TYROBP genetic variants in early-onset Alzheimer's disease
Open accessAbstract
We aimed to identify new candidate genes potentially involved in early-onset Alzheimer's disease (EOAD). Exome sequencing was conducted on 45 EOAD patients with either a family history of Alzheimer's disease (AD, <65 years) or an extremely early age at the onset (≤55 years) followed by multiple variant filtering according to different modes of inheritance. We identified 29 candidate genes potentially involved in EOAD, of which the gene TYROBP, previously implicated in AD, was selected for genetic and functional follow-up. Using 3 patient cohorts, we observed rare coding TYROBP variants in 9 out of 1110 EOAD patients, whereas no such variants were detected in 1826 controls (p = 0.0001), suggesting that at least some rare TYROBP variants might contribute to EOAD risk. Overexpression of the p.D50_L51ins14 TYROBP mutant led to a profound reduction of TREM2 expression, a well-established risk factor for AD. This is the first study supporting a role for genetic variation in TYROBP in EOAD, with in vitro support for a functional effect of the p.D50_L51ins14 TYROBP mutation on TREM2 expression.
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TYROBP is a transmembrane adaptor protein for TREM2, SIRPβ1, and CR3 receptors, which are known to be involved in AD pathogenesis.
“TYROBP is a transmembrane adaptor protein for TREM2, SIRPβ1, and CR3 receptors, which are known to be involved in AD pathogenesis [90–92].”
From Sex-specific DNA methylation differences in Alzheimer’s disease pathology (2021) · cites this paper as [91]
The Introduction and Discussion (page not available in our copy) describe TYROBP as a transmembrane protein, identify it as a TREM2 binding partner, and link TREM2 and TYROBP to Alzheimer’s disease. The passages do not identify SIRPβ1 or CR3 as TYROBP-associated receptors or establish their involvement in AD pathogenesis. (LLM, conf=0.88)
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Cites
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Self-citationLoss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts
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“Moreover, TYROBP is the binding partner of TREM2 (Bouchon, et al., 2001), a well-established genetic risk factor for AD (MIM #107741) (Benitez, et al., 2013, Guerreiro, et al., 2013, Jin, et al., 2014, Jonsson, et al., 2013, Neumann and Daly, 2013, Pottier, et al., 2013, Ruiz, et al., 2014).”
BackgroundTREM2 is associated with the risk of Alzheimer's disease in Spanish population
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- Authors
- Pottier, C., Ravenscroft, T. A., Brown, P. H., Finch, N. A., Baker, M., Parsons, M., Asmann, Y. W., Ren, Y., Christopher, E., Levitch, D., van Blitterswijk, M., Cruchaga, C., Campion, D., Nicolas, G., Richard, A.-C., Guerreiro, R., Bras, J. T., Zuchner, S., Gonzalez, M. A., Bu, G., Younkin, S., Knopman, D. S., Josephs, K. A., Parisi, J. E., Petersen, R. C., Ertekin-Taner, N., Graff-Radford, N. R., Boeve, B. F., Dickson, D. W., & Rademakers, R.
- Affiliations
- Mayo Clinic (US)
- Washington University in St. Louis (US)
- Inserm (FR)
- UCL Queen Square Institute of Neurology (GB)
- University of Miami (US)
- Corresponding author
- Rademakers, Rosa
- ORCID
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2016-12
- Volume
- 48
- Pages
- 222.e9-222.e15
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC5159294
- OpenAlex
- W2488417892
- Cited by
- 94
- References
- 9
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 6 · 2023: 12 · 2022: 12 · 2021: 18 · 2020: 11 · 2019: 6 · 2018: 9 · 2017: 15
- FWCI
- 8.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- US National Institutes of Health (P50-AG016574, R01-NS080882, R01-AG032990, R01-NS080820, U01-AG046139, R21-AG048101, RF1-AG051504)
- 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 › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- early-onset Alzheimer's disease, TYROBP, rare variants, TREM2, candidate genes, genetic risk, family history of Alzheimer's disease, exome sequencing
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Female, HeLa Cells, Humans, Male, Membrane Glycoproteins, Membrane Proteins, Middle Aged, Mutation, Receptors, Immunologic, Genetic Variation, Cohort Studies, Down-Regulation, Gene Expression, Sequence Analysis, Adaptor Proteins, Signal Transducing, Genetic Association Studies, Exome
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