APP中已确定的致病突变,PSEN1和PSEN2可以解释不到1%,阿尔茨海默病(AD)患者。在确定的变体中,PSEN2突变甚至更不常见.
根据北京协和医院(PUMCH)痴呆队列的基因研究,我们旨在说明中国AD患者的PSEN2突变谱和新的功能验证突变.
702名AD参与者,在PUMCH痴呆队列中发现年龄在30-85岁之间.他们都接受了历史调查,体检,生化试验,认知评估,脑部CT/MRI,和下一代DNA测序。通过用含有野生型PSEN2或候选突变的质粒转染HEK293细胞来实现功能分析。
发现了9个PSEN2罕见变种,包括两个报告(M239T,R62C)和七个新变体(N141S,I368F,L396I,G117X,I146T,S147N,H220Y)。用PSEN2N141S转染的HEK293细胞,M239T,相对于野生型PSEN2,I368F质粒显示更高的Aβ42和Aβ42/Aβ40水平。PSEN2L396I,G117X,S147N,H220Y,和R62C没有改变Aβ42,Aβ40水平,或Aβ42/Aβ40比值。1.9%,(13/702)受试者具有罕见的PSEN2变体。0.4%,(3/702)受试者携带致病性/可能致病性PSEN2突变。具有功能验证的PSEN2突变的三名受试者均为家族性早发性AD患者。常见症状包括健忘症和精神症状。此外,M239T突变携带者出现敷料失用症,视觉空间失写症,计算障碍和视觉错误定位。
PSEN2N141S,M239T,和I368F是功能验证的突变。
The established causative mutations in the APP, PSEN1, and PSEN2 can explain less than 1%,Alzheimer\'s disease (AD) patients. Of the identified variants, the PSEN2 mutations are even less common.
With the genetic study from the dementia cohort of Peking Union Medical College Hospital (PUMCH), we aim to illustrate the PSEN2 mutation spectrum and novel functionally validated mutations in Chinese AD patients.
702 AD participants, aged 30-85, were identified in PUMCH dementia cohort. They all received history inquiry, physical examination, biochemical test, cognitive evaluation, brain CT/MRI, and next-generation DNA sequencing. Functional analysis was achieved by transfection of the HEK293 cells with plasmids harboring the wild-type PSEN2 or candidate mutations.
Nine PSEN2 rare variants were found, including two reported (M239T, R62C) and seven novel variants (N141S, I368F, L396I, G117X, I146T, S147N, H220Y). The HEK293 cells transfected with the PSEN2 N141S, M239T, I368F plasmids showed higher Aβ42 and Aβ42/Aβ40 levels relative to the wild-type PSEN2. The PSEN2 L396I, G117X, S147N, H220Y, and R62C did not alter Aβ42, Aβ40 levels, or Aβ42/Aβ40 ratio. 1.9%,(13/702) subjects harbored rare PSEN2 variants. 0.4%,(3/702) subjects carried pathogenic/likely pathogenic PSEN2 mutations. The three subjects with the functionally validated PSEN2 mutations were all familial early-onset AD patients. The common symptoms included amnesia and mental symptom. Additionally, the M239T mutation carrier presented with dressing apraxia, visuospatial agraphia, dyscalculia and visual mislocalization.
The PSEN2 N141S, M239T, and I368F are functionally validated mutations.