Mutations

PSEN1 P436S

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73685899 C>T
dbSNP ID: rs63749925
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CCA to TCA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 12

Findings

This mutation was found in two affected siblings from a family in the UK with members who had been diagnosed with probable or definite AD across two or more generations (Palmer et al., 1999). Disease onset occurred at 50 and 44 years of age. The mutation was absent from 92 controls and from the gnomAD variant database (gnomAD v2.1.1, August 2021).

Neuropathology
Unknown

Biological Effect
In mouse embryonic fibroblasts lacking endogenous PSEN1, the P436S mutant produced less Aβ40, Aβ42, and APP and Notch intracellular domains compared with cells transfected with wild-type PSEN1 (Heilig et al., 2010). Moreover, in an in vitro assay using purified proteins, the mutant produced less Aβ40 than wild-type PSEN1, but similar levels of Aβ42 (Sun et al., 2017). In both cases, P436S increased the Aβ42/Aβ40 ratio. 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).

Last Updated: 13 Sep 2021

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References

Paper Citations

  1. . Pathogenic presenilin 1 mutations (P436S & I143F) in early-onset Alzheimer's disease in the UK. Mutations in brief no. 223. Online. Hum Mutat. 1999;13(3):256. PubMed.
  2. . A presenilin-1 mutation identified in familial Alzheimer disease with cotton wool plaques causes a nearly complete loss of gamma-secretase activity. J Biol Chem. 2010 Jul 16;285(29):22350-9. PubMed.
  3. . 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. . 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 v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Pathogenic presenilin 1 mutations (P436S & I143F) in early-onset Alzheimer's disease in the UK. Mutations in brief no. 223. Online. Hum Mutat. 1999;13(3):256. PubMed.

Other mutations at this position

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