Mutations

PSEN1 G394V

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73683885 G>T
dbSNP ID: rs63750929
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GGT to GTT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This mutation was found in a screen for variants in the open reading frame of the PSEN1 gene in participants from the United States, Germany, and Canada who had been referred for AD diagnostic testing (Rogaeva et al., 2001). The cohort included 372 patients with AD and 42 asymptomatic individuals with a strong family history of AD. Evidence for co-segregation of this mutation with disease is not available.

The mutation was also reported in a Chinese Han individual with probable AD and an age at onset of 45 years (Wang et al., 2019). The mutation was absent from 160 controls.

Neuropathology
Unknown

Biological Effect
In an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate, Aβ40 production was undetectable and Aβ42 production was drastically decreased (Sun et al., 2017). In addition, autoproteolysis was abrogated. However, levels of Aβ40, Aβ42, and the Aβ42/Aβ40 ratio were similar in media from primary skin fibroblasts of double-mutation (E318G/G394V) carriers and non-carriers (Batelli et al., 2008). Four algorithms predicted the PSEN1 G394V mutation to be damaging, with a PHRED-CADD score of 31 (Wang et al., 2019).

Last Updated: 19 Sep 2019

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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. . Mutation and association analyses of dementia-causal genes in Han Chinese patients with early-onset and familial Alzheimer's disease. J Psychiatr Res. 2019 Jun;113:141-147. Epub 2019 Mar 30 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. . Early-onset Alzheimer disease in an Italian family with presenilin-1 double mutation E318G and G394V. Alzheimer Dis Assoc Disord. 2008 Apr-Jun;22(2):184-7. PubMed.

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.

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