Genetic risk and transcriptional variability of amyloid precursor protein in Alzheimer's disease
Identifieur interne : 000A12 ( Istex/Corpus ); précédent : 000A11; suivant : 000A13Genetic risk and transcriptional variability of amyloid precursor protein in Alzheimer's disease
Auteurs : Nathalie Brouwers ; Kristel Sleegers ; Sebastiaan Engelborghs ; Veerle Bogaerts ; Sally Serneels ; Kenan Kamali ; Ellen Corsmit ; Evelyn De Leenheir ; Jean-Jacques Martin ; Peter P. De Deyn ; Christine Van Broeckhoven ; Jessie TheunsSource :
- Brain [ 0006-8950 ] ; 2006-08-24.
Abstract
It is well established that Alzheimer's disease causing mutations in APP, PSEN1 and PSEN2 lead to a relative increased production of Aβ42, thereby fostering its deposition in plaques. Recently others and we showed that amyloid precursor protein (APP) overproduction, either as a result of genomic locus duplication or altered regulatory sequences in the APP promoter region, leads to early-onset disease. Here, we have expanded our study of genetic variability in the APP promoter to a large group of well-documented Belgian patients (n = 750, mean onset age = 75.0 ± 8.6, range = 37–96). We identified three different APP promoter mutations (−369C→G, −534G→A and −479C→T) in seven patients. In patients with onset ≤70 years (n = 204), we identified one patient carrying the London APP V717I mutation while no patients carried an APP locus duplication, indicating that APP promoter mutations (n = 2) were more frequently associated with increased risk for early-onset Alzheimer's disease. The two mutations (−369C→G and −534G→A) increasing APP promoter activity by nearly 2-fold and mimicking an APP duplication, appeared in probands of families with multiple patients with dementia. The −479C→T mutation that increased APP expression only mildly (1.2-fold), was observed in four patients with onset ages ranging from 62 to 79 years (mean 71.5 years), suggesting that its contribution to disease risk is more pronounced at later age due to modulating factors. In conclusion, we provided evidence that mutations in APP regulatory sequences are more frequent than APP coding mutations, and that increased APP transcriptional activity constitutes a risk factor for Alzheimer's disease with onset ages inversely correlated with levels of APP expression.
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DOI: 10.1093/brain/awl212
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title>Genetic risk and transcriptional variability of amyloid precursor protein in Alzheimer's disease</title><author><name sortKey="Brouwers, Nathalie" sort="Brouwers, Nathalie" uniqKey="Brouwers N" first="Nathalie" last="Brouwers">Nathalie Brouwers</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Antwerp Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Sleegers, Kristel" sort="Sleegers, Kristel" uniqKey="Sleegers K" first="Kristel" last="Sleegers">Kristel Sleegers</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Antwerp Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</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, Institute Born-Bunge Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Antwerp Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Memory Clinic and Department of Neurology, Middelheim General Hospital Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</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 Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Antwerp Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Serneels, Sally" sort="Serneels, Sally" uniqKey="Serneels S" first="Sally" last="Serneels">Sally Serneels</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Antwerp Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Kamali, Kenan" sort="Kamali, Kenan" uniqKey="Kamali K" first="Kenan" last="Kamali">Kenan Kamali</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Antwerp Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Corsmit, Ellen" sort="Corsmit, Ellen" uniqKey="Corsmit E" first="Ellen" last="Corsmit">Ellen Corsmit</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Antwerp Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Leenheir, Evelyn De" sort="Leenheir, Evelyn De" uniqKey="Leenheir E" first="Evelyn De" last="Leenheir">Evelyn De Leenheir</name><affiliation><mods:affiliation>Laboratory of Neuropathology, Institute Born-Bunge Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Antwerp Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</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 Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Antwerp Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</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, Institute Born-Bunge Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Antwerp Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Memory Clinic and Department of Neurology, Middelheim General Hospital Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Broeckhoven, Christine Van" sort="Broeckhoven, Christine Van" uniqKey="Broeckhoven C" first="Christine Van" last="Broeckhoven">Christine Van