Mutations

PSEN1 L173W

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73653598 T>G
dbSNP ID: rs63750299
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TTG to TGG
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was detected in two members of a French family (ROU 118) affected by early onset Alzheimer's disease (Campion et al., 1999). The two affected individuals were a parent and child dyad, with onset at ages 24 and 29. Further clinical details were not reported. The APOE genotype of the index case was ε2/ε4.

The mutation was also found in a screen involving whole-exome sequencing of 15 unrelated Chinese patients with familial AD (Jiang et al., 2019). The proband presented with cognitive deficits typical of AD.

Neuropathology

Unknown.

Biological Effect

In an in vitro assay using the APP-C99 substrate, the mutant protein produced less Aβ40 and more Aβ42 than wild-type PSEN1, resulting in a greater than 10-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 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: 13 Aug 2019

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References

News Citations

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

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. . Mutation screening in Chinese patients with familial Alzheimer's disease by whole-exome sequencing. Neurobiol Aging. 2019 Apr;76:215.e15-215.e21. Epub 2018 Dec 6 PubMed.
  3. . 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.
  4. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

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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