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    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.


    Liling Dong, Caiyan Liu, Longze Sha, Chenhui Mao, Jie Li, Xinying Huang, Jie Wang, Shanshan Chu, Bin Peng, Liying Cui, Qi Xu, Jing Gao. PSEN2 Mutation Spectrum and Novel Functionally Validated Mutations in Alzheimer's Disease: Data from PUMCH Dementia Cohort. Journal of Alzheimer's disease : JAD. 2022;87(4):1549-1556

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    PMID: 35491795

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