A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD.
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.
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerpen, Belgium.
Julie
J
van der Zee
Rosa
R
Rademakers
Sebastiaan
S
Engelborghs
Ilse
I
Gijselinck
Veerle
V
Bogaerts
Rik
R
Vandenberghe
Patrick
P
Santens
Jo
J
Caekebeke
Tim
T
De Pooter
Karin
K
Peeters
Ursula
U
Lübke
Marleen
M
Van den Broeck
Jean-Jacques
JJ
Martin
Marc
M
Cruts
Peter P
PP
De Deyn
Christine
C
Van Broeckhoven
Bart
B
Dermaut
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001530:Belgium; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D003704:Dementia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics; D059810:HLA-DR Serological Subtypes; D015802:HLA-DR2 Antigen / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D011446:Prospective Studies; D025801:Ubiquitin / Q000032:analysis; D016875:tau Proteins / Q000032:analysis / Q000235:genetics*
D006684:HLA-DR Antigens; D059810:HLA-DR Serological Subtypes; D015802:HLA-DR2 Antigen; C041559:HLA-DR8 antigen; D025801:Ubiquitin; D016875:tau Proteins