A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD
Identifieur interne : 000A01 ( Istex/Corpus ); précédent : 000A00; suivant : 000A02A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD
Auteurs : Julie Van Der Zee ; Rosa Rademakers ; Sebastiaan Engelborghs ; Ilse Gijselinck ; Veerle Bogaerts ; Rik Vandenberghe ; Patrick Santens ; Jo Caekebeke ; Tim De Pooter ; Karin Peeters ; Ursula Lu Bke ; Marleen Van Den Broeck ; Jean-Jacques Martin ; Marc Cruts ; Peter P. De Deyn ; Christine Van Broeckhoven ; Bart DermautSource :
- Brain [ 0006-8950 ] ; 2006-04.
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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.
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DOI: 10.1093/brain/awl029
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Caekebeke</name><affiliation><mods:affiliation>Department of Neurology, OLV Hospital Aalst, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author><author><name sortKey="De Pooter, Tim" sort="De Pooter, Tim" uniqKey="De Pooter T" first="Tim" last="De Pooter">Tim De Pooter</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author><author><name sortKey="Peeters, Karin" sort="Peeters, Karin" uniqKey="Peeters K" first="Karin" last="Peeters">Karin Peeters</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author><author><name sortKey="Lu Bke, Ursula" sort="Lu Bke, Ursula" uniqKey="Lu Bke U" first="Ursula" last="Lu Bke">Ursula Lu Bke</name><affiliation><mods:affiliation>Laboratory of Neuropathology, Institute Born-Bunge, University of Antwerp,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author><author><name sortKey="Van Den Broeck, Marleen" sort="Van Den Broeck, Marleen" uniqKey="Van Den Broeck M" first="Marleen" last="Van Den Broeck">Marleen Van Den Broeck</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author><author><name sortKey="Martin, Jean Jacques" sort="Martin, Jean Jacques" uniqKey="Martin J" first="Jean-Jacques" last="Martin">Jean-Jacques Martin</name><affiliation><mods:affiliation>Laboratory of Neuropathology, Institute Born-Bunge, University of Antwerp,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author><author><name sortKey="Cruts, Marc" sort="Cruts, Marc" uniqKey="Cruts M" first="Marc" last="Cruts">Marc Cruts</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author><author><name sortKey="De Deyn, Peter P" sort="De Deyn, Peter P" uniqKey="De Deyn P" first="Peter P." last="De Deyn">Peter P. De Deyn</name><affiliation><mods:affiliation>Laboratory of Neurochemistry and Behavior,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author><author><name sortKey="Van Broeckhoven, Christine" sort="Van Broeckhoven, Christine" uniqKey="Van Broeckhoven C" first="Christine" last="Van Broeckhoven">Christine Van Broeckhoven</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author><author><name sortKey="Dermaut, Bart" sort="Dermaut, Bart" uniqKey="Dermaut B" first="Bart" last="Dermaut">Bart Dermaut</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:C19CFA2C3EE2AA9D3C849A26CAF23B6A50952BDE</idno><date when="2006" year="2006">2006</date><idno type="doi">10.1093/brain/awl029</idno><idno type="url">https://api.istex.fr/document/C19CFA2C3EE2AA9D3C849A26CAF23B6A50952BDE/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">000A01</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD</title><author><name sortKey="Van Der Zee, Julie" sort="Van Der Zee, Julie" uniqKey="Van Der Zee J" first="Julie" last="Van Der Zee">Julie Van Der Zee</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author><author><name sortKey="Rademakers, Rosa" sort="Rademakers, Rosa" uniqKey="Rademakers R" first="Rosa" last="Rademakers">Rosa Rademakers</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author><author><name sortKey="Engelborghs, Sebastiaan" sort="Engelborghs, Sebastiaan" uniqKey="Engelborghs S" first="Sebastiaan" last="Engelborghs">Sebastiaan Engelborghs</name><affiliation><mods:affiliation>Laboratory of Neurochemistry and Behavior,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author><author><name sortKey="Gijselinck, Ilse" sort="Gijselinck, Ilse" uniqKey="Gijselinck I" first="Ilse" last="Gijselinck">Ilse Gijselinck</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author><author><name sortKey="Bogaerts, Veerle" sort="Bogaerts, Veerle" uniqKey="Bogaerts V" first="Veerle" last="Bogaerts">Veerle Bogaerts</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author><author><name sortKey="Vandenberghe, Rik" sort="Vandenberghe, Rik" uniqKey="Vandenberghe R" first="Rik" last="Vandenberghe">Rik Vandenberghe</name><affiliation><mods:affiliation>Department of Neurology, University Hospital Gasthuisberg, Catholic University of Leuven,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author><author><name sortKey="Santens, Patrick" sort="Santens, Patrick" uniqKey="Santens P" first="Patrick" last="Santens">Patrick Santens</name><affiliation><mods:affiliation>Department of Neurology, Ghent University Hospital, University of