Identification and characterization of variants in PSEN1, PSEN2, and APP genes in Chinese patients with early-onset Alzheimer's disease
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 clinica...
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BMC
2025-02-01
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| Series: | Alzheimer’s Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13195-025-01702-0 |
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| author | Haitian Nan Min Chu Deming Jiang Wenping Liang Yu Li Yiming Wu Zhe Wang Liyong Wu |
| author_facet | Haitian Nan Min Chu Deming Jiang Wenping Liang Yu Li Yiming Wu Zhe Wang Liyong Wu |
| author_sort | Haitian Nan |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-cf6eb69c33dd4a5380985c81a93a1518 |
| institution | DOAJ |
| issn | 1758-9193 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj-art-cf6eb69c33dd4a5380985c81a93a15182025-08-20T03:00:37ZengBMCAlzheimer’s Research & Therapy1758-91932025-02-0117111810.1186/s13195-025-01702-0Identification and characterization of variants in PSEN1, PSEN2, and APP genes in Chinese patients with early-onset Alzheimer's diseaseHaitian Nan0Min Chu1Deming Jiang2Wenping Liang3Yu Li4Yiming Wu5Zhe Wang6Liyong Wu7Department of Neurology, Xuanwu Hospital, Capital Medical UniversityDepartment of Neurology, Xuanwu Hospital, Capital Medical UniversityDepartment of Neurology, Xuanwu Hospital, Capital Medical UniversityAdvanced Innovation Center for Human Brain Protection, the National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical UniversityAdvanced Innovation Center for Human Brain Protection, the National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical UniversityThe Experimental High School Attached to Beijing Normal UniversityAdvanced Innovation Center for Human Brain Protection, the National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical UniversityDepartment of Neurology, Xuanwu Hospital, Capital Medical UniversityAbstract 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.https://doi.org/10.1186/s13195-025-01702-0Alzheimer’s diseaseEOADAmyloid βAPPPSEN1PSEN2 |
| spellingShingle | Haitian Nan Min Chu Deming Jiang Wenping Liang Yu Li Yiming Wu Zhe Wang Liyong Wu Identification and characterization of variants in PSEN1, PSEN2, and APP genes in Chinese patients with early-onset Alzheimer's disease Alzheimer’s Research & Therapy Alzheimer’s disease EOAD Amyloid β APP PSEN1 PSEN2 |
| title | Identification and characterization of variants in PSEN1, PSEN2, and APP genes in Chinese patients with early-onset Alzheimer's disease |
| title_full | Identification and characterization of variants in PSEN1, PSEN2, and APP genes in Chinese patients with early-onset Alzheimer's disease |
| title_fullStr | Identification and characterization of variants in PSEN1, PSEN2, and APP genes in Chinese patients with early-onset Alzheimer's disease |
| title_full_unstemmed | Identification and characterization of variants in PSEN1, PSEN2, and APP genes in Chinese patients with early-onset Alzheimer's disease |
| title_short | Identification and characterization of variants in PSEN1, PSEN2, and APP genes in Chinese patients with early-onset Alzheimer's disease |
| title_sort | identification and characterization of variants in psen1 psen2 and app genes in chinese patients with early onset alzheimer s disease |
| topic | Alzheimer’s disease EOAD Amyloid β APP PSEN1 PSEN2 |
| url | https://doi.org/10.1186/s13195-025-01702-0 |
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