Identification and characterization of variants in PSEN1, PSEN2, and APP genes in Chinese patients with early-onset Alzheimer's disease.

IF 7.9 1区 医学 Q1 CLINICAL NEUROLOGY
Haitian Nan, Min Chu, Deming Jiang, Wenping Liang, Yu Li, Yiming Wu, Zhe Wang, Liyong Wu
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引用次数: 0

Abstract

Variants in PSEN1, PSEN2, and APP are major genetic causes of early-onset Alzheimer's disease (EOAD). Our study aimed to identify the genotypic and phenotypic spectrums in a Chinese EOAD cohort and confirm their pathogenicity by functional analysis. This study included 304 unrelated clinically diagnosed EOAD participants of Chinese Han ancestry. Whole-exome sequencing revealed that 26 out of 304 individuals (8.6%) carried rare variants in PSEN1, PSEN2, and APP, including 16 in PSEN1 (5.3%), 6 in PSEN2 (2.0%), and 4 in APP (1.3%). Eight variants were novel, including PSEN1 p.Q56R, PSEN1 p.L174P, PSEN1 p.S289P, PSEN1 p.Y466C, PSEN2 p.R17W, PSEN2 p.F331Y, APP p.D197N, and APP p.D252V. Functional study revealed that the PS1 L174P, S289P, R377M, Y466C, PS2 V214L, and M239T mutants increased Aβ42 levels and Aβ42/Aβ40 ratios. The PS1 L174P, R377M, and Y466C mutants decreased the maturation of presenilin-1. Our findings highlight the prevalence and pathogenic significance of APP /PSENs variants in a Chinese EOAD cohort and expand the phenotypic and genotypic spectrum of EOAD.

中国早发性阿尔茨海默病患者PSEN1、PSEN2和APP基因变异的鉴定和表征
PSEN1、PSEN2和APP的变异是早发性阿尔茨海默病(EOAD)的主要遗传原因。我们的研究旨在确定中国EOAD队列的基因型和表型谱,并通过功能分析证实其致病性。本研究纳入304名中国汉族无血缘关系临床诊断的EOAD参与者。全外显子组测序显示,304个个体中有26个(8.6%)携带PSEN1、PSEN2和APP的罕见变异,其中PSEN1有16个(5.3%),PSEN2有6个(2.0%),APP有4个(1.3%)。8个新变异包括PSEN1 p.Q56R、PSEN1 p.L174P、PSEN1 p.S289P、PSEN1 p.Y466C、PSEN2 p.R17W、PSEN2 p.F331Y、APP p.D197N和APP p.D252V。功能研究发现,突变体PS1 L174P、S289P、R377M、Y466C、PS2 V214L和M239T的Aβ42水平和Aβ42/Aβ40比值均升高。PS1 L174P、R377M和Y466C突变体降低了早老素-1的成熟。我们的研究结果强调了APP /PSENs变异在中国EOAD队列中的患病率和致病意义,并扩展了EOAD的表型和基因型谱。
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来源期刊
Alzheimer's Research & Therapy
Alzheimer's Research & Therapy 医学-神经病学
CiteScore
13.10
自引率
3.30%
发文量
172
审稿时长
>12 weeks
期刊介绍: Alzheimer's Research & Therapy is an international peer-reviewed journal that focuses on translational research into Alzheimer's disease and other neurodegenerative diseases. It publishes open-access basic research, clinical trials, drug discovery and development studies, and epidemiologic studies. The journal also includes reviews, viewpoints, commentaries, debates, and reports. All articles published in Alzheimer's Research & Therapy are included in several reputable databases such as CAS, Current contents, DOAJ, Embase, Journal Citation Reports/Science Edition, MEDLINE, PubMed, PubMed Central, Science Citation Index Expanded (Web of Science) and Scopus.
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