Ghent,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author><author><name sortKey="Caekebeke, Jo" sort="Caekebeke, Jo" uniqKey="Caekebeke J" first="Jo" last="Caekebeke">Jo Caekebeke</name><affiliation><mods:affiliation>Department of Neurology, OLV Hospital Aalst, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author><author><name sortKey="De Pooter, Tim" sort="De Pooter, Tim" uniqKey="De Pooter T" first="Tim" last="De Pooter">Tim De Pooter</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author><author><name sortKey="Peeters, Karin" sort="Peeters, Karin" uniqKey="Peeters K" first="Karin" last="Peeters">Karin Peeters</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author><author><name sortKey="Lu Bke, Ursula" sort="Lu Bke, Ursula" uniqKey="Lu Bke U" first="Ursula" last="Lu Bke">Ursula Lu Bke</name><affiliation><mods:affiliation>Laboratory of Neuropathology, Institute Born-Bunge, University of Antwerp,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author><author><name sortKey="Van Den Broeck, Marleen" sort="Van Den Broeck, Marleen" uniqKey="Van Den Broeck M" first="Marleen" last="Van Den Broeck">Marleen Van Den Broeck</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author><author><name sortKey="Martin, Jean Jacques" sort="Martin, Jean Jacques" uniqKey="Martin J" first="Jean-Jacques" last="Martin">Jean-Jacques Martin</name><affiliation><mods:affiliation>Laboratory of Neuropathology, Institute Born-Bunge, University of Antwerp,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author><author><name sortKey="Cruts, Marc" sort="Cruts, Marc" uniqKey="Cruts M" first="Marc" last="Cruts">Marc Cruts</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author><author><name sortKey="De Deyn, Peter P" sort="De Deyn, Peter P" uniqKey="De Deyn P" first="Peter P." last="De Deyn">Peter P. De Deyn</name><affiliation><mods:affiliation>Laboratory of Neurochemistry and Behavior,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author><author><name sortKey="Van Broeckhoven, Christine" sort="Van Broeckhoven, Christine" uniqKey="Van Broeckhoven C" first="Christine" last="Van Broeckhoven">Christine Van Broeckhoven</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author><author><name sortKey="Dermaut, Bart" sort="Dermaut, Bart" uniqKey="Dermaut B" first="Bart" last="Dermaut">Bart Dermaut</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Brain</title><title level="j" type="abbrev">Brain</title><idno type="ISSN">0006-8950</idno><idno type="eISSN">1460-2156</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2006-04">2006-04</date><biblScope unit="volume">129</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="841">841</biblScope><biblScope unit="page" to="852">852</biblScope></imprint><idno type="ISSN">0006-8950</idno></series><idno type="istex">C19CFA2C3EE2AA9D3C849A26CAF23B6A50952BDE</idno><idno type="DOI">10.1093/brain/awl029</idno><idno type="local">awl029</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0006-8950</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>17q21, tau-negative</term><term>DLDH, dementia lacking distinctive histopathology</term><term>FTDU = FTLD with tau-negative and ubiquitin-positive inclusions</term><term>FTLD = frontotemporal lobar degeneration</term><term>LOD = log of the odds</term><term>founder mutation</term><term>frontotemporal lobar degeneration</term><term>ubiquitin-positive</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Julie van der Zee</name><affiliations><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string></affiliations></json:item><json:item><name>Rosa Rademakers</name><affiliations><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string></affiliations></json:item><json:item><name>Sebastiaan Engelborghs</name><affiliations><json:string>Laboratory of Neurochemistry and Behavior,</json:string><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string></affiliations></json:item><json:item><name>Ilse Gijselinck</name><affiliations><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string></affiliations></json:item><json:item><name>Veerle Bogaerts</name><affiliations><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string></affiliations></json:item><json:item><name>Rik Vandenberghe</name><affiliations><json:string>Department of Neurology, University Hospital Gasthuisberg, Catholic University of Leuven,</json:string><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string></affiliations></json:item><json:item><name>Patrick Santens</name><affiliations><json:string>Department of Neurology, Ghent University Hospital, University of Ghent,</json:string><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string></affiliations></json:item><json:item><name>Jo Caekebeke</name><affiliations><json:string>Department of Neurology, OLV Hospital Aalst, Belgium</json:string><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string></affiliations></json:item><json:item><name>Tim De Pooter</name><affiliations><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string></affiliations></json:item><json:item><name>Karin