Overview

Pathogenicity: Alzheimer's Disease : Likely Benign
ACMG/AMP Pathogenicity Criteria: PP1, PP3, BS1, BS2
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226895548 A>C
Position: (GRCh37/hg19):Chr1:227083249 A>C
dbSNP ID: rs63750110
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAC to GCC
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 13

Findings

This mutation was first identified in a three-generation Spanish kindred from Barcelona, known as Barc1. The proband developed behavioral disturbances and progressive cognitive decline starting at age 52. He was diagnosed with probable AD. The proband's mother had AD (onset: 60 years) and his father had unspecified dementia (onset: 67 years). DNA testing in the parents was not possible, but the mutation was absent in all six of the proband's cognitively healthy relatives. It was also absent in 130 unrelated individuals (50 healthy controls and 80 AD patients) indicating it was unlikely to be a common polymorphism (Lleó et al., 2001; Lleó et al., 2002).

The D439A mutation was subsequently detected in one control individual in a study assessing 72 AD cases and 58 controls. There was no family history of AD. The age at which this person died was not reported, nor were details regarding his or her cognitive health. Notably, this D439A carrier lacked significant AD pathology in the brain (Frigerio et al., 2015). 

The variant was reported in the EVS (2 alleles) and ExAC (4 alleles) variant databases (Hsu et al., 2020). Moreover, 10 alleles, all from European heterozygotes, were listed in the gnomAD database (v2.1.1, Nov 2021).

Neuropathology

Neuropathological data are unavailable, but imaging in the proband of the Barcelona kindred showed moderate cortical atrophy in the frontal and parietal regions (Lleó et al., 2001). No significant AD pathology was observed in another carrier of this variant (Frigerio et al., 2015).

Biological Effect

The 439 residue is located near the C-terminal of the presenilin-2 protein and it is conserved in PSEN1. Its functional effect, however, remains uncertain. When transfected into fibroblasts lacking endogenous PSEN1 and PSEN2, the D439A variant did not affect steady-state levels of the proteolytic products PSEN2-CTF and PSEN2-NTF compared with wild-type PSEN2. Similarly, when co-transfected with APP carrying the Swedish mutation, D439A-PSEN2 did not affect Aβ42 levels or the Aβ42/Aβ40 ratio (Walker et al., 2005). However, a subsequent study using mouse neuroblastoma cells lacking endogenous PSEN1 and PSEN2, and expressing APP695 and the PSEN2 D439A mutant, resulted in decreased Aβ40 secretion and an increase in the Aβ42/Aβ40 ratio (Hsu et al., 2020). In silico, PolyPhen2 predicted D439A was probably damaging and SIFT predicted it was damaging (Frigerio et al., 2015; Hsu et al., 2020). Moreover, the variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, also suggesting a deleterious effect (CADD v.1.6, Nov 2021). Based on their pathogenicity guidelines, Hsu and colleagues classified D439A as a risk factor.

Pathogenicity

Alzheimer's Disease : Likely Benign*

*This variant may be a risk factor, a classification not included in the ACMG-AMP guidelines.

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

Paper Citations

1. Lleó A, Blesa R, Gendre J, Castellví M, Pastor P, Queralt R, Oliva R. A novel presenilin 2 gene mutation (D439A) in a patient with early-onset Alzheimer's disease. Neurology. 2001 Nov 27;57(10):1926-8. PubMed.
2. Lleó A, Blesa R, Queralt R, Ezquerra M, Molinuevo JL, Peña-Casanova J, Rojo A, Oliva R. Frequency of mutations in the presenilin and amyloid precursor protein genes in early-onset Alzheimer disease in Spain. Arch Neurol. 2002 Nov;59(11):1759-63. PubMed.
3. 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.
4. Walker ES, Martinez M, Brunkan AL, Goate A. Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. J Neurochem. 2005 Jan;92(2):294-301. PubMed.

Other Citations

1. Frigerio et al., 2015

Further Reading

No Available Further Reading