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
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KARS 突变导致早发性听力损失和白质脑病：潜在的致病机制
DOI：
10.1002/humu.23335
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发表时间：
2017-12-01
期刊：
影响因子：
3.9
通讯作者：
Yang, Tao
中科院分区：
文献类型：
--
作者：
Zhou, Xiao-Long;He, Long-Xia;Yang, Tao
白质脑病是一类常见的神经系统恶化，其病因在许多病例中仍未解决。在一个感音神经性耳聋和白质脑病分离的中国汉族家系中，通过对144个与耳聋相关的基因和108个白质脑病基因进行定向下一代测序，确定了候选致病变异。在编码赖氨酰-tRNA合成酶(LysRS)的KARS中发现了新的复合杂合突变p.R477H和p.P505S，它们是唯一的候选致病变异体。通过酶分析、免疫荧光、圆二色谱分析和凝胶过滤层析对这两个突变进行了功能鉴定。尽管R477H突变没有改变二聚体-四聚体齐聚作用和细胞分布，但R477H突变显著影响了蛋白质结构，随后R477H突变从多合成酶复合体(MSC)释放了蛋白质。同时引入R477H和P505S突变的LysRSs使tRNA(Lys)氨基酰化水平降低，并表现出累积效应。我们的研究表明，KARs的突变导致了一种新定义的与感音神经性听力障碍相关的白质脑病亚型。减少的氨基酰化和从MSC释放LysRS的共同作用可能是本研究中确定的KARS突变的基础。
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 tRNA(Lys) 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.