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Brain Advance Access published online on February 22, 2006
Brain, doi:10.1093/brain/awl029
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received September 5, 2005
Revised January 11, 2006
Accepted January 16, 2006

Article

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

Julie van der Zee 1, Rosa Rademakers 1, Sebastiaan Engelborghs 2, Ilse Gijselinck 1, Veerle Bogaerts 1, Rik Vandenberghe 3, Patrick Santens 4, Jo Caekebeke 5, Tim De Pooter 1, Karin Peeters 1, Ursula Lübke 6, Marleen Van den Broeck 1, Jean-Jacques Martin 6, Marc Cruts 1, Peter P. De Deyn 2, Christine Van Broeckhoven 1 *, and Bart Dermaut 7

1 Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerp, Belgium
2 Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Department of Neurology and Memory Clinic, Middelheim General Hospital, Antwerp, Belgium
3 Department of Neurology, University Hospital Gasthuisberg, Catholic University of Leuven, Antwerp, Belgium
4 Department of Neurology, Ghent University Hospital, University of Ghent, Antwerp, Belgium
5 Department of Neurology, OLV Hospital Aalst, Belgium
6 Laboratory of Neuropathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
7 Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerp, Belgium; Department of Neurology, Ghent University Hospital, University of Ghent, Antwerp, Belgium

* To whom correspondence should be addressed.
Christine Van Broeckhoven, E-mail: christine.vanbroeckhoven{at}ua.ac.be


  Abstract

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.
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