Mutations

PSEN1 E69D

Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73637624 A>T
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GAA to GAT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This variant was identified by whole-exome sequencing in one of 424 French people with early onset Alzheimer's disease. This individual had apparently sporadic AD starting at age 55 (Nicolas et al., 2015). The variant was absent from the EVS and ExAC variant databases (Hsu et al., 2020).

Neuropathology

Unknown.

Biological Effect

Mouse neuroblastoma cells lacking endogenous PSEN1 and PSEN2 and transfected with the PSEN1 E69D variant produced increased amounts of both Aβ42 and Aβ40 compared with cells expressing wild-type PSEN1. Although the Aβ42/Aβ40 ratio was slightly elevated, it was not significantly different from that of controls (Hsu et al., 2020). In silico analyses predicted the variant to be benign (PolyPhen) and tolerated (SIFT), and E69 is not conserved between PSEN1 and PSEN2. Based on their pathogenicity guidelines, Hsu and colleagues classified L238F as probably pathogenic.

Last Updated: 03 Nov 2020

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References

Paper Citations

  1. . Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. Eur J Hum Genet. 2015 Aug 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. Eur J Hum Genet. 2015 Aug 5; PubMed.

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