Mutations

PSEN1 C263R

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73664756 T>C
dbSNP ID: rs63750543
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TGT to CGT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was found in an individual with autopsy-confirmed AD and a family history of the disease (Wasco et al., 1995). Age of onset was approximately 47 years, with an average of 50 years for all four affected family members. The mutation was absent from affected members of 29 families with early onset AD and 12 families with late-onset AD, as well as from 106 controls.

Neuropathology
Neuropathology of the proband was consistent with AD.

Biological Effect
An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed decreased production of both Aβ40 and Aβ42, and an approximately two-fold increase in the Aβ42/Aβ40 ratio (Sun et al., 2017). A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates this residue may help stabilize the structural re-arrangement of PSEN1 upon APP binding (Zhou et al., 2019; Jan 2019 news).

Last Updated: 14 Aug 2019

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References

News Citations

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

Paper Citations

  1. . Familial Alzheimer's chromosome 14 mutations. Nat Med. 1995 Sep;1(9):848. PubMed.
  2. . 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.
  3. . 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. . Mutant presenilin 1 proteins induce cell death and reduce tau-dependent processes outgrowth. Neurosci Lett. 2003 Dec 26;353(3):226-30. PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Familial Alzheimer's chromosome 14 mutations. Nat Med. 1995 Sep;1(9):848. PubMed.

Other mutations at this position

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