Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226885557 G>A
Position: (GRCh37/hg19):Chr1:227073258 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAG to AAG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 6

Findings

This mutation was identified in a woman and her mother who were both affected by dementia. The proband was congenitally deaf. At age 48 her husband noticed increasing forgetfulness. Her disease progressed rapidly, and she was hospitalized by age 50. At age 52 she developed seizures. She did not have hallucinations, vertigo, aphasia, rigidity, tremor, or akinesia. Her mother had died at age 72 with dementia by age 59, possibly earlier. The proband’s sister also developed dementia by age 60, although further details were not available. DNA samples were analyzed from the proband and her affected mother. The mutation was detected in both women. No mutations were found in the coding regions of PSEN1 or APP (Müller et al., 2014).

This variant was absent from the gnomAD variant database (v2.1.1, Nov 2021).

Neuropathology

Unknown.

Biological Effect

PSEN2 with the E126K variant was transfected into human embryonic kidney cells lacking endogenous PSEN1 and PSEN2 and expressing tagged APP-695, as reported in a preprint (Liu et al., 2024). The Aβ42/Aβ40 ratio was increased (0.28 vs 0.15) and the Aβ37/Aβ42 ratio decreased (0.21 vs 0.44) in the cells’ conditioned media compared to cells transfected with wildtype PSEN2. Both ratios are indicators of AD pathogenicity, with the Aβ37/Aβ42 ratio reported to outperform the Aβ42/Aβ40 ratio for PSEN1 variants (Liu et al., 2022, Apr 2022 news).

Also of note, E126K’s homolog in PSEN1, the pathogenic E120K, also increased the Aβ42/Aβ40 ratio (E120K:0.28 vs WT:0.15) and decreased the Aβ37/Aβ42 ratio (E120K:0.21 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.

PSEN2 E126K affects a highly conserved residue in the first hydrophilic loop of PSEN2. In silico, PolyPhen-2 predicted it is probably damaging (Müller et al., 2014). Moreover, its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, also suggesting a deleterious effect (CADD v.1.6, Nov 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.

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References

News Citations

1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40? 20 Apr 2022

Mutations Citations

1. PSEN1 E120K

Paper Citations

1. Müller U, Winter P, Bolender C, Nolte D. Previously unrecognized missense mutation E126K of PSEN2 segregates with early onset Alzheimer's disease in a family. J Alzheimers Dis. 2014;42(1):109-13. PubMed.
2. 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.
3. 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.

Other Citations

1. Liu et al., 2024

Further Reading

No Available Further Reading