Mutations

PSEN1 E280K

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73664807 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GAA to AAA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was identified in three Malaysian siblings whose family was affected by familial early onset Alzheimer’s disease with prominent behavioral changes and atypical features (Ch’ng et al., 2015). The reported five-generation pedigree shows seven family members with dementia, behavioral change (e.g., aggression), and parkinsonism. The female proband developed symptoms at age 48, starting with mood and behavior changes. She also presented with visual and auditory hallucinations and myclonic jerks. Two of her siblings were also affected by dementia with behavioral changes (onset at age 55 and 57, respectively). Their father had dementia when he died of cancer at age 71. The mutation segregated with disease: it was present in the three affected siblings and absent in 10 unaffected family members.

Neuropathology

Neuropathological data are unavailable, but MRI of the proband showed generalized brain atrophy including atrophy of the hippocampus.

Biological Effect

The biological effects of this mutation are unknown, but in silico analysis predicted this mutation to be damaging and additional pathogenic mutations at this site have been reported. Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment, revealed that E280 appears to play a key role in stabilizing the hybrid β-sheet that forms between PSEN1 and APP in preparation for γ-secretase cleavage (Zhou et al., 2019; Jan 2019 news). The carboxylate side chain of E280 makes a bifurcated H-bond to the hydroxyl groups of Y154 and Y159, both from transmembrane domain 2 of PSEN1. These interactions are buttressed by two additional H-bonds from R278 to E280 and Y159.

Last Updated: 06 Aug 2019

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . Identification of two novel mutations, PSEN1 E280K and PRNP G127S, in a Malaysian family. Neuropsychiatr Dis Treat. 2015;11:2315-22. Epub 2015 Sep 8 PubMed.
  2. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Identification of two novel mutations, PSEN1 E280K and PRNP G127S, in a Malaysian family. Neuropsychiatr Dis Treat. 2015;11:2315-22. Epub 2015 Sep 8 PubMed.

Other mutations at this position

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.