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Mutations in KARS cause early‐onset hearing loss and leukoencepha lopathy: Potential pathogenic mechanism


Leukoencephalopathies are a broad class of common neurologic deterioration for which the etiology remain 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.

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Authors:   Xiao‐Long Zhou, Long‐Xia He, Li‐Jia Yu, Yong Wang, Xi‐Jin Wang, En‐Duo Wang, Tao Yang
Journal:   Human Mutation
Year:   2017
Pages:   n/a
DOI:   10.1002/humu.23335
Publication date:   09-Sep-2017
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