Mutations

PSEN1 L248R

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659546 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTC to CGC
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was found in a man who presented with AD symptoms at age 54, with no known family history of the disease.

Neuropathology

Although neuropathology findings are unavailable, the patient showed atrophy in the lateral fissure and, to a lesser extent, in parietofrontal regions as assessed by neuroimaging.

Biological Effect

In vitro studies using APP C99 as a substrate showed the mutation increased the Aβ42/Aβ40 ratio, severely decreasing production of both Aβ40 and Aβ42 (Bai et al., 2015; Sun et al., 2017).

Last Updated: 01 Mar 2019

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References

Paper Citations

  1. . An atomic structure of human γ-secretase. Nature. 2015 Sep 10;525(7568):212-7. Epub 2015 Aug 17 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

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Genetic screening in a large cohort of early-onset Alzheimer's disease patients from Spain: novel mutations in the amyloid precursor protein and presenilines. Alzheimers Demen. 2008 Jul;4(4 Suppl):T583.
  2. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.

Other mutations at this position

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