A rare variant in MLKL confers susceptibility to ApoE ɛ4-negative Alzheimer's disease in Hong Kong Chinese population
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 cas...
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| Veröffentlicht in: | Neurobiology of aging 2018-08, Vol.68, p.160.e1-160.e7 |
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| container_title | Neurobiology of aging |
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| creator | Wang, Binbin Bao, Suying Zhang, Zhigang Zhou, Xueya Wang, Jing Fan, Yanhui Zhang, Yan Li, Yan Chen, Luhua Jia, Yizhen Li, Jiang Li, Miaoxin Zheng, Wenhua Mu, Nan Wang, Liqiu Yu, Zhe Wong, Dana S.M. Zhang, Yalun Kwan, Joseph Ka-Fung Mak, Henry Ambalavanan, Amirthagowri Zhou, Sirui Cai, Wangwei Zheng, Jin Huang, Shishu Rouleau, Guy A. Yang, Wanling Rogaeva, Ekaterina Ma, Xu St George-Hyslop, Peter Chu, Leung Wing Song, You-Qiang |
| description | 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. |
| doi_str_mv | 10.1016/j.neurobiolaging.2018.03.006 |
| format | Article |
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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.</description><identifier>ISSN: 0197-4580</identifier><identifier>EISSN: 1558-1497</identifier><identifier>DOI: 10.1016/j.neurobiolaging.2018.03.006</identifier><identifier>PMID: 29656768</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>ApoE ɛ4-negative ; Late-onset Alzheimer's disease ; MLKL ; Whole exome sequencing</subject><ispartof>Neurobiology of aging, 2018-08, Vol.68, p.160.e1-160.e7</ispartof><rights>2018 Elsevier Inc.</rights><rights>Copyright © 2018 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c367t-b6022b6f040e96abfd76783c3086eaf95b494e5ce31c7a17470821ded00ac6a83</citedby><cites>FETCH-LOGICAL-c367t-b6022b6f040e96abfd76783c3086eaf95b494e5ce31c7a17470821ded00ac6a83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0197458018300848$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29656768$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Binbin</creatorcontrib><creatorcontrib>Bao, Suying</creatorcontrib><creatorcontrib>Zhang, Zhigang</creatorcontrib><creatorcontrib>Zhou, Xueya</creatorcontrib><creatorcontrib>Wang, Jing</creatorcontrib><creatorcontrib>Fan, Yanhui</creatorcontrib><creatorcontrib>Zhang, Yan</creatorcontrib><creatorcontrib>Li, Yan</creatorcontrib><creatorcontrib>Chen, Luhua</creatorcontrib><creatorcontrib>Jia, Yizhen</creatorcontrib><creatorcontrib>Li, Jiang</creatorcontrib><creatorcontrib>Li, Miaoxin</creatorcontrib><creatorcontrib>Zheng, Wenhua</creatorcontrib><creatorcontrib>Mu, Nan</creatorcontrib><creatorcontrib>Wang, Liqiu</creatorcontrib><creatorcontrib>Yu, Zhe</creatorcontrib><creatorcontrib>Wong, Dana S.M.</creatorcontrib><creatorcontrib>Zhang, Yalun</creatorcontrib><creatorcontrib>Kwan, Joseph</creatorcontrib><creatorcontrib>Ka-Fung Mak, Henry</creatorcontrib><creatorcontrib>Ambalavanan, Amirthagowri</creatorcontrib><creatorcontrib>Zhou, Sirui</creatorcontrib><creatorcontrib>Cai, Wangwei</creatorcontrib><creatorcontrib>Zheng, Jin</creatorcontrib><creatorcontrib>Huang, Shishu</creatorcontrib><creatorcontrib>Rouleau, Guy A.