Broeckhoven</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Antwerp Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Theuns, Jessie" sort="Theuns, Jessie" uniqKey="Theuns J" first="Jessie" last="Theuns">Jessie Theuns</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Antwerp Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:8CB76E05CE193825F03AE95403936458E957D393</idno><date when="2006" year="2006">2006</date><idno type="doi">10.1093/brain/awl212</idno><idno type="url">https://api.istex.fr/document/8CB76E05CE193825F03AE95403936458E957D393/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">000A12</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">Genetic risk and transcriptional variability of amyloid precursor protein in Alzheimer's disease</title><author><name sortKey="Brouwers, Nathalie" sort="Brouwers, Nathalie" uniqKey="Brouwers N" first="Nathalie" last="Brouwers">Nathalie Brouwers</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Antwerp Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Sleegers, Kristel" sort="Sleegers, Kristel" uniqKey="Sleegers K" first="Kristel" last="Sleegers">Kristel Sleegers</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Antwerp Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</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, Institute Born-Bunge Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Antwerp Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Memory Clinic and Department of Neurology, Middelheim General Hospital Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</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 Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Antwerp Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Serneels, Sally" sort="Serneels, Sally" uniqKey="Serneels S" first="Sally" last="Serneels">Sally Serneels</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Antwerp Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Kamali, Kenan" sort="Kamali, Kenan" uniqKey="Kamali K" first="Kenan" last="Kamali">Kenan Kamali</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Antwerp Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Corsmit, Ellen" sort="Corsmit, Ellen" uniqKey="Corsmit E" first="Ellen" last="Corsmit">Ellen Corsmit</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Antwerp Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Leenheir, Evelyn De" sort="Leenheir, Evelyn De" uniqKey="Leenheir E" first="Evelyn De" last="Leenheir">Evelyn De Leenheir</name><affiliation><mods:affiliation>Laboratory of Neuropathology, Institute Born-Bunge Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Antwerp Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</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 Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Antwerp Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</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, Institute Born-Bunge Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Antwerp Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Memory Clinic and Department of Neurology, Middelheim General Hospital Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Broeckhoven, Christine Van" sort="Broeckhoven, Christine Van" uniqKey="Broeckhoven C" first="Christine Van" last="Broeckhoven">Christine Van Broeckhoven</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Antwerp Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Theuns, Jessie" sort="Theuns, Jessie" uniqKey="Theuns J" first="Jessie" last="Theuns">Jessie Theuns</name><affiliation><mods:affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Antwerp Antwerpen, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Brain</title><idno type="ISSN">0006-8950</idno><idno type="eISSN">1460-2156</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2006-08-24">2006-08-24</date><biblScope unit="volume">129</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="2984">2984</biblScope><biblScope unit="page" to="2991">2991</biblScope></imprint><idno type="ISSN">0006-8950</idno></series><idno type="istex">8CB76E05CE193825F03AE95403936458E957D393</idno><idno type="DOI">10.1093/brain/awl212</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0006-8950</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">It is well established that Alzheimer's disease causing mutations in APP, PSEN1 and PSEN2 lead to a relative increased production of Aβ42, thereby fostering its deposition in plaques. Recently others and we showed that amyloid precursor protein (APP) overproduction, either as a result of genomic locus duplication or altered regulatory sequences in the APP promoter region, leads to early-onset disease. Here, we have expanded our study of genetic variability in the APP promoter to a large group of well-documented Belgian patients (n = 750, mean onset age = 75.0 ± 8.6, range = 37–96). We identified three different APP promoter mutations (−369C→G, −534G→A and −479C→T) in seven patients. In patients with onset ≤70 years (n = 204), we identified one patient carrying the London APP V717I mutation while no patients carried an APP locus duplication, indicating that APP promoter mutations (n = 2) were more frequently associated with increased risk for