Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73653612 T>C
dbSNP ID: rs63750155
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TCA to CCA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was found in a screen for variants in the open reading frame of the PSEN1 gene in participants from the U.S., Germany, and Canada who had been referred for AD diagnostic testing (Rogaeva et al., 2001). The cohort included 372 patients with AD and 42 asymptomatic individuals with a strong family history of AD. The S178P mutation was identified in two independent families. In one family, the mutation was found to co-segregate with AD in two siblings. 

Neuropathology
Unknown

Biological Effect
In an in vitro assay with isolated proteins, this mutant produced less Aβ42 than wild-type PSEN1, and Aβ40 production was undetectable (Sun et al., 2017). Although S178 is not conserved between PSEN1 and PSEN2, it is conserved between the PSEN1 genes of several vertebrates

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References

Paper Citations

1. Rogaeva EA, Fafel KC, Song YQ, Medeiros H, Sato C, Liang Y, Richard E, Rogaev EI, Frommelt P, Sadovnick AD, Meschino W, Rockwood K, Boss MA, Mayeux R, St George-Hyslop P. Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
2. 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.

Further Reading

No Available Further Reading