Mutations

PSEN1 I229F

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659488 A>T
dbSNP ID: rs63749970
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATT to TTT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

The mutation was found in a study of British AD patients with a family history of AD with at least one affected first-degree relative, and an age of onset of less than 61 years (Janssen et al., 2003). The age of onset of the proband was 33 years. Two members of the individual’s family, spanning two generations, were diagnosed with AD, with a mean age of onset of 33 years. DNA was unavailable from the affected relatives, however, so co-segregation of the mutation and disease could not be demonstrated. The mutation was absent from 100 healthy, unrelated white control patients.

Neuropathology
Unknown

Biological Effects
An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed it generates less Aβ40 and more Aβ42 peptides than the wildtype protein, resulting in a >2-fold elevation of the Aβ42/Aβ40 ratio (Sun et al., 2017).

Last Updated: 29 Mar 2019

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References

Paper Citations

  1. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
  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.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.

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