Mutations

PSEN1 M233I (G>A)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659502 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATG to ATA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was found in a large French study reporting 56 new families with autosomal-dominant, early onset Alzheimer's disease. All probands met NINCDS-ADRDA criteria for probable AD and had a family history of disease (Wallon et al., 2012).

The M233I (G>A) mutation was detected in a family with two confirmed mutation carriers and two additional affected family members of unknown genotype. Age of onset was very early in this family, 24 to 30 years, with duration of approximately 11 years. At least one mutation carrier presented with early extrapyramidal signs. The mutation appears to segregate with disease in this family.

Neuropathology

Unknown.

Biological Effect

A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that, in wild-type PSEN1, this residue is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news). The related M233I (G>A) mutation was classified as definitely pathogenic according to the algorithm proposed by Guerreiro et al., 2010 (Wallon et al., 2012).

 

Last Updated: 01 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. . The French series of autosomal dominant early onset Alzheimer's disease cases: mutation spectrum and cerebrospinal fluid biomarkers. J Alzheimers Dis. 2012 Jan 1;30(4):847-56. PubMed.
  2. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  3. . 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . The French series of autosomal dominant early onset Alzheimer's disease cases: mutation spectrum and cerebrospinal fluid biomarkers. J Alzheimers Dis. 2012 Jan 1;30(4):847-56. 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.