Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73192812 G>C
Position: (GRCh37/hg19):Chr14:73659520 G>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AAG to AAC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was identified in a Spanish family with AD that progressed relatively slowly, with a wide range of ages of onset (Lladó et al., 2010). A total of six family members were affected, with ages of onset ranging from the fifth to eighth decade of life. The mutation was found in all three affected members who were tested, and was absent from 121 controls,163 AD patients, as well as from the gnomAD variant database (gnomAD v2.1.1, July 2021).

The proband was a man who developed cognitive decline with behavioral abnormalities at age 57. His behavioral symptoms included apathy, irritability, social withdrawal, and, ultimately, marked aggressiveness for which he was institutionalized at age 70. Another family member carrying the mutation also initially presented with apathy and irritability, and subsequently became aggressive, but her symptoms started earlier, at age 42. Surprisingly, a third mutation carrier in the same family presented with typical AD at age 71. This is in contrast to the complete penetrance of PSEN1 mutations usually seen by age 65. All three individuals had an APOE 3/3 genotype.

Neuropathology

Neuropathology data are unavailable, but an MRI of the proband’s brain revealed marked atrophy in the medial temporal lobes and to a lesser extent in the frontal lobes (Lladó et al., 2010). Global cerebral atrophy was reported for MRI scans of two other mutation carriers from the same family showed global atrophy.

Biological Effect

In mouse embryonic fibroblasts expressing this mutant, γ-secretase activity was only moderately lower than in cells expressing wild-type PSEN1, and in cells co-expressing the mutant with APP carrying the Swedish mutation, generation of Aβ42 and the Aβ42/Aβ40 ratio were increased (Sarroca et al., 2016). However, the same study also reported the preservation of prosurvival signaling pathways. Moreover, production of both Aβ40  and Aβ42 were undetectable in an in vitro assay using the APP-C99 substrate (Sun et al., 2017).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum because it was found in a single affected family with a variable phenotype and without clear evidence of cosegregation or a consistent functional effect, and it 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

Paper Citations

1. Lladó A, Fortea J, Ojea T, Bosch B, Sanz P, Valls-Solé J, Clarimon J, Molinuevo JL, Sánchez-Valle R. A novel PSEN1 mutation (K239N) associated with Alzheimer's disease with wide range age of onset and slow progression. Eur J Neurol. 2010 Jul;17(7):994-6. Epub 2010 Feb 10 PubMed.
2. Sarroca S, Molina-Martínez P, Aresté C, Etzrodt M, García de Frutos P, Gasa R, Antonell A, Molinuevo JL, Sánchez-Valle R, Saura CA, Lladó A, Sanfeliu C. Preservation of cell-survival mechanisms by the presenilin-1 K239N mutation may cause its milder clinical phenotype. Neurobiol Aging. 2016 Oct;46:169-79. Epub 2016 Jul 15 PubMed.
3. Sun L, Zhou R, Yang G, Shi Y. 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.
4. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. 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 v2.1.1

Further Reading