Mutations

PSEN1 I213F

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659440 A>T
dbSNP ID: rs63750861
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATT to TTT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was identified in a Polish man with a family history of probable AD, including four affected family members spanning two generations (Żekanowski et al, 2003). The proband’s first symptom, at age 33, was memory impairment, followed by mood alterations, including anxiety, and disorientation in time and space. The man also developed rigidity and bradykinesia. Similarly, disease onset in his affected relatives was before 35 years, and they all died before the age of 40 with probable AD.

Neuropathology
Unknown

Biological Effect
Human embryonic kidney cells transfected with an APP construct carrying the Swedish mutation and PSEN1 I213F, secreted more Aβ40 and Aβ42 than cells transfected with wild-type PSEN1, and the Aβ42/Aβ40 ratio was elevated nearly three-fold (Bialopiotrowicz et al., 2012). ConSeq program analysis suggested codon 213 is highly conserved (Żekanowski et al, 2003). Moreover, 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: 16 May 2019

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References

News Citations

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

Paper Citations

  1. . Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland. Exp Neurol. 2003 Dec;184(2):991-6. PubMed.
  2. . Highly Pathogenic Alzheimer's Disease Presenilin 1 P117R Mutation Causes a specific Increase in p53 and p21 Protein Levels and Cell Cycle Dysregulation in Human Lymphocytes. J Alzheimers Dis. 2012 Jan 1;32(2):397-415. PubMed.
  3. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Further Reading

Papers

  1. . Familial Alzheimer's Disease Lymphocytes Respond Differently Than Sporadic Cells to Oxidative Stress: Upregulated p53-p21 Signaling Linked with Presenilin 1 Mutants. Mol Neurobiol. 2016 Sep 19; PubMed.

Protein Diagram

Primary Papers

  1. . Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland. Exp Neurol. 2003 Dec;184(2):991-6. PubMed.

Other mutations at this position

Alzpedia

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