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Mutations in KARS cause early-onset hearing loss and leukoencephalopathy: Potential pathogenic mechanism | |
2017-12 | |
发表期刊 | HUMAN MUTATION (IF:3.3[JCR-2023],4.1[5-Year]) |
ISSN | 1059-7794 |
卷号 | 38期号:12页码:1740-1750 |
发表状态 | 已发表 |
DOI | 10.1002/humu.23335 |
摘要 | 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. |
关键词 | aminoacylation hearing loss KARS leukoencephalopathy multiple-synthetase complex |
收录类别 | SCI |
语种 | 英语 |
资助项目 | Project of National Eastern Tech-transfer Center[201713972877] |
WOS研究方向 | Genetics & Heredity |
WOS类目 | Genetics & Heredity |
WOS记录号 | WOS:000414241200011 |
出版者 | WILEY |
WOS关键词 | TRANSFER-RNA-SYNTHETASE ; PROTEIN-PROTEIN INTERACTIONS ; MACROMOLECULAR ASSEMBLAGE ; AMINO ; LEUKODYSTROPHIES ; HYPOMYELINATION ; AMINOACYLATION ; IMPAIRMENT ; PHENOTYPE ; VARIANTS |
原始文献类型 | Article |
引用统计 | 正在获取...
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文献类型 | 期刊论文 |
条目标识符 | https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/10052 |
专题 | 生命科学与技术学院_博士生 生命科学与技术学院 生命科学与技术学院_特聘教授组_王恩多组 |
通讯作者 | Wang, Xi-Jin; Wang, En-Duo; Yang, Tao |
作者单位 | 1.Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, Dept Neurol, 1665 Kong Jiang Rd, Shanghai 200092, Peoples R China 2.Univ Chinese Acad Sci, Chinese Acad Sci, State Key Lab Mol Biol, Ctr Excellence Mol Cell Sci,Shanghai Inst Biochem, 320Yue Yang Rd, Shanghai 200031, Peoples R China 3.Shanghai Jiao Tong Univ, Sch Med, Shanghai Peoples Hosp 9, Dept Otolaryngol Head & Neck Surg, 639 Zhi Zao Ju Rd, Shanghai 200011, Peoples R China 4.Chengdu Integrated TCM & Western Med Hosp, Dept Otorhinolaryngol Head & Neck Surg, Chengdu, Sichuan, Peoples R China 5.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China |
通讯作者单位 | 生命科学与技术学院 |
推荐引用方式 GB/T 7714 | Zhou, Xiao-Long,He, Long-Xia,Yu, Li-Jia,et al. Mutations in KARS cause early-onset hearing loss and leukoencephalopathy: Potential pathogenic mechanism[J]. HUMAN MUTATION,2017,38(12):1740-1750. |
APA | Zhou, Xiao-Long.,He, Long-Xia.,Yu, Li-Jia.,Wang, Yong.,Wang, Xi-Jin.,...&Yang, Tao.(2017).Mutations in KARS cause early-onset hearing loss and leukoencephalopathy: Potential pathogenic mechanism.HUMAN MUTATION,38(12),1740-1750. |
MLA | Zhou, Xiao-Long,et al."Mutations in KARS cause early-onset hearing loss and leukoencephalopathy: Potential pathogenic mechanism".HUMAN MUTATION 38.12(2017):1740-1750. |
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