Mutations

PSEN1 I439V

Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73685908 A>G
dbSNP ID: rs63750249
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATC to GTC
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 12

Findings

This mutation was found in two sisters affected by early onset Alzheimer's disease (Rogaeva et al., 2001). They inherited the mutation from their mother, who was asymptomatic at age 55. Interestingly, both sisters also carried a second PSEN1 mutation, I143T, which they inherited from their father. Information related to his clinical history was not reported. Both sisters developed symptoms before age 35.

The variant is absent from the EVS and ExAC variant databases (Hsu et al., 2020).

Neuropathology

Unknown.

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed a moderate increase in production of Aβ40 and Aβ42 compared with wildtype PSEN1, without altering the Aβ42/Aβ40 ratio (Sun et al., 2017). Similarly, the Aβ42/Aβ40 ratio remained unchanged in mouse neuroblastoma cells lacking endogenous PSEN1 and PSEN2 and expressing APP695 (N2A695) and the PSEN1 I439V variant (Hsu et al., 2020). In this latter assay, Aβ42, but not Aβ40, secretion was increased. I439 is conserved between PSEN1 and PSEN2, but in silico analyses predicted the isoleucine to valine substitution to be benign (PolyPhen) and tolerated (SIFT). Hsu and colleagues classified I439V as probably pathogenic.

Last Updated: 04 Nov 2020

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References

Paper Citations

  1. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  2. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 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.

Other Citations

  1. I143T

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.

Other mutations at this position

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