</creatorcontrib><creatorcontrib>Yang, Wanling</creatorcontrib><creatorcontrib>Rogaeva, Ekaterina</creatorcontrib><creatorcontrib>Ma, Xu</creatorcontrib><creatorcontrib>St George-Hyslop, Peter</creatorcontrib><creatorcontrib>Chu, Leung Wing</creatorcontrib><creatorcontrib>Song, You-Qiang</creatorcontrib><title>A rare variant in MLKL confers susceptibility to ApoE ɛ4-negative Alzheimer's disease in Hong Kong Chinese population</title><title>Neurobiology of aging</title><addtitle>Neurobiol Aging</addtitle><description>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.</description><subject>ApoE ɛ4-negative</subject><subject>Late-onset Alzheimer's disease</subject><subject>MLKL</subject><subject>Whole exome sequencing</subject><issn>0197-4580</issn><issn>1558-1497</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNqNkM9q3DAQxkVpaLZpX6HoUGgvdkf-I9nQy7IkTciGXtqzkOXxZhav5Er2QvoqeaK8VW02LeTWywwM3_cN34-xjwJSAUJ-2acOp-Ab8r3ZkdulGYgqhTwFkK_YSpRllYiiVq_ZCkStkqKs4Jy9jXEPAKpQ8g07z2pZSiWrFTuueTAB-dEEMm7k5Pjd9nbLrXcdhsjjFC0OIzXU0_jAR8_Xg7_kT49F4nBnRjoiX_e_75EOGD5F3lJEE3HJufZux2-Xsbknh_Nx8MPUzx7v3rGzzvQR3z_vC_bz6vLH5jrZfv92s1lvE5tLNSaNhCxrZAcFYC1N07VKqiq3OVQSTVeXTVEXWFrMhVVGzO2gykSLLYCx0lT5Bft8yh2C_zVhHPWB5kJ9bxz6KeoMslLVCtQi_XqS2uBjDNjpIdDBhActQC_k9V6_JK8X8hpyPZOf7R-eP03NAdt_5r-oZ8HVSYBz3yNh0NESOostBbSjbj3936c_jTOe8w</recordid><startdate>20180801</startdate><enddate>20180801</enddate><creator>Wang, Binbin</creator><creator>Bao, Suying</creator><creator>Zhang, Zhigang</creator><creator>Zhou, Xueya</creator><creator>Wang, Jing</creator><creator>Fan, Yanhui</creator><creator>Zhang, Yan</creator><creator>Li, Yan</creator><creator>Chen, Luhua</creator><creator>Jia, Yizhen</creator><creator>Li, Jiang</creator><creator>Li, Miaoxin</creator><creator>Zheng, Wenhua</creator><creator>Mu, Nan</creator><creator>Wang, Liqiu</creator><creator>Yu, Zhe</creator><creator>Wong, Dana S.M.</creator><creator>Zhang, Yalun</creator><creator>Kwan, Joseph</creator><creator>Ka-Fung Mak, Henry</creator><creator>Ambalavanan, Amirthagowri</creator><creator>Zhou, Sirui</creator><creator>Cai, Wangwei</creator><creator>Zheng, Jin</creator><creator>Huang, Shishu</creator><creator>Rouleau, Guy A.</creator><creator>Yang, Wanling</creator><creator>Rogaeva, Ekaterina</creator><creator>Ma, Xu</creator><creator>St George-Hyslop, Peter</creator><creator>Chu, Leung Wing</creator><creator>Song, You-Qiang</creator><general>Elsevier Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20180801</creationdate><title>A rare variant in MLKL confers susceptibility to ApoE ɛ4-negative Alzheimer's disease in Hong Kong Chinese population</title><author>Wang, Binbin ; Bao, Suying ; Zhang, Zhigang ; Zhou, Xueya ; Wang, Jing ; Fan, Yanhui ; Zhang, Yan ; Li, Yan ; Chen, Luhua ; Jia, Yizhen ; Li, Jiang ; Li, Miaoxin ; Zheng, Wenhua ; Mu, Nan ; Wang, Liqiu ; Yu, Zhe ; Wong, Dana S.M. ; Zhang, Yalun ; Kwan, Joseph ; Ka-Fung Mak, Henry ; Ambalavanan, Amirthagowri ; Zhou, Sirui ; Cai, Wangwei ; Zheng, Jin ; Huang, Shishu ; Rouleau, Guy A. ; Yang, Wanling ; Rogaeva, Ekaterina ; Ma, Xu ; St George-Hyslop, Peter ; Chu, Leung Wing ; Song, You-Qiang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c367t-b6022b6f040e96abfd76783c3086eaf95b494e5ce31c7a17470821ded00ac6a83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>ApoE ɛ4-negative</topic><topic>Late-onset Alzheimer's disease</topic><topic>MLKL</topic><topic>Whole exome