Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73637706 G>T
dbSNP ID: rs63750852
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTG to TTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This rare missense mutation was identified in a Han Chinese family. The reported pedigree consisted of three affected individuals over four generations. The affected family members were diagnosed with probable Alzheimer's disease according to NINCDS-ADRDA criteria. The mean age of onset was 36.5 ± 15.9 years. The mutation was present in all three affected individuals and absent in five healthy family members and 50 healthy unrelated controls (Jia et al., 2005). It was also absent from the gnomAD variant database (May 2021).

Neuropathology

Postmortem analysis was unavailable, but MRI from two mutation carriers showed enlarged lateral ventricles and atrophy of the cerebral cortex, especially the temporal lobes (Jia et al., 2005).

Biological Effect

Human neuroblastoma cells (SH-SY5Y) transfected with V97L PSEN1 had elevated intracellular and extracellular Aβ42 compared to mock-transfected cells and those expressing wild-type PSEN1 (Fang et al., 2006). However, an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed slight decreases in both Aβ40 and Aβ42 production, with a Aβ42/Aβ40 ratio similar to that of wildtype PSEN1 (Sun et al., 2017).

Other effects reported for this mutation include decreased expression and activity of insulin-degrading enzyme in the cytosol and endoplasmic reticulum (Qin and Jia, 2008), enhanced sensitivity to trophic withdrawal (Fang and Jia, 2008), and disruption of intracellular calcium homeostasis (Wang et al., 2015; Tong et al., 2016; Sep 2016 news).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021)

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References

News Citations

1. Mutant Presenilin Skews Calcium Homeostasis by Chomping on ER Sensor 9 Sep 2016

Paper Citations

1. Jia J, Xu E, Shao Y, Jia J, Sun Y, Li D. One novel presenilin-1 gene mutation in a Chinese pedigree of familial Alzheimer's disease. J Alzheimers Dis. 2005 Apr;7(2):119-24; discussion 173-80. PubMed.
2. Fang B, Jia L, Jia J. Chinese Presenilin-1 V97L mutation enhanced Abeta42 levels in SH-SY5Y neuroblastoma cells. Neurosci Lett. 2006 Oct 2;406(1-2):33-7. PubMed.
3. 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.
4. Qin W, Jia J. Down-regulation of insulin-degrading enzyme by presenilin 1 V97L mutant potentially underlies increased levels of amyloid beta 42. Eur J Neurosci. 2008 May;27(9):2425-32. PubMed.
5. 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.
6. Shao Y, Li M, Wu M, Shi K, Fang B, Wang J. FAD-linked Presenilin-1 V97L mutation impede tranport regulation and intracellular Ca(2+) homeostasis under ER stress. Int J Clin Exp Med. 2015;8(11):20742-50. Epub 2015 Nov 15 PubMed.
7. 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.
8. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

External Citations

1. gnomAD variant database

Further Reading