Mutations

PSEN1 H163P

Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73653568 A>C
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CAT to CCT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was identified in a Korean woman with apparently sporadic early onset Alzheimer’s disease. She was a scientific researcher with 20 years of education, who began to experience behavioral and personality changes, namely emotional lability and neglect of personal hygiene, at the age of 33. She was originally diagnosed with depression, but three years later exhibited growing cognitive disturbance, including deficits in memory and executive functioning. As her disease progressed, she developed disorientation, nonfluent speech, Parkinsonian symptoms, apraxia, limb myoclonus, gait disturbance, and seizures.

Her family history was negative for dementia and other neurological disease. Her father died at age 50 from myocardial infarction and her mother was cognitively healthy at age 68. Her three older siblings were also unaffected. Segregation with disease could not be assessed due to lack of DNA from family members. The mutation was absent in 146 ethnically matched healthy controls (Kim et al., 2012).

Neuropathology

Brain biopsy of the frontal cortex showed numerous senile plaques and neurofibrillary tangles compatible with a diagnosis of AD. No spongiform changes or abnormal prion protein were detected.

Biological Effect

When transfected into HEK293 cells stably expressing Swedish mtAPP 695 and BACE1, this mutation impaired the carboxypeptidase-like γ-cleavage, but spared the endoproteolytic ε-cleavage activity of PSEN1. This resulted in reduced secreted Aβ40, increased Aβ42, and an increased Aβ42/Aβ40 ratio (Li et al., 2016).

Last Updated: 17 Jun 2016

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

  1. . A novel PSEN1 H163P mutation in a patient with early-onset Alzheimer's disease: clinical, neuroimaging, and neuropathological findings. Neurosci Lett. 2012 Nov 21;530(2):109-14. PubMed.
  2. . Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. Epub 2016 Mar 11 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A novel PSEN1 H163P mutation in a patient with early-onset Alzheimer's disease: clinical, neuroimaging, and neuropathological findings. Neurosci Lett. 2012 Nov 21;530(2):109-14. PubMed.

Other mutations at this position

Alzpedia

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.