Brain Advance Access originally published online on February 22, 2006
Brain 2006 129(4):841-852; doi:10.1093/brain/awl029
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A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD
1 Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, 2 Laboratory of Neurochemistry and Behavior, 3 Laboratory of Neuropathology, Institute Born-Bunge, University of Antwerp, 4 Department of Neurology, Ghent University Hospital, University of Ghent, 5 Department of Neurology, University Hospital Gasthuisberg, Catholic University of Leuven, 6 Department of Neurology and Memory Clinic, Middelheim General Hospital, Antwerp and 7 Department of Neurology, OLV Hospital Aalst, Belgium
Correspondence to: Prof. Dr Christine Van Broeckhoven, Neurodegenerative Brain Diseases Group, VIB8 Department of Molecular Genetics, University of Antwerp, Building V, Room 0.10, Universiteitsplein 1, BE-2610 Antwerpen, Belgium E-mail: christine.vanbroeckhoven{at}ua.ac.be
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.
Key Words: founder mutation; frontotemporal lobar degeneration; ubiquitin-positive; 17q21, tau-negative
Abbreviations: FTLD = frontotemporal lobar degeneration; FTDU = FTLD with tau-negative and ubiquitin-positive inclusions; DLDH, dementia lacking distinctive histopathology; LOD = log of the odds
Received September 5, 2005. Revised January 11, 2006. Accepted January 16, 2006.
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