Mutations

PSEN1 V82L

Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
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

Initial results suggested this variant had no damaging effect on the production of Aβ peptides, but subsequent more extensive observations indicate otherwise. In CHO and HEK-293 cells expressing APP695, the mutation resulted in a slightly lower ratio of secreted Aβ42/Aβ40 (Shioi et al., 2007), and in an in vitro assay using purified proteins to test the mutant's ability to cleave the APP-C99 substrate, the Aβ42/Aβ40 ratio was similar to that produced by wild-type PSEN1 (Sun et al., 2017). In the latter case, production of both Aβ42 and Aβ40 was reduced. However, a subsequent study that examined the full set of Aβ peptides generated by PSEN1 activity in transfected cells, revealed a robust increase in toxic Aβ43 and a decrease in Aβ37, the shortest Aβ peptide and, as such, an indicator of fully effective PSEN1 activity (Liu et al., 2022, Apr 2022 news). Moreover, this variant decreased the Aβ37/Aβ42 ratio, as did known pathogenic mutations. Of note, this ratio outperformed the standard Aβ42/Aβ40 ratio for distinguishing between control and AD samples.

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).

Pathogenicity

Alzheimer's Disease : Likely Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PS3-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. V82L: Results were mixed. Although all indicated little or no change in Aβ42/Aβ40, one assay showed a robust increase in Aβ43 and a decrease in Aβ37, with a decreased Aβ37/Aβ42 ratio.

PM1-P

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. V82L: Variant located at edge of mutational hot spot.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 25 Mar 2022

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References

News Citations

  1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?

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. . Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
  6. . 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.

Alzpedia

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