Mutations

PSEN1 C263F

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73664757 G>T
dbSNP ID: rs63751102
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TGT to TTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

The mutation was found in a study of British AD patients with a family history of AD with at least one affected first-degree relative, and an age of onset of less than 61 years (Janssen et al., 2003). The age of onset of the proband was 58 years. Three members of the individual’s family, spanning two generations, were diagnosed with AD, with a mean age of onset of 58 years. DNA was unavailable from the affected relatives, however, so co-segregation of the mutation and disease could not be demonstrated. The mutation was absent from 100 healthy, unrelated white control patients. It is also absent from the gnomAD variant database (v2.1.1, October 2020).

The mutation was subsequently identified in five Belgian patients with AD, three with onset before age 66 (Perrone et al., 2020). Except for one early onset carrier who had an APOE3/4 genotype, all others were homozygous for APOE3.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology
Neuropathological data are unavailable. However, cerebrospinal fluid biomarkers from two carriers suffering from AD suggest variability (Perrone et al., 2020). One carrier, who had late-onset AD, had reduced levels of Aβ42 and Aβ43, and increased levels of Aβ40, resulting in a decreased Aβ42/Aβ40 ratio characteristic of AD. This individual also had increased levels of sAPPα, and sAPPβ, as well as increased levels of tau and phospho-tau. In contrast, a carrier with early onset AD, had increased levels of Aβ40, Aβ42, and Aβ43, decreased levels of sAPPα, and sAPPβ, and normal levels of tau and phospho-tau. The Aβ42/Aβ40 ratio in this case was borderline. Both carriers were homozygous for APOE3.

Biological Effects
As described above, CSF levels of Aβ peptides in carriers of this mutation are variable. A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates this residue may help stabilize the structural re-arrangement of PSEN1 upon APP binding (Zhou et al., 2019; Jan 2019 news).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021). These authors classified the variant as likely pathogenic using the ACMG-AMP guidelines (Richards et al., 2015).

Last Updated: 21 Jul 2021

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References

News Citations

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

Paper Citations

  1. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
  2. . Amyloid-β1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations. Alzheimers Res Ther. 2020 Sep 11;12(1):108. PubMed.
  3. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  4. . APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.
  5. . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.

Other mutations at this position

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