De novo deleterious genetic variations target a biological network centered on Aβ peptide in early-onset Alzheimer disease
Abstract
We hypothesized that de novo variants (DNV) might participate in the genetic determinism of sporadic early-onset Alzheimer disease (EOAD, onset before 65 years). We investigated 14 sporadic EOAD trios first by array-comparative genomic hybridization. Two patients carried a de novo copy number variation (CNV). We then performed whole-exome sequencing in the 12 remaining trios and identified 12 non-synonymous DNVs in six patients. The two de novo CNVs (an amyloid precursor protein (APP) duplication and a BACE2 intronic deletion) and 3/12 non-synonymous DNVs (in PSEN1, VPS35 and MARK4) targeted genes from a biological network centered on the Amyloid beta (Aβ) peptide. We showed that this a priori-defined genetic network was significantly enriched in amino acid-altering DNV, compared with the rest of the exome. The causality of the APP de novo duplication (which is the first reported one) was obvious. In addition, we provided evidence of the functional impact of the following three non-synonymous DNVs targeting this network: the novel PSEN1 variant resulted in exon 9 skipping in patient's RNA, leading to a pathogenic missense at exons 8-10 junction; the VPS35 missense variant led to partial loss of retromer function, which may impact neuronal APP trafficking and Aβ secretion; and the MARK4 multiple nucleotide variant resulted into increased Tau phosphorylation, which may trigger enhanced Aβ-induced toxicity. Despite the difficulty to recruit Alzheimer disease (AD) trios owing to age structures of the pedigrees and the genetic heterogeneity of the disease, this strategy allowed us to highlight the role of de novo pathogenic events, the putative involvement of new genes in AD genetics and the key role of Aβ network alteration in AD.
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De novo variants in APP, PSEN1, and PSEN2 have been identified by sequencing in sporadic cases of EOAD that occur with no family history of disease.
“Although causal variants in these genes are typically thought to be inherited in an autosomal dominant fashion, de novo variants in APP, PSEN1, and PSEN2 have also been identified by sequencing in sporadic cases of EOAD that occur with no family history of disease [158, 159].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [159]
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- Authors
- Rovelet-Lecrux, A., Charbonnier, C., Wallon, D., Nicolas, G., Seaman, M. N. J., Pottier, C., Breusegem, S. Y., Mathur, P. P., Jenardhanan, P., Le Guennec, K., Mukadam, A. S., Quenez, O., Coutant, S., Rousseau, S., Richard, A.-C., Boland, A., Deleuze, J.-F., Frebourg, T., Hannequin, D., Campion, D., & collaborators, C.-M.
- Affiliations
- Inserm (FR)
- University of Cambridge (GB)
- Pondicherry University (IN)
- Corresponding author
- Campion, D
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2015-07-21
- Volume
- 20
- Issue
- 9
- Pages
- 1046-1056
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- OpenAlex
- W1512606137
- Cited by
- 106
- References
- 57
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 7 · 2023: 9 · 2022: 11 · 2021: 15 · 2020: 14 · 2019: 5 · 2018: 13 · 2017: 9 · 2016: 5 · 2015: 2
- FWCI
- 7.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Wellcome Trust (100140)
- Medical Research Council (MR/L007533/1)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- early-onset Alzheimer's disease, amyloid-beta, VPS35, MARK4, tau phosphorylation, copy number variation
- MeSH terms
- Alzheimer Disease, Female, Humans, Male, Middle Aged, Pedigree, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Gene Regulatory Networks, Presenilin-1, Comparative Genomic Hybridization, DNA Copy Number Variations, Exome, Multiplex Polymerase Chain Reaction
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