Mutations

PSEN1 P267S

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73664768 C>T
dbSNP ID: rs63751229
Coding/Non-Coding: Coding
Genomic Region: Exon 8
Mutation Type: Point, Missense
Codon Change: CCA to TCA

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.

Neuropathology

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

Biological Effect

In mouse embryonic fibroblasts lacking presenilin-1 and presenilin-2, expression of the mutant presenilin-1 protein produced less Aβ42 and Aβ40 than equivalent expression of wild-type presenilin-1 protein. The relative ratio of Aβ42/Aβ40 is unchanged. This mutation abolishes a recognition site for cyclophilin B, a chaperone protein in the endoplasmic reticulum that assists in presenilin-1 folding and maturation. In vitro, presenilin-1 with this mutation undergoes enhanced proteolytic degradation. When expressed in presenilin–deficient cells, γ-secretase activity is virtually abolished (Ben-Gedalya et al., 2015).

P267S is one of several mutations in presenilin-1 found to potentiate cell-cycle arrest when mutant protein is overexpressed in HeLa cells, compared to wild-type presenilin-1 (Janicki et al., 2000).

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References

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. . Familial Alzheimer's disease presenilin-1 mutants potentiate cell cycle arrest. Neurobiol Aging. 2000 Nov-Dec;21(6):829-36. PubMed.

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.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

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

Alzpedia