Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Department of Molecular Genetics, Oncode Institute, Erasmus Medical Center, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 CN Rotterdam, the Netherlands.
Am J Hum Genet. 2019 Mar 7;104(3):520-529. doi: 10.1016/j.ajhg.2019.01.006. Epub 2019 Feb 26.
Aminoacyl-tRNA synthetases (ARSs) are essential enzymes responsible for charging tRNA molecules with cognate amino acids. Consistent with the essential function and ubiquitous expression of ARSs, mutations in 32 of the 37 ARS-encoding loci cause severe, early-onset recessive phenotypes. Previous genetic and functional data suggest a loss-of-function mechanism; however, our understanding of the allelic and locus heterogeneity of ARS-related disease is incomplete. Cysteinyl-tRNA synthetase (CARS) encodes the enzyme that charges tRNA with cysteine in the cytoplasm. To date, CARS variants have not been implicated in any human disease phenotype. Here, we report on four subjects from three families with complex syndromes that include microcephaly, developmental delay, and brittle hair and nails. Each affected person carries bi-allelic CARS variants: one individual is compound heterozygous for c.1138C>T (p.Gln380) and c.1022G>A (p.Arg341His), two related individuals are compound heterozygous for c.1076C>T (p.Ser359Leu) and c.1199T>A (p.Leu400Gln), and one individual is homozygous for c.2061dup (p.Ser688Glnfs2). Measurement of protein abundance, yeast complementation assays, and assessments of tRNA charging indicate that each CARS variant causes a loss-of-function effect. Compared to subjects with previously reported ARS-related diseases, individuals with bi-allelic CARS variants are unique in presenting with a brittle-hair-and-nail phenotype, which most likely reflects the high cysteine content in human keratins. In sum, our efforts implicate CARS variants in human inherited disease, expand the locus and clinical heterogeneity of ARS-related clinical phenotypes, and further support impaired tRNA charging as the primary mechanism of recessive ARS-related disease.
氨酰-tRNA 合成酶（ARSs）是负责将氨基酸与 tRNA 分子结合的必需酶。与 ARS 的必需功能和广泛表达一致，37 个 ARS 编码基因中的 32 个基因突变导致严重的早发性隐性表型。先前的遗传和功能数据表明存在功能丧失机制；然而，我们对 ARS 相关疾病的等位基因和基因座异质性的理解并不完整。半胱氨酰-tRNA 合成酶（CARS）编码在细胞质中为 tRNA 加载半胱氨酸的酶。迄今为止，CARS 变体尚未与任何人类疾病表型相关联。在这里，我们报告了来自三个家庭的四个具有复杂综合征的个体，包括小头畸形、发育迟缓、脆弱的头发和指甲。每个受影响的人都携带双等位基因 CARS 变体：一个个体为 c.1138C>T（p.Gln380）和 c.1022G>A（p.Arg341His）的复合杂合子，两个相关个体为 c.1076C>T（p.Ser359Leu）和 c.1199T>A（p.Leu400Gln）的复合杂合子，一个个体为 c.2061dup（p.Ser688Glnfs2）的纯合子。蛋白质丰度的测量、酵母互补测定和 tRNA 加载的评估表明，每个 CARS 变体都导致功能丧失效应。与具有先前报道的 ARS 相关疾病的个体相比，具有双等位基因 CARS 变体的个体具有独特的脆弱头发和指甲表型，这很可能反映了人类角蛋白中的高半胱氨酸含量。总之，我们的研究结果表明 CARS 变体与人类遗传性疾病有关，扩展了 ARS 相关临床表型的基因座和临床异质性，并进一步支持受损的 tRNA 加载是隐性 ARS 相关疾病的主要机制。
