Mutations

PSEN1 I213L

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659440 A>C
dbSNP ID: rs63750861
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATT to CTT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was found in a screen for variants in the open reading frame of the PSEN1 gene in participants from the United States, Germany, and Canada who had been referred for AD diagnostic testing (Rogaeva et al., 2001). The cohort included 372 patients with AD and 42 asymptomatic individuals with a strong family history of AD. The mutation was found in multiple affected members in the same family, suggesting co-segregation.

In addition, the mutation was found in a Polish family with probable familial AD (Gołąb-Janowska et al., 2009). Four affected siblings had progressive cognitive impairments, including memory loss, starting before age 50 and ultimately resulting in severe dementia. Aphasia, agnosia, apraxia, agraphia, acalculia, and extrapyramidal syndrome were reported, as well as myoclonia in two individuals. The father, grandfather, and five other relatives also suffered from dementia before their 50th birthdays.

Neuropathology
Unknown.

Biological Effect
An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed a dramatic increase in Aβ42 production, as well as an increase in Aβ40 generation relative to wild-type PSEN1, resulting in an elevated Aβ42:Aβ40 ratio (Bai et al., 2015; Sun et al. 2017). A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates 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).

Last Updated: 13 Aug 2019

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References

News Citations

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

Paper Citations

  1. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  2. . Identification of I213L mutation in PSEN1 gene in a Polish family M. Neurodegener Dis 2009 6(Suppl 1): 1427
  3. . An atomic structure of human γ-secretase. Nature. 2015 Sep 10;525(7568):212-7. Epub 2015 Aug 17 PubMed.
  4. . 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.
  5. . 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. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.

Other mutations at this position

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