sequencing</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Binbin</creatorcontrib><creatorcontrib>Bao, Suying</creatorcontrib><creatorcontrib>Zhang, Zhigang</creatorcontrib><creatorcontrib>Zhou, Xueya</creatorcontrib><creatorcontrib>Wang, Jing</creatorcontrib><creatorcontrib>Fan, Yanhui</creatorcontrib><creatorcontrib>Zhang, Yan</creatorcontrib><creatorcontrib>Li, Yan</creatorcontrib><creatorcontrib>Chen, Luhua</creatorcontrib><creatorcontrib>Jia, Yizhen</creatorcontrib><creatorcontrib>Li, Jiang</creatorcontrib><creatorcontrib>Li, Miaoxin</creatorcontrib><creatorcontrib>Zheng, Wenhua</creatorcontrib><creatorcontrib>Mu, Nan</creatorcontrib><creatorcontrib>Wang, Liqiu</creatorcontrib><creatorcontrib>Yu, Zhe</creatorcontrib><creatorcontrib>Wong, Dana S.M.</creatorcontrib><creatorcontrib>Zhang, Yalun</creatorcontrib><creatorcontrib>Kwan, Joseph</creatorcontrib><creatorcontrib>Ka-Fung Mak, Henry</creatorcontrib><creatorcontrib>Ambalavanan, Amirthagowri</creatorcontrib><creatorcontrib>Zhou, Sirui</creatorcontrib><creatorcontrib>Cai, Wangwei</creatorcontrib><creatorcontrib>Zheng, Jin</creatorcontrib><creatorcontrib>Huang, Shishu</creatorcontrib><creatorcontrib>Rouleau, Guy A.</creatorcontrib><creatorcontrib>Yang, Wanling</creatorcontrib><creatorcontrib>Rogaeva, Ekaterina</creatorcontrib><creatorcontrib>Ma, Xu</creatorcontrib><creatorcontrib>St George-Hyslop, Peter</creatorcontrib><creatorcontrib>Chu, Leung Wing</creatorcontrib><creatorcontrib>Song, You-Qiang</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Neurobiology of aging</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Binbin</au><au>Bao, Suying</au><au>Zhang, Zhigang</au><au>Zhou, Xueya</au><au>Wang, Jing</au><au>Fan, Yanhui</au><au>Zhang, Yan</au><au>Li, Yan</au><au>Chen, Luhua</au><au>Jia, Yizhen</au><au>Li, Jiang</au><au>Li, Miaoxin</au><au>Zheng, Wenhua</au><au>Mu, Nan</au><au>Wang, Liqiu</au><au>Yu, Zhe</au><au>Wong, Dana S.M.</au><au>Zhang, Yalun</au><au>Kwan, Joseph</au><au>Ka-Fung Mak, Henry</au><au>Ambalavanan, Amirthagowri</au><au>Zhou, Sirui</au><au>Cai, Wangwei</au><au>Zheng, Jin</au><au>Huang, Shishu</au><au>Rouleau, Guy A.</au><au>Yang, Wanling</au><au>Rogaeva, Ekaterina</au><au>Ma, Xu</au><au>St George-Hyslop, Peter</au><au>Chu, Leung Wing</au><au>Song, You-Qiang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A rare variant in MLKL confers susceptibility to ApoE ɛ4-negative Alzheimer's disease in Hong Kong Chinese population</atitle><jtitle>Neurobiology of aging</jtitle><addtitle>Neurobiol Aging</addtitle><date>2018-08-01</date><risdate>2018</risdate><volume>68</volume><spage>160.e1</spage><epage>160.e7</epage><pages>160.e1-160.e7</pages><issn>0197-4580</issn><eissn>1558-1497</eissn><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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>29656768</pmid><doi>10.1016/j.neurobiolaging.2018.03.006</doi></addata></record> |
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| source | Elsevier ScienceDirect Journals Complete |
| subjects | ApoE ɛ4-negative Late-onset Alzheimer's disease MLKL Whole exome sequencing |
| title | A rare variant in MLKL confers susceptibility to ApoE ɛ4-negative Alzheimer's disease in Hong Kong Chinese population |
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