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  • Heterozygous Seryl-tRNA Synthetase 1 Variants Cause Charcot-Marie-Tooth Disease.

Heterozygous Seryl-tRNA Synthetase 1 Variants Cause Charcot-Marie-Tooth Disease.

Annals of neurology (2022-09-12)
Jin He, Xiao-Xuan Liu, Ming-Ming Ma, Jing-Jing Lin, Jun Fu, Yi-Kun Chen, Guo-Rong Xu, Liu-Qing Xu, Zhi-Fei Fu, Dan Xu, Wen-Feng Chen, Chun-Yan Cao, Yan Shi, Yi-Heng Zeng, Jing Zhang, Xiao-Chun Chen, Ru-Xu Zhang, Ning Wang, Marina Kennerson, Dong-Sheng Fan, Wan-Jin Chen
ABSTRACT

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. 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. 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. 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.

MATERIALS
Product Number
Brand
Product Description

Millipore
ANTI-FLAG® antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Pyrophosphatase, Inorganic from baker′s yeast (S. cerevisiae), powder, ≥500 units/mg protein (E1%/280)