Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3, PS3
DIAN-TU Eligibility: Yes
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.

In a subsequent study, average age at onset for a group of carriers from Spain was reported as 56.7 years (std. error = 3.1; Liu et al., 2025). It is unknown if these carriers were related to the ones described above.

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

Experiments assessing the biological effects of this variant have yielded mixed results but, taken together, they suggest a pathogenic 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. A subsequent cell-based study also reported an elevated Aβ42/Aβ40 ratio, although production of both Aβ40 and Aβ42 peptides were reduced (Marsh et al., 2025). Moreover, production of the two peptides was undetectable in an in vitro assay using the APP-C99 substrate (Sun et al., 2017), but this assay's ability to recapitulate physiological cleavage efficiency appears to be limited (see Liu et al., 2021).

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 : 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

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. Liu H, Marsh TW, Shi X, Renton AE, Bowling KM, Ziegemeier E, Wang G, Cao Y, Aristel A, Li J, Dickson A, Perrin RJ, Goate AM, Fernández V, Day GS, Doering M, Daniels A, Gordon BA, Benzinger TL, Hassenstab J, Ibanez L, Supnet-Bell C, Xiong C, Allegri R, Berman SB, Fox NC, Ryan N, Huey ED, Vöglein J, Noble JM, Roh JH, Jucker M, Laske C, Ikeuchi T, Sanchez-Valle R, Schofield PR, Chrem Mendez P, Chhatwal JP, Farlow M, Lee JH, Levey AI, Levin J, Lopera F, Martins R, Niimi Y, Rosa-Neto P, Morris JC, Bateman RJ, Karch CM, Cruchaga C, McDade E, Llibre-Guerra JJ. The landscape of autosomal-dominant Alzheimer's disease: global distribution and age of onset. Brain. 2025 Feb 4; Epub 2025 Feb 4 PubMed.
3. 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.
4. Marsh JA, Huang G, Bowling K, Renton AE, Ziegemeier E, Ball T, Pottier C, Cruchaga C, Day GS, Bateman RJ, Llibre-Guerra JJ, McDade E, Karch CM. Evaluating pathogenicity of variants of unknown significance in APP, PSEN1, and PSEN2. Neurotherapeutics. 2025 Jan 27;:e00527. Epub 2025 Jan 27 PubMed.
5. 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.
6. Liu L, Lauro BM, Wolfe MS, Selkoe DJ. Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. J Biol Chem. 2021;296:100393. Epub 2021 Feb 8 PubMed.
7. 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