Mutations

PSEN1 V272A

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Parkinsonism, Subcortical Dementia
Reference Assembly: GRCh37 (105)
Position: Chr14:73664784 T>C
dbSNP ID: rs63750680
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTT to GCT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was first identified in two members of a Spanish family with four affected individuals, spanning three generations, with early onset subcortical dementia and parkinsonism (Jimenez-Escrig et al., 2004). The age of onset ranged from 26 to 36 years old. The proband developed dementia characterized by forgetfulness, slowness of thought, impaired ability to manipulate acquired knowledge, as well as apathy and depression, fulfilling the criteria for subcortical dementia. The initial symptom of the other mutation carrier, the proband’s sister, was attention deficit.  Medical records from the proband’s mother indicated her main symptoms were depression and parkinsonism, and family accounts revealed the grandmother suffered for several years from cognitive decline before dying in her 40s.

The mutation was also found in a screening for variants in coding regions of the PSEN1, PSEN2, and APP genes in 231 Iberian patients with a clinical diagnosis of early onset AD (Guerreiro et al., 2010). In this case, the proband presented with myoclonus and dementia beginning at 34 years of age. The father and three siblings who carried the mutation also developed dementia. The mutation was absent from 121 age-matched Iberian controls and 130 individuals from seven different African populations.

As defined by the scheme developed by Guerreiro et al., this mutation is definitely pathogenic (Guerreiro et al., 2010).

Neuropathology
Neuropathology in the original proband was typical of AD, but also included Lewy bodies in the cortex and substantia nigra, and widespread subcortical neuritic lesions (Jimenez-Escrig et al., 2004). In addition, MRI and PET imaging revealed abnormalities only in the later stages of disease, most prominently in subcortical-frontal areas. This is in contrast to the classic AD profile with early hypometabolism in temporal and parietal cortices. 

Biological Effect
Elevated levels of Aβ42 peptide were detected in the plasma of two patients (Jimenez-Escrig et al., 2004). Moreover, an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate indicated it boosts Aβ42 production, resulting in an approximately fivefold increase in the Aβ42/Aβ40 ratio (Sun et al., 2017). The V272 position is conserved between PSEN1 and PSEN2, but is not in a transmembrane domain.

Last Updated: 29 Mar 2019

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References

Paper Citations

  1. . New V272A presenilin 1 mutation with very early onset subcortical dementia and parkinsonism. Eur J Neurol. 2004 Oct;11(10):663-9. PubMed.
  2. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
  3. . 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.

Further Reading

Papers

  1. . Cerebrospinal fluid levels of phosphorylated tau and Aβ1-38/Aβ1-40/Aβ1-42 in Alzheimer's disease with PS1 mutations. Amyloid. 2013 Jun;20(2):107-12. PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database
  2. Japanese Familial Alzheimer's Disease Database

Protein Diagram

Primary Papers

  1. . New V272A presenilin 1 mutation with very early onset subcortical dementia and parkinsonism. Eur J Neurol. 2004 Oct;11(10):663-9. PubMed.

Other mutations at this position

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