TY - JOUR
T1 - A Belgian ancestral haplotype harbours a highly prevalent mutation for I7q21-linked tau-negative FTLD
AU - Van Der Zee, Julie
AU - Rademakers, Rosa
AU - Engelborghs, Sebastiaan
AU - Gijselinck, Ilse
AU - Bogaerts, Veerle
AU - Vandenberghe, Rik
AU - Santens, Patrick
AU - Caekebeke, Jo
AU - De Pooter, Tim
AU - Peeters, Karin
AU - Lübke, Ursula
AU - Van Den Broeck, Marleen
AU - Martin, Jean Jacques
AU - Cruts, Marc
AU - De Deyn, Peter P.
AU - Van Broeckhoven, Christine
AU - Dermaut, Bart
N1 - Funding Information:
The authors are grateful to the family members for their kind cooperation in this study, and to the personnel of the VIB8 Genetic Service Facility (http://www.vibgeneticservicefacility. be) for the genetic analyses. The research described in this paper was supported by the Special Research Fund of the University of Antwerp, the Fund for Scientific Research Flanders (FWO-F), the Interuniversity Attraction Poles program P5/19 of the Belgian Science Policy Office, the International Alzheimer Research Foundation, Belgium; the EU contract LSHM-CT-2003-503330 (APOPIS) and the Alzheimer’s Association, USA. S.E., R.R. and M.C. are postdoctoral fellows and I.G. and V.B. are PhD fellows of the FWO-F. R.V. is a clinical investigator of the FWO-F. Funding to pay the Open Access publication charges for this article was provided by The Special Research Fund of the University of Antwerp.
PY - 2006/4
Y1 - 2006/4
N2 - Among patients with frontotemporal lobar degeneration (FTLD), the respective frequencies of dominant I7q21-linked tau-negative FTLD (with unidentified molecular defect) and I7q21-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.
AB - Among patients with frontotemporal lobar degeneration (FTLD), the respective frequencies of dominant I7q21-linked tau-negative FTLD (with unidentified molecular defect) and I7q21-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.
KW - 17q21
KW - Founder mutation
KW - Frontotemporal lobar degeneration
KW - Tau-negative
KW - Ubiquitin-positive
UR - http://www.scopus.com/inward/record.url?scp=33645089933&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33645089933&partnerID=8YFLogxK
U2 - 10.1093/brain/awl029
DO - 10.1093/brain/awl029
M3 - Article
C2 - 16495329
AN - SCOPUS:33645089933
SN - 0006-8950
VL - 129
SP - 841
EP - 852
JO - Brain
JF - Brain
IS - 4
ER -