Peeters</name><affiliations><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string></affiliations></json:item><json:item><name>Ursula Lübke</name><affiliations><json:string>Laboratory of Neuropathology, Institute Born-Bunge, University of Antwerp,</json:string><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string></affiliations></json:item><json:item><name>Marleen Van den Broeck</name><affiliations><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string></affiliations></json:item><json:item><name>Jean-Jacques Martin</name><affiliations><json:string>Laboratory of Neuropathology, Institute Born-Bunge, University of Antwerp,</json:string><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string></affiliations></json:item><json:item><name>Marc Cruts</name><affiliations><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string></affiliations></json:item><json:item><name>Peter P. De Deyn</name><affiliations><json:string>Laboratory of Neurochemistry and Behavior,</json:string><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string></affiliations></json:item><json:item><name>Christine Van Broeckhoven</name><affiliations><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string></affiliations></json:item><json:item><name>Bart Dermaut</name><affiliations><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>founder mutation</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>frontotemporal lobar degeneration</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>ubiquitin-positive</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>17q21, tau-negative</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>FTLD = frontotemporal lobar degeneration</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>FTDU = FTLD with tau-negative and ubiquitin-positive inclusions</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>DLDH, dementia lacking distinctive histopathology</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>LOD = log of the odds</value></json:item></subject><language><json:string>eng</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><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.</abstract><qualityIndicators><score>7.9</score><pdfVersion>1.4</pdfVersion><pdfPageSize>624.307 x 804.307 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>8</keywordCount><abstractCharCount>1347</abstractCharCount><pdfWordCount>6091</pdfWordCount><pdfCharCount>40791</pdfCharCount><pdfPageCount>12</pdfPageCount><abstractWordCount>200</abstractWordCount></qualityIndicators><title>A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD</title><genre><json:string>research-article</json:string></genre><host><volume>129</volume><publisherId><json:string>brainj</json:string></publisherId><pages><last>852</last><first>841</first></pages><issn><json:string>0006-8950</json:string></issn><issue>4</issue><genre><json:string>journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1460-2156</json:string></eissn><title>Brain</title></host><categories><wos><json:string>CLINICAL NEUROLOGY</json:string><json:string>NEUROSCIENCES</json:string></wos></categories><publicationDate>2006</publicationDate><copyrightDate>2006</copyrightDate><doi><json:string>10.1093/brain/awl029</json:string></doi><id>C19CFA2C3EE2AA9D3C849A26CAF23B6A50952BDE</id><score>0.26695943</score><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/C19CFA2C3EE2AA9D3C849A26CAF23B6A50952BDE/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/C19CFA2C3EE2AA9D3C849A26CAF23B6A50952BDE/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/C19CFA2C3EE2AA9D3C849A26CAF23B6A50952BDE/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Oxford University Press</publisher><availability><p>© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</p></availability><date>2006-02-22</date></publicationStmt><notesStmt><note>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@ua.ac.be</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD</title><author xml:id="author-1"><persName><forename type="first">Julie</forename><surname>van der Zee</surname></persName><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation></author><author xml:id="author-2"><persName><forename type="first">Rosa</forename><surname>Rademakers</surname></persName><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation></author><author xml:id="author-3"><persName><forename type="first">Sebastiaan</forename><surname>Engelborghs</surname></persName><affiliation>Laboratory of Neurochemistry and Behavior,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation></author><author xml:id="author-4"><persName><forename type="first">Ilse</forename><surname>Gijselinck</surname></persName><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation></author><author xml:id="author-5"><persName><forename type="first">Veerle</forename><surname>Bogaerts</surname></persName><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation></author><author