Mutations

PSEN1 L262F

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73664755 G>C
dbSNP ID: rs63750248
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TTG to TTC
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was found in a fibroblast line from the NIA Aging Cell Repository derived from an individual diagnosed with AD (Forsell et al., 1997). Age at onset was 56 years and symptoms included disorientation, aphasia, and memory loss. Two other fibroblast lines derived from affected siblings also carried the mutation. These individuals suffered from dementia onset at 47 and 48 years of age. One of them, diagnosed with AD based on a brain biopsy, experienced short-term memory loss and decreased word-finding ability. The other sibling presented with inappropriate jocularity and occasional paraphrasias. Samples from unaffected individuals in the same family were unavailable.

Neuropathology
A brain biopsy in one case revealed neuropathology consistent with AD.

Biological Effect
An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed L262F generates less Aβ40 and more Aβ42 than the wildtype protein, resulting in an elevated Aβ42/Aβ40 ratio (Sun et al., 2017).

Last Updated: 15 Nov 2019

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References

Paper Citations

  1. . A novel pathogenic mutation (Leu262Phe) found in the presenilin 1 gene in early-onset Alzheimer's disease. Neurosci Lett. 1997 Sep 26;234(1):3-6. 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. . A novel pathogenic mutation (Leu262Phe) found in the presenilin 1 gene in early-onset Alzheimer's disease. Neurosci Lett. 1997 Sep 26;234(1):3-6. PubMed.

Other mutations at this position

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