Mutations

PSEN1 Q127_R128del(CAGA);InsG(G) (c.379_382delXXXXinsG)

Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
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 in two population-based exome sequencing databases, EVS and ExAC.

Neuropathology
Unknown

Biological Effect
N2A695 cells expressing this mutant produced Aβ42 and Aβ40 levels similar to those expressing the wild-type protein. In silico analysis using SIFT predicted the mutation to be tolerated. The position is conserved between PSEN1 and PSEN2.  The authors suggest the mutation could be an AD risk factor or a benign polymorphism.

Last Updated: 11 Apr 2019

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References

Paper Citations

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

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