xml:id="author-6"><persName><forename type="first">Rik</forename><surname>Vandenberghe</surname></persName><affiliation>Department of Neurology, University Hospital Gasthuisberg, Catholic University of Leuven,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation></author><author xml:id="author-7"><persName><forename type="first">Patrick</forename><surname>Santens</surname></persName><affiliation>Department of Neurology, Ghent University Hospital, University of Ghent,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation></author><author xml:id="author-8"><persName><forename type="first">Jo</forename><surname>Caekebeke</surname></persName><affiliation>Department of Neurology, OLV Hospital Aalst, Belgium</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation></author><author xml:id="author-9"><persName><forename type="first">Tim</forename><surname>De Pooter</surname></persName><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation></author><author xml:id="author-10"><persName><forename type="first">Karin</forename><surname>Peeters</surname></persName><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation></author><author xml:id="author-11"><persName><forename type="first">Ursula</forename><surname>Lübke</surname></persName><affiliation>Laboratory of Neuropathology, Institute Born-Bunge, University of Antwerp,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation></author><author xml:id="author-12"><persName><forename type="first">Marleen</forename><surname>Van den Broeck</surname></persName><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation></author><author xml:id="author-13"><persName><forename type="first">Jean-Jacques</forename><surname>Martin</surname></persName><affiliation>Laboratory of Neuropathology, Institute Born-Bunge, University of Antwerp,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation></author><author xml:id="author-14"><persName><forename type="first">Marc</forename><surname>Cruts</surname></persName><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation></author><author xml:id="author-15"><persName><forename type="first">Peter P.</forename><surname>De Deyn</surname></persName><affiliation>Laboratory of Neurochemistry and Behavior,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation></author><author xml:id="author-16"><persName><forename type="first">Christine</forename><surname>Van Broeckhoven</surname></persName><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation></author><author xml:id="author-17"><persName><forename type="first">Bart</forename><surname>Dermaut</surname></persName><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation></author></analytic><monogr><title level="j">Brain</title><title level="j" type="abbrev">Brain</title><idno type="pISSN">0006-8950</idno><idno type="eISSN">1460-2156</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2006-04"></date><biblScope unit="volume">129</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="841">841</biblScope><biblScope unit="page" to="852">852</biblScope></imprint></monogr><idno type="istex">C19CFA2C3EE2AA9D3C849A26CAF23B6A50952BDE</idno><idno type="DOI">10.1093/brain/awl029</idno><idno type="local">awl029</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2006-02-22</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>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.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>KWD</head><item><term>founder mutation</term></item><item><term>frontotemporal lobar degeneration</term></item><item><term>ubiquitin-positive</term></item><item><term>17q21, tau-negative</term></item></list></keywords></textClass><textClass xml:lang="en"><keywords scheme="keyword"><list><head>ABR</head><item><term>FTLD = frontotemporal lobar degeneration</term></item><item><term>FTDU = FTLD with tau-negative and ubiquitin-positive inclusions</term></item><item><term>DLDH, dementia lacking distinctive histopathology</term></item><item><term>LOD = log of the odds</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2006-02-22">Created</change><change when="2006-04">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/C19CFA2C3EE2AA9D3C849A26CAF23B6A50952BDE/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="US-ASCII"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article xml:lang="en" article-type="research-article"><front><journal-meta><journal-id journal-id-type="hwp">brain</journal-id><journal-id journal-id-type="nlm-ta">Brain</journal-id><journal-id journal-id-type="publisher-id">brainj</journal-id><journal-title>Brain</journal-title><abbrev-journal-title abbrev-type="publisher">Brain</abbrev-journal-title><issn pub-type="ppub">0006-8950</issn><issn pub-type="epub">1460-2156</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="other">awl029</article-id><article-id pub-id-type="doi">10.1093/brain/awl029</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Articles</subject></subj-group></article-categories><title-group><article-title>A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>van