Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genome Build: 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


Biological Effect

When expressed in mouse embryonic fibroblasts lacking endogenous presenilin-1 and presenilin-2,  expression of the P267S mutant protein produces much lower levels of Aβ42 and Aβ40 compared to Aβ levels produced by wild-type 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 protein carrying this mutation undergoes enhanced proteolytic degredation. When expressed in presenilin–deficient cells, γ-secretase activity is virtually abolished (Ben-Gedalya et al., 2015).


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Paper Citations

  1. . 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.

Further Reading


  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