2. Academic Validation
  3. Mutations in KARS cause early-onset hearing loss and leukoencephalopathy: Potential pathogenic mechanism

Mutations in KARS cause early-onset hearing loss and leukoencephalopathy: Potential pathogenic mechanism

  • Hum Mutat. 2017 Dec;38(12):1740-1750. doi: 10.1002/humu.23335.
Xiao-Long Zhou 1,  Long-Xia He 2 3,  Li-Jia Yu 4,  Yong Wang 5,  Xi-Jin Wang 4,  En-Duo Wang 1 5,  Tao Yang 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
  • 2 Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 3 Department of Otorhinolaryngology-Head and Neck Surgery, Chengdu Integrated TCM & Western Medicine Hospital, Sichuan Province, China.
  • 4 Department of Neurology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 5 School of Life Science and Technology, Shanghai Tech University, Shanghai, China.
PMID: 28887846 DOI: 10.1002/humu.23335
Abstract

Leukoencephalopathies are a broad class of common neurologic deterioration for which the etiology remains unsolved in many cases. In a Chinese Han family segregated with sensorineural hearing loss and leukoencephalopathy, candidate pathogenic variants were identified by targeted next-generation Sequencing of 144 genes associated with deafness and 108 genes with leukoencephalopathy. Novel compound heterozygous mutations p.R477H and p.P505S were identified in KARS, which encodes lysyl-tRNA synthetase (LysRS), as the only candidate causative variants. These two mutations were functionally characterized by enzymatic assays, immunofluorescence, circular dichroism analysis, and gel filtration chromatography. 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). Mutant LysRSs with the R477H and P505S mutations had decreased tRNALys aminoacylation and displayed a cumulative effect when introduced simultaneously. Our studies showed that mutations in KARS lead to a newly defined subtype of leukoencephalopathy associated with sensorineural hearing impairment. The combined effect of reduced aminoacylation and release of LysRS from the MSC likely underlies the pathogenesis of the KARS mutations identified in this study.

Keywords

KARS; aminoacylation; hearing loss; leukoencephalopathy; multiple-synthetase complex.

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