Mutations

PSEN1 W165C (G>C)

Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73653575 G>C
dbSNP ID: rs63751484
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TGG to TGC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was initially detected in a French kindred (Alz 064) reported to have three individuals affected by AD, spanning three generations (Campion et al., 1999). Age at onset ranged from 37 to 47 years. The proband was homozygous for the APOE3 allele.

The variant was also found in a Chinese man with a family history of AD and age at onset of 47 years (Mao et al., 2021). His APOE genotype was E2/E3.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, June 2021).

Neuropathology

Unknown

Biological Effect

Although the biological effect of this mutation is unknown, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that, in wild-type PSEN1, W165 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). Moreover, three in silico algorithms (SIFT, Polyphen2, and LRT) predicted the W165C is deleterious (Mao et al., 2021) and three-dimensional modeling of a synonymous substitution, W165C (G>T), suggested it induces significant conformational changes (Van Giau et al., 2019).

 

Last Updated: 01 Sep 2021

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References

News Citations

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

Mutations Citations

  1. PSEN1 W165C (G>T)

Paper Citations

  1. . Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
  2. . Clinical Phenotype and Mutation Spectrum of Alzheimer's Disease with Causative Genetic Mutation in a Chinese Cohort. Curr Alzheimer Res. 2021;18(3):265-272. PubMed.
  3. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  4. . A pathogenic PSEN1 Trp165Cys mutation associated with early-onset Alzheimer's disease. BMC Neurol. 2019 Aug 7;19(1):188. PubMed.

External Citations

  1. gnomAD v2.1.1,

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.

Other mutations at this position

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