Heterozygous Seryl-tRNA Synthetase 1 Variants Cause Charcot-Marie-Tooth Disease
Heterozygous Seryl-tRNA Synthetase 1 Variants Cause Charcot-Marie-Tooth Disease
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杂合 Seryl-tRNA 合成酶 1 变异体导致 Charcot-Marie-牙齿疾病
DOI：
10.1002/ana.26501
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发表时间：
2022-09-28
影响因子：
11.2
通讯作者：
Chen, Wan-Jin
中科院分区：
文献类型：
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作者：
He, Jin;Liu, Xiao-Xuan;Chen, Wan-Jin
目的尽管与腓骨肌萎缩症（CMT）相关的基因越来越多，但目前仍有许多患者缺乏合适的基因诊断。氨酰-tRNA合成酶（ARS）的常染色体显性突变与CMT有关。在这里，我们描述了因果错义突变的基因编码丝氨酰-tRNA合成酶1（SerRS）的3个家庭受CMT。方法对3个无关家系的16名患者和14名正常人进行全外显子测序。使用生物信息学预测工具研究了所鉴定的遗传变体的功能影响，并使用细胞和生物化学测定法进行了确认。结果3个家系的联合连锁分析显示，1号染色体108681600-110300504之间存在显著连锁（Zmax LOD = 6.9）。在3个家系中，在连锁区域内，杂合子SerRS错义变异与临床表型分离。突变体SerRS蛋白表现出降低的氨酰化活性和异常的SerRS二聚化，这表明总蛋白合成的损害和eIF 2 α磷酸化的诱导。解释我们的研究结果表明，杂合子SerRS变异的确定代表了一个新的原因常染色体显性CMT。已知突变的SerRS蛋白影响各种分子和细胞功能。我们的研究结果为目前对与ARS相关CMT相关的分子机制的理解提供了重大进展。ANN NEUROL 2022
Objective Despite the increasing number of genes associated with Charcot-Marie-Tooth (CMT) disease, many patients currently still lack appropriate genetic diagnosis for this disease. Autosomal dominant mutations in aminoacyl-tRNA synthetases (ARSs) have been implicated in CMT. Here, we describe causal missense mutations in the gene encoding seryl-tRNA synthetase 1 (SerRS) for 3 families affected with CMT. Methods Whole-exome sequencing was performed in 16 patients and 14 unaffected members of 3 unrelated families. The functional impact of the genetic variants identified was investigated using bioinformatic prediction tools and confirmed using cellular and biochemical assays. Results Combined linkage analysis for the 3 families revealed significant linkage (Zmax LOD = 6.9) between the genomic co-ordinates on chromosome 1: 108681600-110300504. Within the linkage region, heterozygous SerRS missense variants segregated with the clinical phenotype in the 3 families. The mutant SerRS proteins exhibited reduced aminoacylation activity and abnormal SerRS dimerization, which suggests the impairment of total protein synthesis and induction of eIF2 alpha phosphorylation. Interpretation Our findings suggest the heterozygous SerRS variants identified represent a novel cause for autosomal dominant CMT. Mutant SerRS proteins are known to impact various molecular and cellular functions. Our findings provide significant advances on the current understanding of the molecular mechanisms associated with ARS-related CMT. ANN NEUROL 2022