Mutations

PSEN1 Q127_R128del(CAGA);InsG(G)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73640314 CAGAGA>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Insertion/Deletion
Codon Change: CAGAGA to GGA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation is a four base-pair deletion, including Q127 (CAG) and the first base pair of Q128 (A), with an insertion of a G at the deletion site, resulting in the replacement of glutamine and arginine by a glycine (Hsu et al., 2018). It was found in a family with early-onset AD from the Dominantly Inherited Alzheimer Network (DIAN) Extended Registry. The proband had an age at symptomatic onset of 50 years, and the average age of onset in family members was 43 years. The mutation was absent from two population-based exome sequencing databases, EVS and ExAC.

Neuropathology
Unknown

Biological Effect
Hsu et al. initially reported that mouse neuroblastoma cells expressing this mutant on a PSEN1/PSEN2 null background secreted Aβ42 and Aβ40 at levels similar to those secreted by cells expressing wild-type PSEN1 (Hsu et al., 2018). However, in a subsequent paper, the researchers reported that the variant actually increased Aβ42 and decreased Aβ40 secretion in the same cells, resulting in a nearly fivefold increase in the Aβ42/Aβ40 ratio (Hsu et al., 2020). An explanation for this discrepancy was not offered. Also of note, the position is conserved between PSEN1 and PSEN2.  Hsu et al. first suggested the mutation could be an AD risk factor or a benign polymorphism (Hsu et al., 2018), but later classified it as probably pathogenic (Hsu et al., 2020).

Last Updated: 26 Feb 2020

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

  1. . Discovery and validation of autosomal dominant Alzheimer's disease mutations. Alzheimers Res Ther. 2018 Jul 18;10(1):67. 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Discovery and validation of autosomal dominant Alzheimer's disease mutations. Alzheimers Res Ther. 2018 Jul 18;10(1):67. PubMed.

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.