Mutations

PSEN1 T99A

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73637712 A>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ACC to GCC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This mutation was identified in a Japanese man with early onset Alzheimer’s disease. Signs of cognitive impairment began at age 43 and he met NINCDS-ADRDA criteria for AD (Ikeda et al., 2013). APOE genotyping revealed he carried APOE3 and APOE4 alleles. This variant was absent from the EVS and ExAC variant databases (Hsu et al., 2020).

Neuropathology

Neuropathological data are unavailable, but seven years after dementia onset, MRI showed atrophy of the parietal and frontal lobes.

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed reduced production of Aβ42, and particularly Aβ40, resulting in an approximately 7-fold increase in the Aβ42/Aβ40 ratio (Sun et al., 2017). An assessment of secreted Aβ40 and Aβ42 in N2 cells expressing the PSEN1 T99A on a PSEN1/PSEN2 null background also revealed an increased Aβ42/Aβ40 ratio (Hsu et al., 2020).

Position 99 is conserved between PSEN1 and PSEN2. Although some in silico algorithms to predict the effects of this variant on protein function (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, REVEL, and Reve in the VarCards database) yielded conflicting results (Xiao et al., 2021), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021). Hsu et al. classified it as probably pathogenic (Hsu et al., 2020). 

 

Last Updated: 09 Sep 2021

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References

Paper Citations

  1. . Cerebrospinal fluid levels of phosphorylated tau and Aβ1-38/Aβ1-40/Aβ1-42 in Alzheimer's disease with PS1 mutations. Amyloid. 2013 Jun;20(2):107-12. PubMed.
  2. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.
  3. . 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.
  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.

External Citations

  1. CADD v.1.6

Further Reading

Learn More

  1. Japanese Familial Alzheimer's Disease Database

Protein Diagram

Primary Papers

  1. . Cerebrospinal fluid levels of phosphorylated tau and Aβ1-38/Aβ1-40/Aβ1-42 in Alzheimer's disease with PS1 mutations. Amyloid. 2013 Jun;20(2):107-12. PubMed.

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