Heterozygous TREM2 mutations in frontotemporal dementia
Open accessAbstract
A causative association was recently demonstrated between homozygous TREM2 mutations and frontotemporal dementia (FTD)-like syndrome and between heterozygous TREM2 exon2 genetic variations and late-onset Alzheimer's disease (AD). The objective of this study was to evaluate whether heterozygous TREM2 genetic variations might be associated to the risk of FTD. TREM2 exon 2 was sequenced in a group of 1030 subjects-namely, 352 patients fulfilling clinical criteria for FTD, 484 healthy control subjects (HCs), and 194 patients with AD. The mutation frequency and the associated clinical characteristics were analyzed. We identified 8 missense and nonsense mutations in TREM2 exon 2 in 24 subjects. These mutations were more frequent in patients with FTD than in HCs (4.0% vs. 1.0%, p = 0.005). In particular, TREM2 Q33X, R47H, T66M, and S116C mutations were found in FTD and were absent in HCs. These mutations were associated with either the semantic variant of primary progressive aphasia or the behavioral variant FTD phenotypes. The FTD and AD groups were not significantly different with regard to TREM2 genetic variation frequency (AD: 2.6%, p = 0.39). Heterozygous TREM2 mutations modulate the risk of FTD in addition to increasing susceptibility to AD. Additional studies are warranted to investigate the possible role of these mutations in the pathogenesis of neurodegenerative disorders.
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Homozygous Q33X, Y38C and T66M variants have been identified in patients with Nasu-Hakola disease.
“Homozygous Q33X, Y38C and T66M variants have been identified in patients with Nasu-Hakola disease [44, 47, 95].”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [44]
The Discussion states that homozygous Q33X and T66M mutations have previously been demonstrated to cause Nasu-Hakola disease. The Results also links both variants to the disease in homozygosity, but our copy does not identify Y38C in patients with Nasu-Hakola disease (searched: Y38C Nasu-Hakola homozygous). No page numbers were available in the indexed passages. (LLM, conf=0.88)
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- Authors
- Borroni, B., Ferrari, F., Galimberti, D., Nacmias, B., Barone, C., Bagnoli, S., Fenoglio, C., Piaceri, I., Archetti, S., Bonvicini, C., Gennarelli, M., Turla, M., Scarpini, E., Sorbi, S., & Padovani, A.
- Affiliations
- University of Brescia (IT)
- University of Milan (IT)
- University of Florence (IT)
- Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT)
- Centro San Giovanni di Dio Fatebenefratelli (IT)
- Corresponding author
- Borroni, Barbara
- ORCID
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 35
- Issue
- 4
- Pages
- 934.e7-934.e10
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2169355884
- Cited by
- 173
- References
- 7
- Citations by year
- 2026: 11 · 2025: 13 · 2024: 9 · 2023: 9 · 2022: 11 · 2021: 8 · 2020: 14 · 2019: 13 · 2018: 22 · 2017: 20 · 2016: 15 · 2015: 19 · 2014: 9
- FWCI
- 9.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Florence Research (University of Florence) (submittedVersion)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
- Funders
- Italian Ministry of Health (Ricerca Corrente)
- Fondazione Monzino
- Cassa di Risparmio di Pistoia e Pescia
- Cassa di Risparmio di Firenze
- 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
- TREM2, frontotemporal dementia, heterozygous mutation, genetic susceptibility, missense mutations, nonsense mutation, semantic dementia, behavioral variant frontotemporal dementia, late-onset Alzheimer's disease
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Exons, Female, Heterozygote, Humans, Male, Membrane Glycoproteins, Middle Aged, Mutation, Receptors, Immunologic, Cohort Studies, Genetic Predisposition to Disease, Frontotemporal Dementia
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