Mutations

PSEN1 E273A

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73664787 A>C
dbSNP ID: rs63750772
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GAA to GCA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was found in a screen of 25 Japanese families with early onset AD (Kamimura et al., 1998). The proband presented with AD symptoms at age 63. One other family member was reported to be affected.

Neuropathology
Unknown

Biological function
An in vitro assay using purified proteins to test the ability of E273A PSEN1 to cleave the APP-C99 substrate revealed this mutation generates more Aβ42 than the wild-type protein, resulting in an elevated Aβ42/Aβ40 ratio (Sun et al., 2017). In addition, presenilins have been reported to act as passive calcium leak channels in the endoplasmic reticulum, and E273A abolished this function in vitro and in cultured cells (Nelson et al., 2007).

Last Updated: 10 Apr 2019

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References

Paper Citations

  1. . Familial Alzheimer's disease genes in Japanese. J Neurol Sci. 1998 Sep 18;160(1):76-81. PubMed.
  2. . 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.
  3. . Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1. J Clin Invest. 2007 May;117(5):1230-9. Epub 2007 Apr 12 PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Familial Alzheimer's disease genes in Japanese. J Neurol Sci. 1998 Sep 18;160(1):76-81. PubMed.

Other mutations at this position

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