Mutations

PSEN1 Y159C

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Parkinsonism, Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73640411 A>G
dbSNP ID: rs778630379
Coding/Non-Coding: Coding
Mutation Type:
Codon Change: TAT to TGT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was identified in a Korean woman with probable AD and a family history of the disease (Kim et al., 2020). Her symptoms, starting at age 59, included memory impairment, visuospatial dysfunction, aphasia, anxiety, and parkinsonism. Disease duration was five years.  Her APOE genotype was APOE3/APOE4.

In a cohort of individuals without neuronal-associated diseases, the variant’s frequency was extremely low (0.000005, gnomAD), and it was absent from 500 Korean controls.

Neuropathology
Neuropathological data are unavailable, but MRI revealed diffuse parietal and hippocampal atrophy, and FDG-PET showed severe hypometabolism in bilateral frontoparieto-temporal cortex.

Biological Effect
The biological effect of this mutation is unknown, but the site is evolutionarily conserved (GERP score = 4.65) and another mutation tied to AD, Y159F, has been identified at this site. In silico algorithms predicted it is probably damaging (Polyphen2), and not tolerated (SIFT). Moreover, it has a CADD score of 28.3, suggesting it is in the top 1 percent of deleterious variants.

In addition, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment, showed that Y159 appears to help stabilize the hybrid β-sheet that forms between PSEN1 and APP in preparation for cleavage (Zhou et al., 2019; Jan 2019).

Kim et al. classified this mutation as probably pathogenic (Kim et al., 2020).

Last Updated: 09 Mar 2020

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References

Mutations Citations

  1. PSEN1 Y159F

News Citations

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

Paper Citations

  1. . PSEN1 variants in Korean patients with clinically suspicious early-onset familial Alzheimer's disease. Sci Rep. 2020 Feb 26;10(1):3480. PubMed.
  2. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . PSEN1 variants in Korean patients with clinically suspicious early-onset familial Alzheimer's disease. Sci Rep. 2020 Feb 26;10(1):3480. PubMed.

Other mutations at this position

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