Mutations

PSEN1 P267S

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73664768 C>T
dbSNP ID: rs63751229
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CCA to TCA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was identified in a family from the United Kingdom referred to as F196 (Clark et al., 1995; Hutton et al., 1996). In three generations, five family members were affected by Alzheimer’s disease and had postmortem confirmation of the diagnosis. It is unclear how many family members were genotyped, but the P267S mutation was said to segregate with disease in this family. Onset was very early in this family, ranging from 32 to 38 years of age.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology

Five affected family members had neuropathology consistent with Alzheimer's disease (Clark et al., 1995).

Biological Effect

Experiments in cells and in vitro indicate this mutation alters APP processing, although its effects remain uncertain. In mouse embryonic fibroblasts lacking PSEN1 and PSEN2, expression of the P267S mutant resulted in reduced Aβ42 and Aβ40 production with no change in the Aβ42/Aβ40 ratio compared with cells expressing wild-type PSEN1 (Ben-Gedalya et al., 2015). A study using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate, however, indicated the mutant reduced Aβ40 production and sightly increased Aβ42 production, resulting in an approximately five-fold increase in the Aβ42/Aβ40 ratio (Sun et al., 2017). Interestingly, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicated this residue may help stabilize the structural re-arrangement of PSEN1 upon APP binding (Zhou et al., 2019; Jan 2019 news).

The mutation has also been reported to abolish a recognition site for cyclophilin B, a chaperone protein in the endoplasmic reticulum that assists in PSEN1 folding and maturation, and in vitro, the mutant undergoes enhanced proteolytic degradation (Ben-Gedalya et al., 2015). Moreover, P267S is one of several mutations in PSEN1 found to potentiate cell-cycle arrest when mutant protein is overexpressed in HeLa cells (Janicki et al., 2000).

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). These authors classified the variant as likely pathogenic using the ACMG-AMP guidelines (Richards et al., 2015).

Last Updated: 22 Jul 2021

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References

News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet. 1995 Oct;11(2):219-22. PubMed.
  2. . Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease. Neuroreport. 1996 Feb 29;7(3):801-5. PubMed.
  3. . Alzheimer's disease-causing proline substitutions lead to presenilin 1 aggregation and malfunction. EMBO J. 2015 Nov 12;34(22):2820-39. Epub 2015 Oct 5 PubMed.
  4. . 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.
  5. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  6. . Familial Alzheimer's disease presenilin-1 mutants potentiate cell cycle arrest. Neurobiol Aging. 2000 Nov-Dec;21(6):829-36. PubMed.
  7. . 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.
  8. . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

External Citations

  1. gnomAD v2.1.1

Further Reading

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.

Protein Diagram

Primary Papers

  1. . The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet. 1995 Oct;11(2):219-22. PubMed.
  2. . Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease. Neuroreport. 1996 Feb 29;7(3):801-5. PubMed.

Other mutations at this position

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