酸加载到 tRNA 上——这是蛋白质合成的第一步。在 37 个人类核编码的 ARS 基因中，有 17 个编码的酶专门靶向线粒体（mt-ARSs）。核 mt-ARS 基因突变与罕见的隐性人类疾病有关，这些疾病具有广泛的临床表型。虽然假设的疾病机制是功能丧失效应，但在不同 mt-ARS 基因突变的患者以及同一 mt-ARS 基因突变的患者之间存在显著的临床异质性。这一观察结果表明，其他因素也参与了疾病的病因。在这篇综述中，我们介绍了对由编码 mt-ARSs 的基因突变引起的疾病的现有认识，并提出了对观察到的临床异质性的解释。