early-onset Alzheimer's disease. The two mutations (−369C→G and −534G→A) increasing APP promoter activity by nearly 2-fold and mimicking an APP duplication, appeared in probands of families with multiple patients with dementia. The −479C→T mutation that increased APP expression only mildly (1.2-fold), was observed in four patients with onset ages ranging from 62 to 79 years (mean 71.5 years), suggesting that its contribution to disease risk is more pronounced at later age due to modulating factors. In conclusion, we provided evidence that mutations in APP regulatory sequences are more frequent than APP coding mutations, and that increased APP transcriptional activity constitutes a risk factor for Alzheimer's disease with onset ages inversely correlated with levels of APP expression.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Nathalie Brouwers</name><affiliations><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</json:string><json:string>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</json:string><json:string>University of Antwerp Antwerpen, Belgium</json:string><json:string>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</json:string></affiliations></json:item><json:item><name>Kristel Sleegers</name><affiliations><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</json:string><json:string>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</json:string><json:string>University of Antwerp Antwerpen, Belgium</json:string><json:string>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</json:string></affiliations></json:item><json:item><name>Sebastiaan Engelborghs</name><affiliations><json:string>Laboratory of Neurochemistry and Behavior, Institute Born-Bunge Antwerpen, Belgium</json:string><json:string>University of Antwerp Antwerpen, Belgium</json:string><json:string>Memory Clinic and Department of Neurology, Middelheim General Hospital Antwerpen, Belgium</json:string><json:string>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</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 Antwerpen, Belgium</json:string><json:string>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</json:string><json:string>University of Antwerp Antwerpen, Belgium</json:string><json:string>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</json:string></affiliations></json:item><json:item><name>Sally Serneels</name><affiliations><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</json:string><json:string>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</json:string><json:string>University of Antwerp Antwerpen, Belgium</json:string><json:string>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</json:string></affiliations></json:item><json:item><name>Kenan Kamali</name><affiliations><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</json:string><json:string>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</json:string><json:string>University of Antwerp Antwerpen, Belgium</json:string><json:string>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</json:string></affiliations></json:item><json:item><name>Ellen Corsmit</name><affiliations><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</json:string><json:string>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</json:string><json:string>University of Antwerp Antwerpen, Belgium</json:string><json:string>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</json:string></affiliations></json:item><json:item><name>Evelyn De Leenheir</name><affiliations><json:string>Laboratory of Neuropathology, Institute Born-Bunge Antwerpen, Belgium</json:string><json:string>University of Antwerp Antwerpen, Belgium</json:string><json:string>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</json:string></affiliations></json:item><json:item><name>Jean-Jacques Martin</name><affiliations><json:string>Laboratory of Neuropathology, Institute Born-Bunge Antwerpen, Belgium</json:string><json:string>University of Antwerp Antwerpen, Belgium</json:string><json:string>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</json:string></affiliations></json:item><json:item><name>Peter P. De Deyn</name><affiliations><json:string>Laboratory of Neurochemistry and Behavior, Institute Born-Bunge Antwerpen, Belgium</json:string><json:string>University of Antwerp Antwerpen, Belgium</json:string><json:string>Memory Clinic and Department of Neurology, Middelheim General Hospital Antwerpen, Belgium</json:string><json:string>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</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 Antwerpen, Belgium</json:string><json:string>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</json:string><json:string>University of Antwerp Antwerpen, Belgium</json:string><json:string>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</json:string></affiliations></json:item><json:item><name>Jessie Theuns</name><affiliations><json:string>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</json:string><json:string>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</json:string><json:string>University of Antwerp Antwerpen, Belgium</json:string><json:string>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Original