Mutations

PSEN1 R278T

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Reference Assembly: GRCh37/hg19
Position: Chr14:73664802 G>C
dbSNP ID: rs63749891
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: AGA to ACA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was found in one individual in a screen of the PSEN1 and PSEN2 genes of 11 families with early onset dementia (Kwok et al., 1997). The age of onset for this case was 37 years. Members of this family suffered from spastic paraparesis.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1 https://gnomad.broadinstitute.org/, July 2021).

Neuropathology
Neuropathology consistent with AD was detected in a brain biopsy.

Biological Effect
Although the biological effect of this mutation is unknown, other mutations at this site have been reported to impair γ-secretase activity. Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment, showed that R278 appears to play a key role in stabilizing the hybrid β-sheet that forms between PSEN1 and APP in preparation for APP cleavage (Zhou et al., 2019; Jan 2019 news). Moreover, 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: 13 Sep 2021

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References

News Citations

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

Paper Citations

  1. . Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. Neuroreport. 1997 Apr 14;8(6):1537-42. PubMed.
  2. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  3. . 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.
  4. . 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. Neuroreport. 1997 Apr 14;8(6):1537-42. PubMed.

Other mutations at this position

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