Mutations

PSEN2 A85V

Overview

Pathogenicity: Alzheimer's Disease : Not Classified, Dementia with Lewy Bodies : Not Classified
Clinical Phenotype: Alzheimer's Disease, Dementia with Lewy Bodies
Reference Assembly: GRCh37/hg19
Position: Chr1:227071518 C>T
dbSNP ID: rs63750048
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GCG to GTG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 5

Findings

This mutation was identified in a three-generation Sardinian kindred. There was considerable variability in the clinical presentation within the family, with diagnoses of Alzheimer's disease as well as dementia with Lewy bodies. The A85V mutation is associated with a complex phenotype characterized by dementia with parkinsonism, a relatively late onset (60 to 71 years), and a long duration (22 and 25 years). All mutation carriers (except one young individual thought to be presymptomatic) developed AD, dementia with Lewy bodies, or both. Two healthy non-carriers were identified in the family, but their ages were not reported and, given they were in the youngest reported generation, they likely had not yet reached the ages at onset observed in affected members. The A85V mutation was also absent from 211 unrelated individuals from the same Sardinian population (Piscopo et al., 2008).

A single heterozygote of non-FInnish European ancestry is reported in the gnomAD variant database (v2.1.1, Nov 2021).

Neuropathology

Neuropathologic data are available for the proband. In the neocortex amyloid deposition, neurofibrillary changes and diffuse Lewy bodies were observed. Neuroimaging in two patients showed bilateral basal ganglia calcifications (Piscopo et al., 2008).

Biological Effect

In an experimental assay using mouse neuroblastoma cells transfected with this variant, secretion of Aβ40 and Aβ42, and the Aβ42/Aβ40 ratio were found to be similar to those of cells transfected with wildtype PSEN2 (Hsu et al., 2020). However, the variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Nov 2021).

Last Updated: 01 Nov 2021

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References

Paper Citations

  1. . A novel PSEN2 mutation associated with a peculiar phenotype. Neurology. 2008 Apr 22;70(17):1549-54. PubMed.
  2. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A novel PSEN2 mutation associated with a peculiar phenotype. Neurology. 2008 Apr 22;70(17):1549-54. PubMed.

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