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A rare variant in MLKL confers susceptibility to ApoE ɛ4-negative Alzheimer's disease in Hong Kong Chinese population.
- Source :
-
Neurobiology of aging [Neurobiol Aging] 2018 Aug; Vol. 68, pp. 160.e1-160.e7. Date of Electronic Publication: 2018 Mar 10. - Publication Year :
- 2018
-
Abstract
- 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.<br /> (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Subjects :
- Aged
Aged, 80 and over
Alzheimer Disease etiology
Alzheimer Disease metabolism
Amyloid beta-Protein Precursor metabolism
Animals
Apolipoproteins E genetics
Asian People genetics
Cells, Cultured
Female
HEK293 Cells
HeLa Cells
Hong Kong
Humans
Male
Mice, Inbred C57BL
Middle Aged
Alzheimer Disease genetics
Genetic Association Studies
Genetic Predisposition to Disease genetics
Genetic Variation genetics
Loss of Function Mutation
Protein Kinases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1558-1497
- Volume :
- 68
- Database :
- MEDLINE
- Journal :
- Neurobiology of aging
- Publication Type :
- Academic Journal
- Accession number :
- 29656768
- Full Text :
- https://doi.org/10.1016/j.neurobiolaging.2018.03.006