Mutations

PSEN2 A85V

Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance, Dementia with Lewy Bodies : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PP3, BS1, BS2
Clinical Phenotype: Alzheimer's Disease, Dementia with Lewy Bodies
Position: (GRCh38/hg38):Chr1:226883817 C>T
Position: (GRCh37/hg19):Chr1:227071518 C>T
dbSNP ID: rs63750048
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCG to GTG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 5

Findings

This variant has been identified in a family with dementia, as well as in a cognitively healthy control, and a public variant database. It was initially reported in a three-generation Sardinian kindred with considerable variability in the clinical presentation within the family, including diagnoses of Alzheimer's disease as well as dementia with Lewy bodies. A85V was 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).

At least one cognitively healthy carrier was identified in a control group of the Alzheimer’s Disease Sequencing Project (ADSP) (Fernández et al., 2017; Wang et al., 2023). In the latter study, posted as a preprint, genetic data from 13,825 AD cases and 14,715 controls were analyzed.

The variant was also reported in the gnomAD variant database at a frequency of 0.000010, including 15 heterozygotes of European (8), East Asian (6) and African (1) ancestries (gnomAD v4.0.0, Jan 2024).

Neuropathology

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

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, a subsequent study using human embryonic kidney cells revealed a moderate elevation of the Aβ42/Aβ40 ratio (A85V:0.17 vs WT:0.15) and a more substantial decrease in the Aβ37/Aβ42 ratio (A85V:0.29 vs WT:0.44) (Liu et al., 2024 preprint). Notably, the latter ratio has been reported to outperform the former as an indicator of AD pathogenicity for PSEN1 variants (Liu et al., 2022, Apr 2022 news).

Also of note, A85V’s homolog in PSEN1, the likely pathogenic A79V, also increased the Aβ42/Aβ40 ratio (A79V:0.18 vs WT:0.15) and decreased the Aβ37/Aβ42 ratio (A79V:0.26 vs WT:0.41) (Liu et al., 2024 preprint). Across multiple PSEN1 and PSEN2 variants, the effects of PSEN1/PSEN2 homologs  were correlated and PSEN2 variants with known PSEN1 homologs were more likely to be classified as pathogenic than those without.

Moreover, progressive mitochondrial fragmentation was observed in neurons derived from induced pluripotent stem cells (iPSCs) carrying the A85V variant, as reported in another preprint (MacMullen et al., 2024). Basal mitochondrial respiration, as well as ATP-linked oxygen consumption, were modestly decreased.

A85V's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Nov 2021).

Pathogenicity

Alzheimer's Disease : Uncertain Significance

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

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. A85V: Although results were mixed, most data (in human cells) indicate a deleterious effect.

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. A85V: This variant has a PSEN1 homolog (A79V) classified as likely pathogenic, suggesting disruption of a functional domain.

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.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database. 

BS2-S

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.

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

Research Models

Neuron-like cells have been derived from an induced pluripotent stem cell line (MacMullen et al., 2024).

Last Updated: 05 Aug 2024

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References

News Citations

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

Mutations Citations

  1. PSEN1 A79V

Paper Citations

  1. MacMullen CM, Sharma N, Davis RL. Mitochondrial Dynamics and Bioenergetics in iPSC-Derived Neurons with Familial Alzheimer's Disease Mutations. 2024 Jun 28 10.1101/2024.06.24.600414 (version 1) bioRxiv.
  2. Piscopo P, Marcon G, Piras MR, Crestini A, Campeggi LM, Deiana E, Cherchi R, Tanda F, Deplano A, Vanacore N, Tagliavini F, Pocchiari M, Giaccone G, Confaloni A. A novel PSEN2 mutation associated with a peculiar phenotype. Neurology. 2008 Apr 22;70(17):1549-54. PubMed.
  3. Fernández MV, Kim JH, Budde JP, Black K, Medvedeva A, Saef B, Deming Y, Del-Aguila J, Ibañez L, Dube U, Harari O, Norton J, Chasse R, Morris JC, Goate A, NIA-LOAD family study group, NCRAD, Cruchaga C. Analysis of neurodegenerative Mendelian genes in clinically diagnosed Alzheimer Disease. PLoS Genet. 2017 Nov;13(11):e1007045. PubMed.
  4. Wang D, Scalici A, Wang Y, Lin H, Pitsillides A, Heard-Costa N, Cruchaga C, Ziegemeier E, Bis JC, Fornage M, Boerwinkle E, DeJager PL, Wijsman E, Dupuis J, Renton AE, Seshadri S, Goate AM, The Alzheimer's Disease Sequencing Project, DeStefano AL, Peloso GM. Frequency of Variants in Mendelian Alzheimer's Disease Genes within the Alzheimer's Disease Sequencing Project (ADSP). 2023 Oct 25 10.1101/2023.10.24.23297227 (version 1) medRxiv.
  5. Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, Goate AM, Karch CM. Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.
  6. Liu L, Schultz S, Saba A, Yang H-S, Li A, Selkoe D, Chhatwal J. The pathogenicity of PSEN2 variants is tied to Aβ production and homology to PSEN1. 2024 Jun 28 10.1101/2024.06.22.600217 (version 1) bioRxiv.
  7. Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Piscopo P, Marcon G, Piras MR, Crestini A, Campeggi LM, Deiana E, Cherchi R, Tanda F, Deplano A, Vanacore N, Tagliavini F, Pocchiari M, Giaccone G, Confaloni A. A novel PSEN2 mutation associated with a peculiar phenotype. Neurology. 2008 Apr 22;70(17):1549-54. PubMed.

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