Researchers identified new KARS mutations causing prelingual hearing loss and leukoencephalopathy

Aminoacyl-tRNA synthetases (aaRSs) catalyze tRNA aminoacylation with generation of aminoacyl-tRNAs for translation. There are two separate translation machineries (cytosolic and mitochondrial translation machineries) in eukaryotes. AaRS gene mutations frequently lead to various types of human disorders.

KARS encodes both cytosolic and mitochondrial lysyl-tRNA synthetases (LysRSs) via mRNA alternative splicing in human. Human LysRS forms homodimer (and tetramer to a minor extent) in the cells and is incorporated into human cytosolic multiple-synthetase complex (MSC) via interaction with AIMP2/p38.

In collaboration with Profs. Xi-Jin Wang and Tao Yang from Shanghai Jiao Tong University School of Medicine, Dr. Xiao-Long Zhou, under the guidance of Prof. En-Duo Wang in the Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, identified two novel heterozygous mutations c.1430G>A (p.Arg477His) and c.1513C>T (p.Pro505Ser) in KARS as the only candidate causative variants in a Chinese Han family segregated with sensorineural hearing loss and leukoencephalopathy. Despite no alteration in the dimer-tetramer oligomerization and cellular distribution by either mutation, the protein structure was notably influenced by the R477H mutation, which subsequently released the protein from the multiple-synthetase complex (MSC), likely disrupting interaction between Arg⁴⁷⁷and Asp³⁴⁶ and consequently the p38-binding surface. Compared with the wild-type LysRS, mutant LysRSs with the R477H and P505S mutations decreased aminoacylation of tRNA^Lys and displayed a cumulative effect when introduced simultaneously. The combined effect of reduced aminoacylation and release of LysRS from the MSC likely underlies the pathogenesis of the two novel KARS mutations identified. This investigation shed light on the pathogenic mechanism for KARS mutations in leukoencephalopathies.

This study was supported by the grants from National Natural Science Foundation of China, Science and Technology Commission of Shanghai Municipality and Chinese Academy of Sciences.

 

CONTACT:
WANG En-Duo, Principal Investigator
Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences 
Phone: 86-21-54921241
E-mail: edwang@sibcb.ac.cn