A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD
Open accessAbstract
Among patients with frontotemporal lobar degeneration (FTLD), the respective frequencies of dominant 17q21-linked tau-negative FTLD (with unidentified molecular defect) and 17q21-linked tau-positive FTLD (due to MAPT mutations) remain unknown. Here, in a series of 98 genealogically unrelated Belgian FTLD patients, we identified an ancestral 8 cM MAPT containing haplotype in two patients belonging to multiplex families DR2 and DR8, without demonstrable MAPT mutations, in which FTLD was conclusively linked to 17q21 [maximum summed log of the odds (LOD) score of 5.28 at D17S931]. Interestingly, the same DR2-DR8 ancestral haplotype was observed in five additional familial FTLD patients, indicative of a founder effect. In the FTLD series, the DR2-DR8 ancestral haplotype explained 7% (7 out of 98) of FTLD and 17% (7 out of 42) of familial FTLD and was seven times more frequent than MAPT mutations (1 out of 98 or 1%). Clinically, DR2-DR8 haplotype carriers presented with FTLD often characterized by language impairment, and in one carrier the neuropathological diagnosis was FTLD with rare tau-negative ubiquitin-positive inclusions. Together, these results strongly suggest that the DR2-DR8 founder haplotype at 17q21 harbours a tau-negative FTLD causing mutation that is a much more frequent cause of FTLD in Belgium than MAPT mutations.
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In genetic familial frontotemporal dementia, known founder effects for C9orf72 and GRN mutations with European ancestry lead to strong associations with particular racial and ethnic groups.
“in genetic f-FTD there are known founder effects for C9orf7245 and GRN mutations46 with European ancestry, leading to strong associations with particular racial and ethnic groups.”
From Temporal order of clinical and biomarker changes in familial frontotemporal dementia (2022) · cites this paper as [46]
The Introduction (page not provided) reports a founder haplotype associated with a substantial fraction of familial FTLD in Belgium, supporting the general founder-effect point. But the paper does not identify the causal mutation as GRN, and it does not establish strong associations with particular racial or ethnic groups. The GRN and racial/ethnic claims therefore are not supported by this source. (LLM, conf=0.85)
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- Authors
- van der Zee, J., Rademakers, R., Engelborghs, S., Gijselinck, I., Bogaerts, V., Vandenberghe, R., Santens, P., Caekebeke, J., De Pooter, T., Peeters, K., Lübke, U., Van den Broeck, M., Martin, J.-J., Cruts, M., De Deyn, P. P., Van Broeckhoven, C., & Dermaut, B.
- Affiliations
- Vlaams Instituut voor Biotechnologie (BE)
- University of Antwerp (BE)
- KU Leuven (BE)
- Ghent University Hospital (BE)
- Onze Lieve Vrouwziekenhuis Hospital (BE)
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-02-22
- Volume
- 129
- Issue
- 4
- Pages
- 841-852
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W2155448579
- Cited by
- 90
- References
- 39
- Citations by year
- 2022: 3 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 1 · 2017: 2 · 2016: 6 · 2015: 5 · 2014: 1 · 2013: 6 · 2012: 4
- FWCI
- 11.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- Brain (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Funders
- Alzheimer's Association
- Belgian Federal Science Policy Office
- Fonds Wetenschappelijk Onderzoek
- Universiteit Antwerpen
- Vlaamse regering
- Fondation pour la Recherche sur Alzheimer
- Bijzonder Onderzoeksfonds UGent
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- frontotemporal lobar degeneration, 17q21, MAPT, ancestral haplotypes, founder effect, ubiquitin-positive inclusions, language impairment, Belgian patients, genetic linkage
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Belgium, Chromosome Mapping, Chromosomes, Human, Pair 17, Dementia, DNA Mutational Analysis, Female, Haplotypes, HLA-DR Antigens, Humans, Lod Score, Male, Middle Aged, Mutation, Pedigree, Prospective Studies, HLA-DR2 Antigen, tau Proteins, Founder Effect, Genetic Predisposition to Disease, Ubiquitin, HLA-DR Serological Subtypes
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