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

doi:10.1002/humu.23335

	Mutations in KARS cause early-onset hearing loss and leukoencephalopathy: Potential pathogenic mechanism
	Zhou, Xiao-Long 2; He, Long-Xia 3,4; Yu, Li-Jia 1; Wang, Yong5 ; Wang, Xi-Jin 1; Wang, En-Duo2,5 ; Yang, Tao 3
	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...
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.