文献类型：期刊文献

英文题名：A rare variant in MLKL confers susceptibility to ApoE ε4-negative Alzheimer's disease in Hong Kong Chinese population

作者：Wang, Binbin[1,2];Bao, Suying[3];Zhang, Zhigang[3];Zhou, Xueya[3];Wang, Jing[1];Fan, Yanhui[3];Zhang, Yan[4];Li, Yan[5];Chen, Luhua[3];Jia, Yizhen[3];Li, Jiang[3];Li, Miaoxin[6];Zheng, Wenhua[7];Mu, Nan[8];Wang, Liqiu[9];Yu, Zhe[3];Wong, Dana S. M.[3];Zhang, Yalun[3,10];Kwan, Joseph[11];Mak, Henry Ka-Fung[12];Ambalavanan, Amirthagowri[13];Zhou, Sirui[13];Cai, Wangwei[14];Zheng, Jin[15];Huang, Shishu[16];Rouleau, Guy A.[13];Yang, Wanling[4];Rogaeva, Ekaterina[10];Ma, Xu[1,2];St George-Hyslop, Peter[10,17];Chu, Leung Wing[11];Song, You-Qiang[3,18,19,20,21]

机构：[1]Natl Res Inst Family Planning, Dept Genet, Beijing, Peoples R China;[2]Peking Union Med Coll, Grad Sch, Beijing, Peoples R China;[3]Univ Hong Kong, Sch Biomed Sci, Hong Kong, Peoples R China;[4]Univ Hong Kong, Dept Paediat & Adolescent Med, Hong Kong, Peoples R China;[5]Shandong Acad Sci, Energy Res Inst, Ctr Transport Phenomena, Jinan, Shandong, Peoples R China;[6]Sun Yat Sen Univ, Zhongshan Sch Med, Dept Med Genet, Ctr Genome Res,Ctr Precis Med, Guangzhou, Guangdong, Peoples R China;[7]Univ Macau, Fac Hlth Sci, Macau, Peoples R China;[8]Guangzhou Brain Hosp, Guangzhou, Guangdong, Peoples R China;[9]Univ Hong Kong, Dept Mech Engn, Hong Kong, Hong Kong, Peoples R China;[10]Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada;[11]Univ Hong Kong, Dept Med, Hong Kong, Hong Kong, Peoples R China;[12]Univ Hong Kong, Dept Diagnost Radiol, Hong Kong, Hong Kong, Peoples R China;[13]McGill Univ, Montreal Neurol Inst & Hosp, Montreal, PQ, Canada;[14]Hainan Med Coll, Dept Biochem & Mol Biol, Haikou, Hainan, Peoples R China;[15]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai, Peoples R China;[16]Sichuan Univ, West China Hosp, Dept Orthoped Surg, Chengdu, Sichuan, Peoples R China;[17]Univ Cambridge, Cambridge Inst Med Res, Dept Clin Neurosci, Cambridge, England;[18]Univ Hong Kong, Ctr Genome Sci, Hong Kong, Hong Kong, Peoples R China;[19]Univ Hong Kong, State Key Lab Cognit & Brain Sci, Hong Kong, Hong Kong, Peoples R China;[20]Univ Hong Kong, HKU SIRI ZIRI, Hong Kong, Hong Kong, Peoples R China;[21]Univ Hong Kong, HKU SUSTech Joint Labs Matrix Biol & Dis, Hong Kong, Hong Kong, Peoples R China

年份：2018

卷号：68

外文期刊名：NEUROBIOLOGY OF AGING

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000434462100021)】；

基金：This work was supported by grants from the National Natural Science Foundation of China (YQS No. 81271226), Independent Innovation Program of National Research Institute of Family Planning of China, and the National Infrastructure of Chinese Genetic Resources (YCZYPT[2017]01-6). In part, this work was also supported by Wellcome Trust, Medical Research Council, Canadian Institute of Health Research, and National Institutes of Health.

语种：英文

外文关键词：Late-onset Alzheimer's disease; ApoE epsilon 4-negative; Whole exome sequencing; MLKL

摘要：Alzheimer's disease (AD) is the most common neurodegenerative disorders in the elderly. To identify rare genetic factors other than apolipoprotein E epsilon 4 allele (ApoE epsilon 4) contributing to the pathogenesis of late-onset AD (LOAD), we conducted a whole-exome analysis of 246 ApoE epsilon 4-negative LOAD cases and 172 matched controls in Hong Kong Chinese population. LOAD patients showed a significantly higher burden of rare loss-of-function variants in genes related to immune function than healthy controls. Among the genes involved in immune function, we identified a rare stop-gain variant (p.Q48X) in mixed lineage kinase domain like pseudokinase (MLKL) gene present exclusively in 6 LOAD cases. MLKL is expressed in neurons, and the its expression levels in the p.Q48X carriers were significantly lower than that in age-matched wild-type controls. The ratio of A beta 42 to A beta 40 significantly increased in MLKL knockdown cells compared to scramble controls. MLKL loss-of-function mutation might contribute to late-onset ApoE epsilon 4-negative AD in the Hong Kong Chinese population. (C) 2018 Elsevier Inc. All rights reserved.