Mutations

PSEN1 V82L

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73637661 G>C
dbSNP ID: rs63749967
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTG to CTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This mutation was originally identified in a French family referred to as SAL 508. The three affected individuals, across three generations, presented with early-onset Alzheimer’s disease (AD) with onset ranging from 53 to 58 years of age. Co-segregation between the muation and AD could not be demonstrated (Campion et al., 1995). This mutation was reported in 1995, the same year that the presenilin-1 gene was cloned (Sherrington et al., 1995). The variant is absent from the gnomAD variant database (May 2021).

Neuropathology

Unknown.

Biological Effect

In CHO and HEK-293 cells expressing APP695, the mutation resulted in a slightly lower ratio of secreted Aβ42/Aβ40 (Shioi et al., 2007). In an in vitro assay using purified proteins to test the mutant's ability to cleave the APP-C99 substrate, however, the Aβ42/Aβ40 ratio was similar to that produced by wild-type PSEN1.  Production of both Aβ42 and Aβ40 was reduced (Sun et al., 2017).

In silico algorithms to predict the effects of this variant on protein function (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicated this variant is damaging (Xiao et al., 2021).

Last Updated: 22 Sep 2021

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References

Paper Citations

  1. . Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. PubMed.
  2. . Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754-60. PubMed.
  3. . FAD mutants unable to increase neurotoxic Abeta 42 suggest that mutation effects on neurodegeneration may be independent of effects on Abeta. J Neurochem. 2007 May;101(3):674-81. Epub 2007 Jan 24 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. . APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

External Citations

  1. gnomAD variant database

Further Reading

Papers

  1. . Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet. 1998 Jan;7(1):43-51. PubMed.
  2. . Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.

Protein Diagram

Primary Papers

  1. . Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. PubMed.

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