Mutations

PSEN1 Y389H

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Parkinsonism, Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73683869 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TAC to CAC
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This mutation was first reported in a Korean woman with AD and a family history of early onset dementia (Park et al., 2020). Her symptoms, including memory impairment, anxiety, apathy, and disinhibition, began at age 40. Her mother, two sisters, and one brother were diagnosed with early onset dementia. Her APOE genotype was APOE3/APOE3.

The mutation was also identified in another Korean woman with a family history of dementia (Kim et al., 2020). Her symptoms, starting at age 39, included memory impairment, acalculia, anomia, and parkinsonism. Disease duration was four years. Her APOE genotype was APOE3/APOE4.

This variant was not found in the gnomAD database (Kim et al., 2020).

Neuropathology
Neuropathological data are unavailable, but MRI revealed severe atrophy especially in frontotemporal areas in one case (Park et al., 2020), and in another mild, diffuse cortical atrophy (Kim et al. 2020). Additionally, in the latter case, FDG-PET showed bilateral hypometabolism in parietal and temporal cortices. Both cases tested positive for amyloid deposition assessed by PiB-PET or FBB-PET.

Biological Effect
The biological effect of this mutation is unknown. The site is evolutionarily conserved (GERP score = 4.54) and in silico algorithms predicted it is probably damaging (Polyphen2), and not tolerable or damaging (SIFT) (Park et al., 2020; Kim et al, 2020). Moreover, it has a CADD score of 26.9, suggesting it is in the top 1 percent of deleterious variants. The mutation was considered a “variant of unknown significance” given that its site had not been linked to AD previously. However, in the Kim et al. study, another mutation was discovered at the site, Y389S, in a patient that also suffered from apparent early onset familial AD.

Last Updated: 17 Mar 2020

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References

Mutations Citations

  1. PSEN1 Y389S

Paper Citations

  1. . Analysis of dementia-related gene variants in APOE ε4 noncarrying Korean patients with early-onset Alzheimer's disease. Neurobiol Aging. 2020 Jan;85:155.e5-155.e8. Epub 2019 May 22 PubMed.
  2. . PSEN1 variants in Korean patients with clinically suspicious early-onset familial Alzheimer's disease. Sci Rep. 2020 Feb 26;10(1):3480. PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Analysis of dementia-related gene variants in APOE ε4 noncarrying Korean patients with early-onset Alzheimer's disease. Neurobiol Aging. 2020 Jan;85:155.e5-155.e8. Epub 2019 May 22 PubMed.
  2. . PSEN1 variants in Korean patients with clinically suspicious early-onset familial Alzheimer's disease. Sci Rep. 2020 Feb 26;10(1):3480. PubMed.

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