Mutations

PSEN1 D333G

Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Dilated Cardiomyopathy
Reference Assembly: GRCh37 (105)
Position: Chr14:73678519 A>G
dbSNP ID: rs121917809
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GAT to GGT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 10

Findings

This mutation was identified in a screen of the PSEN1 and PSEN2 genes of 132 families with familial dilated cardiomyopathy (Li et al., 2006). The African American family carrying this mutation had six affected members with aggressive heart disease emerging between 24 and 69 years of age. One mutation carrier was diagnosed with AD dementia at age 71, but no autopsy was performed. Three members with heart disease who were tested for the mutation were found to be carriers, while six unaffected members tested negative. In addition, the mutation was absent from 413 unrelated and unaffected controls.

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 moderate reduction in Aβ42 production with little or no effect on the Aβ42/Aβ40 ratio (Sun et al., 2017).
The D333 position is highly conserved and the mutation results in a nonconservative substitution. It may affect intracellular calcium dynamics as suggested by the observation of altered calcium signaling in cultured skin fibroblasts (Li et al., 2006).

Last Updated: 09 Apr 2019

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References

Paper Citations

  1. . Mutations of presenilin genes in dilated cardiomyopathy and heart failure. Am J Hum Genet. 2006 Dec;79(6):1030-9. Epub 2006 Oct 24 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Mutations of presenilin genes in dilated cardiomyopathy and heart failure. Am J Hum Genet. 2006 Dec;79(6):1030-9. Epub 2006 Oct 24 PubMed.

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