Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73640342 C>G
dbSNP ID: rs41345849
Mutation Type: Point, Missense
Codon Change: GCT to GGT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 5
This mutation was found in an analysis of 130 members of a Chinese family. The search, which focused on PSEN1 exons 4 and 5, identified the mutation in nine individuals, five of whom had been diagnosed with Alzheimer's disease. The mutation was absent from 50 controls.
Neuroblastoma cells carrying the mutation showed enhanced sensitivity to trophic withdrawal (Fang and Jia, 2007, Fang and Jia, 2008). Polyphen analysis predicted the mutation is probably damaging, while SIFT analysis classified it as "tolerated." In vitro assays showed a moderate decrease in both Aβ40 and Aβ42 production, with the Aβ42/Aβ40 ratio remaining roughly similar to wild-type (Sun et al., 2017). Moreover, the mutation has been reported to enhance PSEN1 cleavage of STIM1, a calcium sensor in the endoplasmic reticulum that promotes the replenishment of the cation when stores run low (Tong et al., 2016, see also Sep 2016 news). The enhanced cleavage causes calcium influx to drop, which appears to disrupt dendritic spines.
Last Updated: 04 Mar 2019
- Fang BY, Jia JP. [The effect of two newly Chinese presenilin-1 mutations on the sensitivity to trophic factor withdrawal in human neuroblastoma cells]. Zhonghua Yi Xue Za Zhi. 2007 Jan 30;87(5):336-40. PubMed.
- Fang BY, Jia JP. Human neuroblastoma cells transfected with two Chinese presenilin 1 mutations are sensitized to trophic factor withdrawal and protected by insulin-like growth factor-1. Chin Med J (Engl). 2008 May 20;121(10):910-5. PubMed.
- Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
- Tong BC, Lee CS, Cheng WH, Lai KO, Foskett JK, Cheung KH. Familial Alzheimer's disease-associated presenilin 1 mutants promote γ-secretase cleavage of STIM1 to impair store-operated Ca2+ entry. Sci Signal. 2016 Sep 6;9(444):ra89. PubMed.
- Xu E, Jia J, Sun W. [Mutation site of presenilin-1 gene in familial Alzheimer's disease]. Zhonghua Yi Xue Za Zhi. 2002 Nov 25;82(22):1518-20. PubMed.
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