Heterozygous Seryl‐tRNA Synthetase 1 Variants Cause Charcot–Marie–Tooth Disease

• Published in: Annals of neurology Vol. 93; no. 2; pp. 244 - 256
• Main Authors: He, Jin, Liu, Xiao‐Xuan, Ma, Ming‐Ming, Lin, Jing‐Jing, Fu, Jun, Chen, Yi‐Kun, Xu, Guo‐Rong, Xu, Liu‐Qing, Fu, Zhi‐Fei, Xu, Dan, Chen, Wen‐Feng, Cao, Chun‐Yan, Shi, Yan, Zeng, Yi‐Heng, Zhang, Jing, Chen, Xiao‐Chun, Zhang, Ru‐Xu, Wang, Ning, Kennerson, Marina, Fan, Dong‐Sheng, Chen, Wan‐Jin
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.02.2023; Wiley Subscription Services, Inc
• Subjects: Aminoacylation; Charcot-Marie-Tooth disease; Charcot-Marie-Tooth Disease - genetics; Charcot-Marie-Tooth Disease - metabolism; Chromosome 1; Dimerization; Genetic diversity; Genetic screening; Genetic variance; Heterozygote; Humans; Linkage analysis; Missense mutation; Molecular modelling; Mutants; Mutation; Mutation, Missense - genetics; Phenotypes; Phosphorylation; Protein biosynthesis; Protein synthesis; Proteins; Serine-tRNA Ligase - genetics; Transfer RNA; tRNA
• ISSN: 0364-5134; 1531-8249; 1531-8249
• DOI: 10.1002/ana.26501

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 eIF2α 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 2023;93:244–256