Mutations

PSEN1 A431V

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73685885 C>T
dbSNP ID: rs63750083
Coding/Non-Coding: Both
Mutation Type: Point, Missense
Codon Change: GCA to GTA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 12

Findings

This mutation was found in a Japanese man with a family history of early onset dementia affecting six members, spanning three generations (Matsushita et al., 2002). The mutation was absent from the proband’s unaffected mother and from 200 healthy controls and 120 patients with sporadic AD. The proband presented with mild cognitive impairment at age 47 and was diagnosed with AD 16 months later.

Neuropathology
Although neuropathological data are unavailable, FDG-PET imaging of the proband’s brain a month after the initial MCI diagnosis, revealed hypometabolism in the posterior cingulate gyrus, posterior and lateral parietal cortices, and medial temporal regions. One day after the MCI diagnosis, the proband’s levels of Aβ42 in the CSF were within the normal range, but tau and phospho-tau levels were elevated.

Biological effect
Unknown. At the MCI-AD stage, the proband had normal levels of CSF Aβ42. A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that A431 is apposed to the β-strand of APP which forms part of a hybrid, three-stranded β–sheet required for cleavage (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. . Clinical and biomarker investigation of a patient with a novel presenilin-1 mutation (A431V) in the mild cognitive impairment stage of Alzheimer's disease. Biol Psychiatry. 2002 Nov 1;52(9):907-10. PubMed.
  2. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Clinical and biomarker investigation of a patient with a novel presenilin-1 mutation (A431V) in the mild cognitive impairment stage of Alzheimer's disease. Biol Psychiatry. 2002 Nov 1;52(9):907-10. PubMed.

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