der Zee</surname><given-names>Julie</given-names></name><xref rid="AFF1">1</xref></contrib><contrib contrib-type="author"><name><surname>Rademakers</surname><given-names>Rosa</given-names></name><xref rid="AFF1">1</xref></contrib><contrib contrib-type="author"><name><surname>Engelborghs</surname><given-names>Sebastiaan</given-names></name><xref rid="AFF2">2</xref><xref rid="AFF6">6</xref></contrib><contrib contrib-type="author"><name><surname>Gijselinck</surname><given-names>Ilse</given-names></name><xref rid="AFF1">1</xref></contrib><contrib contrib-type="author"><name><surname>Bogaerts</surname><given-names>Veerle</given-names></name><xref rid="AFF1">1</xref></contrib><contrib contrib-type="author"><name><surname>Vandenberghe</surname><given-names>Rik</given-names></name><xref rid="AFF5">5</xref></contrib><contrib contrib-type="author"><name><surname>Santens</surname><given-names>Patrick</given-names></name><xref rid="AFF4">4</xref></contrib><contrib contrib-type="author"><name><surname>Caekebeke</surname><given-names>Jo</given-names></name><xref rid="AFF7">7</xref></contrib><contrib contrib-type="author"><name><surname>De Pooter</surname><given-names>Tim</given-names></name><xref rid="AFF1">1</xref></contrib><contrib contrib-type="author"><name><surname>Peeters</surname><given-names>Karin</given-names></name><xref rid="AFF1">1</xref></contrib><contrib contrib-type="author"><name><surname>Lübke</surname><given-names>Ursula</given-names></name><xref rid="AFF3">3</xref></contrib><contrib contrib-type="author"><name><surname>Van den Broeck</surname><given-names>Marleen</given-names></name><xref rid="AFF1">1</xref></contrib><contrib contrib-type="author"><name><surname>Martin</surname><given-names>Jean-Jacques</given-names></name><xref rid="AFF3">3</xref></contrib><contrib contrib-type="author"><name><surname>Cruts</surname><given-names>Marc</given-names></name><xref rid="AFF1">1</xref></contrib><contrib contrib-type="author"><name><surname>De Deyn</surname><given-names>Peter P.</given-names></name><xref rid="AFF2">2</xref><xref rid="AFF6">6</xref></contrib><contrib contrib-type="author"><name><surname>Van Broeckhoven</surname><given-names>Christine</given-names></name><xref rid="AFF1">1</xref></contrib><contrib contrib-type="author"><name><surname>Dermaut</surname><given-names>Bart</given-names></name><xref rid="AFF1">1</xref><xref rid="AFF4">4</xref></contrib><aff><target target-type="aff" id="AFF1"></target><label>1</label>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, <target target-type="aff" id="AFF2"></target><label>2</label>Laboratory of Neurochemistry and Behavior, <target target-type="aff" id="AFF3"></target><label>3</label>Laboratory of Neuropathology, Institute Born-Bunge, University of Antwerp, <target target-type="aff" id="AFF4"></target><label>4</label>Department of Neurology, Ghent University Hospital, University of Ghent, <target target-type="aff" id="AFF5"></target><label>5</label>Department of Neurology, University Hospital Gasthuisberg, Catholic University of Leuven, <target target-type="aff" id="AFF6"></target><label>6</label>Department of Neurology and Memory Clinic, Middelheim General Hospital, Antwerp and <target target-type="aff" id="AFF7"></target><label>7</label>Department of Neurology, OLV Hospital Aalst, Belgium</aff></contrib-group><author-notes><corresp>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: <ext-link xlink:href="christine.vanbroeckhoven@ua.ac.be" ext-link-type="email">christine.vanbroeckhoven@ua.ac.be</ext-link></corresp></author-notes><pub-date pub-type="ppub"><month>April</month><year>2006</year></pub-date><pub-date pub-type="epub"><day>22</day><month>2</month><year>2006</year></pub-date><volume>129</volume><issue>4</issue><fpage>841</fpage><lpage>852</lpage><history><date date-type="accepted"><day>16</day><month>1</month><year>2006</year></date><date date-type="received"><day>5</day><month>9</month><year>2005</year></date><date date-type="rev-recd"><day>11</day><month>1</month><year>2006</year></date></history><copyright-statement>© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</copyright-statement><copyright-year>2006</copyright-year><license license-type="open-access"><p></p></license><abstract xml:lang="en"><p>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 <italic>MAPT</italic> mutations) remain unknown. Here, in a series of 98 genealogically unrelated Belgian FTLD patients, we identified an ancestral 8 cM <italic>MAPT</italic> containing haplotype in two patients belonging to multiplex families DR2 and DR8, without demonstrable <italic>MAPT</italic> 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 <italic>MAPT</italic> 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 <italic>MAPT</italic> mutations.