Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM2, PP3, BS2
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226885549 C>T
Position: (GRCh37/hg19):Chr1:227073250 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCA to CTA
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 6

Findings

This mutation was identified in a Chinese family affected by familial Alzheimer’s disease (Xia et al., 2015). The reported pedigree shows four affected individuals over four generations. In this family the disease presented as cognitive decline with parkinsonism and myoclonic jerks. The proband developed symptoms at age 57, staring with memory loss and personality changes, including irritability and apathy. She later developed rigidity in her hands and a persistent myoclonic jerking of her left hand. 

Of the 15 family members genotyped, seven were mutation carriers; however, only the proband met diagnostic criteria for AD. The other six mutation carriers were asymptomatic at the time of the report at ages 81, 58, 49, 53, 37, and 27 years. The mutation was absent from nine unaffected family members, 100 controls, and the gnomAD variant database (v2.1.1, Nov 2021).

Neuropathology

Unknown. Neuroimaging showed diffuse cortical atrophy, predominantly in the right hemisphere. FDG-PET showed hypoperfusion in the right temporal and parietal regions.

Biological Effect

In a mouse neuroblastoma cell assay, this variant increased Aβ42 and decreased Aβ40 secretion, resulting in an approximately twofold increase in the Aβ42/Aβ40 ratio compared with that of cells expressing wildtype PSEN2 (Hsu et al., 2020). Consistent with these findings, another cell-based assay revealed an increased Aβ42/Aβ40 ratio (P123L:0.18 vs WT:0.15) and a decreased Aβ37/Aβ42 ratio (P123L:0.28 vs WT:0.44), as reported in a preprint (Liu et al., 2024). Notably, the latter ratio has been reported to outperform the Aβ42/Aβ40 ratio as an indicator of AD pathogenicity for PSEN1 variants (Liu et al., 2022, Apr 2022 news).

Also of note, P123L’s homolog in PSEN1, the pathogenic P117L, also increased the Aβ42/Aβ40 ratio (P117L:0.18 vs WT:0.015) and decreased the Aβ37/Aβ42 (P117L:0.16 vs WT:0.41) ratio (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.

This mutation was predicted to be probably damaging by in silico analysis (Xia et al., 2015, Hsu et al., 2020) and its 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 : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

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 P117L

Paper Citations

1. Xia M, Chen S, Shi Y, Huang Y, Xu J, Zhao T, He S, Wu Y, Xu C, Zang W, Zhang J. Probable novel PSEN2 Pro123Leu mutation in a Chinese Han family of Alzheimer's disease. Neurobiol Aging. 2015 Dec;36(12):3334.e13-8. Epub 2015 Sep 8 PubMed.
2. 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.
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.
4. 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