Mutations

PSEN1 G209R

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659428 G>A
dbSNP ID: rs63749880
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GGA to AGA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was found in a Japanese family affected by early onset Alzheimer’s disease (Sugiyama et al., 1999). At least six family members were affected (Marui et al., 2003). The proband developed symptoms at age 46. His sister and mother were also affected, with onset at age 48 and 53, respectively. All three showed progressive memory impairment, disorientation, and personality changes. The mutation was found in all three affected family members tested, suggesting segregation with disease; however, no unaffected family members were genotyped.

Neuropathology

Unknown. Imaging showed mild brain atrophy in the temporal lobes at early stages and diffuse brain atrophy predominantly in the frontotemporal lobes at advanced stages. Hypoperfusion in the frontotemporal areas was also seen at early stages, extending to the parieto-occipital areas at advanced stages (Marui et al., 2003).

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed it abrogates Aβ40 production and drastically reduces Aβ42 production (Sun et al., 2017). A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment suggests mutations in G209 could alter the protein's local conformation and affect the positioning of residues that directly contribute to substrate 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. . A novel missense mutation (G209R) in exon 8 of the presenilin 1 gene in a Japanese family with presenile familial Alzheimer's disease. Mutation in brief no. 254. Online. Hum Mutat. 1999;14(1):90. PubMed.
  2. . [A Japanese family with familial Alzheimer's disease associated with presenilin 1 mutation: relationship between younger age of onset and ApoE gene polymorphism]. No To Shinkei. 2003 Apr;55(4):349-53. 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

Learn More

  1. Japanese Familial Alzheimer's Disease Database

Protein Diagram

Primary Papers

  1. . A novel missense mutation (G209R) in exon 8 of the presenilin 1 gene in a Japanese family with presenile familial Alzheimer's disease. Mutation in brief no. 254. Online. Hum Mutat. 1999;14(1):90. PubMed.

Other mutations at this position

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