A rare variant in MLKL confers susceptibility to ApoE ɛ4-negative Alzheimer's disease in Hong Kong Chinese population.

Autor: Wang B; Department of Genetics, National Research Institute for Family Planning, Beijing, China; Graduate School of Peking Union Medical College, Beijing, China., Bao S; School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China., Zhang Z; School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China., Zhou X; School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China., Wang J; Department of Genetics, National Research Institute for Family Planning, Beijing, China., Fan Y; School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China., Zhang Y; Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China., Li Y; Center for Transport Phenomena, Energy Research Institute of Shandong Academy of Sciences, Jinan, Shandong, China., Chen L; School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China., Jia Y; School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China., Li J; School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China., Li M; Department of Medical Genetics, Center for Genome Research, Center for Precision Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China., Zheng W; The Faculty of Health Sciences, The University of Macau, Macau, China., Mu N; Guangzhou Brain Hospital, Guangzhou, China., Wang L; Department of Mechanical Engineering, The University of Hong Kong, Hong Kong, China., Yu Z; School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China., Wong DSM; School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China., Zhang Y; School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada., Kwan J; Department of Medicine, The University of Hong Kong, Hong Kong, China., Ka-Fung Mak H; Department of Diagnostic Radiology, The University of Hong Kong, Hong Kong, China., Ambalavanan A; Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada., Zhou S; Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada., Cai W; Department of Biochemistry and Molecular Biology, Hainan Medical College, Haikou, Hainan, China., Zheng J; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China., Huang S; Department of Orthopedic Surgery, West China Hospital, Sichuan University, Chengdu, China., Rouleau GA; Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada., Yang W; Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China., Rogaeva E; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada., Ma X; Department of Genetics, National Research Institute for Family Planning, Beijing, China; Graduate School of Peking Union Medical College, Beijing, China. Electronic address: Nicgr@263.net., St George-Hyslop P; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada; Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK., Chu LW; Department of Medicine, The University of Hong Kong, Hong Kong, China. Electronic address: lwchu@hku.hk., Song YQ; School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China; Centre for Genome Sciences, The University of Hong Kong, Hong Kong, China; State Key Laboratory for Cognitive and Brain Sciences, The University of Hong Kong, Hong Kong, China; HKU-SIRI/ZIRI, The University of Hong Kong, Hong Kong, China; HKU-SUSTech Joint Laboratories of Matrix Biology and Diseases, The University of Hong Kong, Hong Kong, China. Electronic address: songy@hku.hk.
Jazyk: angličtina
Zdroj: Neurobiology of aging [Neurobiol Aging] 2018 Aug; Vol. 68, pp. 160.e1-160.e7. Date of Electronic Publication: 2018 Mar 10.
DOI: 10.1016/j.neurobiolaging.2018.03.006
Abstrakt: Alzheimer's disease (AD) is the most common neurodegenerative disorders in the elderly. To identify rare genetic factors other than apolipoprotein E ɛ4 allele (ApoE ɛ4) contributing to the pathogenesis of late-onset AD (LOAD), we conducted a whole-exome analysis of 246 ApoE ɛ4-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 Aβ42 to Aβ40 significantly increased in MLKL knockdown cells compared to scramble controls. MLKL loss-of-function mutation might contribute to late-onset ApoE ɛ4-negative AD in the Hong Kong Chinese population.
(Copyright © 2018 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: