Mutations

PSEN1 I143V

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genome Build: GRCh37 (105)
Position: Chr14:73640362 A>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Genomic Region: Exon 5
Mutation Type: Point, Missense
Codon Change: ATT to GTT

Findings

This mutation was identified in an Italian woman with early onset Alzheimer’s disease (Gallo et al., 2011). She had a strong family history of dementia: 13 family members over four generations showed signs of the disease. Disease transmission appeared to be autosomal-dominant. Segregation of the mutation with disease could not be formally shown due to lack of DNA from family members; however; the presence of other known pathogenic mutations at codon 143 strongly supports the pathogenicity of the I143V mutation.

The proband in the Italian family developed symptoms at age 55. She presented with personality changes, apathy, decreased verbal fluency, and temporal and spatial disorientation. She later developed visual hallucinations and myoclonus. She died at age 75. The average age of onset in the family was 54 and the average age at death was 65.

Neuropathology

Autopsy of the proband confirmed the diagnosis of AD. There was severe atrophy of the frontal and temporal lobes. Amyloid plaques were abundant in the cerebral cortex and also present in other regions including the caudate nucleus, putamen, thalamus, globus pallidus, and brainstem. Amyloid deposits were comprised largely of Aβ42, with little to no Aβ40. Neurofibrillary pathology was severe (stage VI Braak and Braak). There was little to no amyloid angiopathy in vessels (Gallo et al., 2011).

Biological Effect

When transfected into HEK293 cells stably expressing Swedish mtAPP695 and BACE1, this mutation impaired the carboxypeptidase-like γ-cleavage, but spared the endoproteolytic ε-cleavage activity of PSEN1. This resulted in higher levels of secreted Aβ42 (Li et al., 2016).

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References

Paper Citations

  1. . A novel pathogenic PSEN1 mutation in a family with Alzheimer's disease: phenotypical and neuropathological features. J Alzheimers Dis. 2011;25(3):425-31. 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

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . A novel pathogenic PSEN1 mutation in a family with Alzheimer's disease: phenotypical and neuropathological features. J Alzheimers Dis. 2011;25(3):425-31. PubMed.

Other mutations at this position

Alzpedia