Mutations

PSEN1 P436S

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
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.

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.

Last Updated: 17 Apr 2019

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References

Paper Citations

  1. Palmer MS, Beck JA, Campbell TA, Humphries CB, Roques PK, Fox NC, Harvey R, Rossor MN, Collinge J. 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. Heilig EA, Xia W, Shen J, Kelleher RJ. 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. 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

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. Palmer MS, Beck JA, Campbell TA, Humphries CB, Roques PK, Fox NC, Harvey R, Rossor MN, Collinge J. 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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