Journal Article

A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD

Julie van der Zee, Rosa Rademakers, Sebastiaan Engelborghs, Ilse Gijselinck, Veerle Bogaerts, Rik Vandenberghe, Patrick Santens, Jo Caekebeke, Tim De Pooter, Karin Peeters, Ursula Lübke, Marleen Van den Broeck, Jean-Jacques Martin, Marc Cruts, Peter P. De Deyn, Christine Van Broeckhoven and Bart Dermaut

in Brain

Published on behalf of The Guarantors of Brain

Volume 129, issue 4, pages 841-852
Published in print April 2006 | ISSN: 0006-8950
Published online February 2006 | e-ISSN: 1460-2156 | DOI: http://dx.doi.org/10.1093/brain/awl029
A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD

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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.

Keywords: founder mutation; frontotemporal lobar degeneration; ubiquitin-positive; 17q21, tau-negative; FTLD = frontotemporal lobar degeneration; FTDU = FTLD with tau-negative and ubiquitin-positive inclusions; DLDH, dementia lacking distinctive histopathology; LOD = log of the odds

Journal Article.  6279 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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