Mutations

PSEN1 K239N

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659520 G>C
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: AAG to AAC
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was identified in a Spanish family with AD that progressed relatively slowly, with a wide range of ages of onset (Lladó et al., 2010). A total of six family members were affected, with ages of onset ranging from the fifth to eighth decade of life. The mutation was found in all three affected members who were tested, and was absent from 121 controls and 163 AD patients.

The proband was a man who developed cognitive decline with behavioral abnormalities at age 57. His behavioral symptoms included apathy, irritability, social withdrawal, and, ultimately, marked aggressiveness for which he was institutionalized at age 70. Another family member carrying the mutation also initially presented with apathy and irritability, and subsequently became aggressive, but her symptoms started earlier, at age 42. Surprisingly, a third mutation carrier in the same family presented with typical AD at age 71. This is in contrast to the complete penetrance of PSEN1 mutations usually seen by age 65. All three individuals had an APOE 3/3 genotype.

Neuropathology

Neuropathology data are unavailable, but an MRI of the proband’s brain revealed marked atrophy in the medial temporal lobes and to a lesser extent in the frontal lobes (Lladó et al., 2010). Global cerebral atrophy was reported for MRI scans of two other mutation carriers from the same family showed global atrophy.

Biological Effect

In mouse embryonic fibroblasts expressing this mutant, γ-secretase activity was only moderately lower than in cells expressing wild-type PSEN1, and in cells co-expressing the mutant with APP carrying the Swedish mutation, generation of Aβ42 and the Aβ42/Aβ40 ratio were increased (Sarroca et al., 2016). However, production of both Aβ40  and Aβ42 were undetectable in an in vitro assay using the APP-C99 substrate (Sun et al., 2017).

Last Updated: 10 Apr 2019

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

  1. . A novel PSEN1 mutation (K239N) associated with Alzheimer's disease with wide range age of onset and slow progression. Eur J Neurol. 2010 Jul;17(7):994-6. Epub 2010 Feb 10 PubMed.
  2. . Preservation of cell-survival mechanisms by the presenilin-1 K239N mutation may cause its milder clinical phenotype. Neurobiol Aging. 2016 Oct;46:169-79. Epub 2016 Jul 15 PubMed.
  3. . 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

Papers

  1. . Increased cortical thickness and caudate volume precede atrophy in PSEN1 mutation carriers. J Alzheimers Dis. 2010;22(3):909-22. PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . A novel PSEN1 mutation (K239N) associated with Alzheimer's disease with wide range age of onset and slow progression. Eur J Neurol. 2010 Jul;17(7):994-6. Epub 2010 Feb 10 PubMed.

Alzpedia

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.