Mutations

PSEN1 R358Q

Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73678594 G>A
dbSNP ID: rs63751174
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CGA to CAA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 10

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.

In a subsequent study, the allele count and frequency of this variant in the gnomAD variant database were reported as 11 and 0.0044 percent, respectively (Koriath et al., 2018). The penetrance was calculated to be two percent or less. Thus, the authors described the variant as "most likely benign" or causing an "only small increase in risk."

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 drop in Aβ40 and Aβ42 production, and an increase in the Aβ42/Aβ40 ratio (Sun et al., 2017). Although R358Q is not conserved between PSEN1 and PSEN2, it is conserved between the PSEN1 genes of several vertebrates.

Last Updated: 16 Jul 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. . Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; 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.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

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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