Mutations

PSEN1 I143V

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73640362 A>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATT to GTT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 5

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). Consistent with this finding, an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed it produces similar levels of Aβ40 as wild-type PSEN1, but increased levels of Aβ42 resulting in an elevated Aβ42/Aβ40 ratio (Bai et al., 2015; Sun et al., 2017). A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that, in wild-type PSEN1, I143 is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019Jan 2019 news).

Last Updated: 03 Aug 2019

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References

News Citations

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

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.
  3. . An atomic structure of human γ-secretase. Nature. 2015 Sep 10;525(7568):212-7. Epub 2015 Aug 17 PubMed.
  4. . 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.
  5. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

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

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