Mutations

PSEN1 P267L

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73664769 C>T
dbSNP ID: rs63750779
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CCA to CTA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was identified in a Polish individual who met clinical criteria (NINCDS-ADRDA) for AD (Kowalska et al., 2003). This individual had a family history of dementia and belonged to a pedigree referred to as “H.A.” The reported pedigree shows seven affected individuals over three generations (Kowalska et al., 2004). Segregation with disease could not be established due to lack of DNA from family members. The mutation carrier experienced symptom onset at age 59. APOE genotype was 3/3; further clinical details were not reported.

Neuropathology

Unknown.

Biological Effect

Unknown. A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates this residue appears to help stabilize the structural re-arrangement of PSEN1 upon APP binding (Zhou et al., 2019; Jan 2019 news).

Last Updated: 13 Aug 2019

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References

News Citations

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

Paper Citations

  1. Kowalska A, Wender M, Florczak J, Pruchnik-Wolinska D, Modestowicz R, Szczech J, Rossa G, Kozubski W. Molecular genetics of Alzheimer's disease: presenilin 1 gene analysis in a cohort of patients from the Poznań region. J Appl Genet. 2003;44(2):231-4. PubMed.
  2. Kowalska A, Pruchnik-Wolińska D, Florczak J, Modestowicz R, Szczech J, Kozubski W, Rossa G, Wender M. Genetic study of familial cases of Alzheimer's disease. Acta Biochim Pol. 2004;51(1):245-52. PubMed.
  3. Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Further Reading

Papers

  1. Kowalska A, Pruchnik-Wolińska D, Florczak J, Szczech J, Kozubski W, Rossa G, Wender M. Presenilin 1 mutations in Polish families with early-onset Alzheimer's disease. Folia Neuropathol. 2004;42(1):9-14. PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. Kowalska A, Wender M, Florczak J, Pruchnik-Wolinska D, Modestowicz R, Szczech J, Rossa G, Kozubski W. Molecular genetics of Alzheimer's disease: presenilin 1 gene analysis in a cohort of patients from the Poznań region. J Appl Genet. 2003;44(2):231-4. PubMed.

Other mutations at this position

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