</p></abstract><kwd-group kwd-group-type="KWD" xml:lang="en"><kwd>founder mutation</kwd><kwd>frontotemporal lobar degeneration</kwd><kwd>ubiquitin-positive</kwd><kwd>17q21, tau-negative</kwd></kwd-group><kwd-group kwd-group-type="ABR" xml:lang="en"><kwd>FTLD = frontotemporal lobar degeneration</kwd><kwd>FTDU = FTLD with tau-negative and ubiquitin-positive inclusions</kwd><kwd>DLDH, dementia lacking distinctive histopathology</kwd><kwd>LOD = log of the odds</kwd></kwd-group><custom-meta-wrap><custom-meta><meta-name>hwp-legacy-fpage</meta-name><meta-value>841</meta-value></custom-meta><custom-meta><meta-name>cover-date</meta-name><meta-value>April 2006</meta-value></custom-meta><custom-meta><meta-name>hwp-legacy-dochead</meta-name><meta-value>Original Article</meta-value></custom-meta></custom-meta-wrap></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD</title></titleInfo><name type="personal"><namePart type="given">Julie</namePart><namePart type="family">van der Zee</namePart><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Rosa</namePart><namePart type="family">Rademakers</namePart><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sebastiaan</namePart><namePart type="family">Engelborghs</namePart><affiliation>Laboratory of Neurochemistry and Behavior,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ilse</namePart><namePart type="family">Gijselinck</namePart><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Veerle</namePart><namePart type="family">Bogaerts</namePart><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Rik</namePart><namePart type="family">Vandenberghe</namePart><affiliation>Department of Neurology, University Hospital Gasthuisberg, Catholic University of Leuven,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Patrick</namePart><namePart type="family">Santens</namePart><affiliation>Department of Neurology, Ghent University Hospital, University of Ghent,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jo</namePart><namePart type="family">Caekebeke</namePart><affiliation>Department of Neurology, OLV Hospital Aalst, Belgium</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Tim</namePart><namePart type="family">De Pooter</namePart><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Karin</namePart><namePart type="family">Peeters</namePart><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ursula</namePart><namePart type="family">Lübke</namePart><affiliation>Laboratory of Neuropathology, Institute Born-Bunge, University of Antwerp,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Marleen</namePart><namePart type="family">Van den Broeck</namePart><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jean-Jacques</namePart><namePart type="family">Martin</namePart><affiliation>Laboratory of Neuropathology, Institute Born-Bunge, University of Antwerp,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Marc</namePart><namePart type="family">Cruts</namePart><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Peter P.</namePart><namePart type="family">De Deyn</namePart><affiliation>Laboratory of Neurochemistry and Behavior,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christine</namePart><namePart type="family">Van Broeckhoven</namePart><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Bart</namePart><namePart type="family">Dermaut</namePart><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2006-04</dateIssued><dateCreated encoding="w3cdtf">2006-02-22</dateCreated><copyrightDate encoding="w3cdtf">2006</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract lang="en">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.</abstract><note type="author-notes">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@ua.ac.be</note><subject lang="en"><genre>KWD</genre><topic>founder mutation</topic><topic>frontotemporal lobar degeneration</topic><topic>ubiquitin-positive</topic><topic>17q21, tau-negative</topic></subject><subject lang="en"><genre>ABR</genre><topic>FTLD = frontotemporal lobar degeneration</topic><topic>FTDU = FTLD with tau-negative and ubiquitin-positive inclusions</topic><topic>DLDH, dementia lacking distinctive histopathology</topic><topic>LOD = log of the odds</topic></subject><relatedItem type="host"><titleInfo><title>Brain</title></titleInfo><titleInfo type="abbreviated"><title>Brain</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">0006-8950</identifier><identifier type="eISSN">1460-2156</identifier><identifier type="PublisherID">brainj</identifier><identifier type="PublisherID-hwp">brain</identifier><identifier type="PublisherID-nlm-ta">Brain</identifier><part><date>2006</date><detail type="volume"><caption>vol.</caption><number>129</number></detail><detail type="issue"><caption>no.</caption><number>4</number></detail><extent unit="pages"><start>841</start><end>852</end></extent></part></relatedItem><identifier type="istex">C19CFA2C3EE2AA9D3C849A26CAF23B6A50952BDE</identifier><identifier type="DOI">10.1093/brain/awl029</identifier><identifier type="local">awl029</identifier><accessCondition type="use and reproduction" contentType="copyright">© The Author 2006. Published by Oxford University Press. All rights reserved. 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