Mutations

PSEN1 W165G

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73653573 T>G
dbSNP ID: rs63751010
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TGG to GGG
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was identified in a Japanese woman who developed memory impairment at age 38 and experienced rapid subsequent cognitive decline (Higuchi et al., 2000). The family had at least five members affected by AD with mean ages of onset of 36 years, but co-segregation of the mutation with disease was not confirmed. The mutation was absent from 207 unrelated AD patients and 200 controls.

Neuropathology
Neuropathological data are not available. However, two years after onset, the proband had slight, bilateral hypoperfusion of the parieto-occipital region and thalamus, as assessed by SPECT, as well as EEG alterations. No abnormalities were detected by MRI. Three years after onset, tau levels in the CSF were highly elevated.

Biological Effect
In experiments with isolated proteins, the mutation robustly increased the production of Aβ42, while reducing that of Aβ40, resulting in an 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 that, in wild-type PSEN1, this residue is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news).

Last Updated: 04 Aug 2019

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References

News Citations

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

Paper Citations

  1. . A novel PS1 Mutation (W165G) in a Japanese family with early-onset Alzheimer's disease. Alzheimer's Rep. 2000;3:227-31.
  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. . Quantifying correlations between mutational sites in the catalytic subunit of γ-secretase. J Mol Graph Model. 2019 May;88:221-227. Epub 2019 Feb 8 PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . A novel PS1 Mutation (W165G) in a Japanese family with early-onset Alzheimer's disease. Alzheimer's Rep. 2000;3:227-31.

Other mutations at this position

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