Department of Genetics, National Research Institute for Family Planning, Beijing, China; Graduate School of Peking Union Medical College, Beijing, China.
School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China.
Neurobiol Aging. 2018 Aug;68:160.e1-160.e7. doi: 10.1016/j.neurobiolaging.2018.03.006. Epub 2018 Mar 10.
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.
阿尔茨海默病（AD）是老年人中最常见的神经退行性疾病。为了鉴定除载脂蛋白 E ɛ4 等位基因（ApoE ɛ4）以外的罕见遗传因素对晚发性 AD（LOAD）发病机制的影响，我们对 246 例 ApoE ɛ4 阴性 LOAD 病例和 172 例匹配对照进行了全外显子组分析在香港的华人人群中。LOAD 患者表现出与免疫功能相关的基因中罕见的功能丧失变异负担明显高于健康对照者。在涉及免疫功能的基因中，我们在混合谱系激酶结构域样伪激酶（MLKL）基因中发现了一个罕见的无义变异（p.Q48X），仅存在于 6 例 LOAD 病例中。MLKL 在神经元中表达，其在 p.Q48X 携带者中的表达水平明显低于年龄匹配的野生型对照。与 scramble 对照相比，MLKL 敲低细胞中的 Aβ42 与 Aβ40 的比值显著增加。MLKL 功能丧失突变可能导致香港华人中晚发性 ApoE ɛ4 阴性 AD。