Articles</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Alzheimer disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>risk factor</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>amyloid precursor protein</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>promoter</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>mutations</value></json:item></subject><language><json:string>eng</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>It is well established that Alzheimer's disease causing mutations in APP, PSEN1 and PSEN2 lead to a relative increased production of Aβ42, thereby fostering its deposition in plaques. Recently others and we showed that amyloid precursor protein (APP) overproduction, either as a result of genomic locus duplication or altered regulatory sequences in the APP promoter region, leads to early-onset disease. Here, we have expanded our study of genetic variability in the APP promoter to a large group of well-documented Belgian patients (n = 750, mean onset age = 75.0 ± 8.6, range = 37–96). We identified three different APP promoter mutations (−369C→G, −534G→A and −479C→T) in seven patients. In patients with onset ≤70 years (n = 204), we identified one patient carrying the London APP V717I mutation while no patients carried an APP locus duplication, indicating that APP promoter mutations (n = 2) were more frequently associated with increased risk for early-onset Alzheimer's disease. The two mutations (−369C→G and −534G→A) increasing APP promoter activity by nearly 2-fold and mimicking an APP duplication, appeared in probands of families with multiple patients with dementia. The −479C→T mutation that increased APP expression only mildly (1.2-fold), was observed in four patients with onset ages ranging from 62 to 79 years (mean 71.5 years), suggesting that its contribution to disease risk is more pronounced at later age due to modulating factors. In conclusion, we provided evidence that mutations in APP regulatory sequences are more frequent than APP coding mutations, and that increased APP transcriptional activity constitutes a risk factor for Alzheimer's disease with onset ages inversely correlated with levels of APP expression.</abstract><qualityIndicators><score>8.5</score><pdfVersion>1.4</pdfVersion><pdfPageSize>612.685 x 793.252 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>6</keywordCount><abstractCharCount>1749</abstractCharCount><pdfWordCount>5954</pdfWordCount><pdfCharCount>38506</pdfCharCount><pdfPageCount>8</pdfPageCount><abstractWordCount>267</abstractWordCount></qualityIndicators><title>Genetic risk and transcriptional variability of amyloid precursor protein in Alzheimer's disease</title><genre><json:string>research-article</json:string></genre><host><volume>129</volume><publisherId><json:string>brainj</json:string></publisherId><pages><last>2991</last><first>2984</first></pages><issn><json:string>0006-8950</json:string></issn><issue>11</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/awl212</json:string></doi><id>8CB76E05CE193825F03AE95403936458E957D393</id><score>0.26687372</score><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/8CB76E05CE193825F03AE95403936458E957D393/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/8CB76E05CE193825F03AE95403936458E957D393/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/8CB76E05CE193825F03AE95403936458E957D393/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a">Genetic risk and transcriptional variability of amyloid precursor protein in Alzheimer's disease</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>2006-08-24</date></publicationStmt><notesStmt><note>Abbreviations AAOage at onset in patients Aβamyloid β APPamyloid precursor protein MAQmultiplex amplicon quantification MMSEMini-Mental State Examination SPECTsingle photon emission computed tomography STRshort tandem repeat</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Genetic risk and transcriptional variability of amyloid precursor protein in Alzheimer's disease</title><author xml:id="author-1"><persName><forename type="first">Nathalie</forename><surname>Brouwers</surname></persName><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</affiliation><affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</affiliation><affiliation>University of Antwerp Antwerpen, Belgium</affiliation><affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</affiliation></author><author xml:id="author-2"><persName><forename type="first">Kristel</forename><surname>Sleegers</surname></persName><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</affiliation><affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</affiliation><affiliation>University of Antwerp Antwerpen, Belgium</affiliation><affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</affiliation></author><author xml:id="author-3"><persName><forename type="first">Sebastiaan</forename><surname>Engelborghs</surname></persName><affiliation>Laboratory of Neurochemistry and Behavior, Institute Born-Bunge Antwerpen, Belgium</affiliation><affiliation>University of Antwerp Antwerpen, Belgium</affiliation><affiliation>Memory Clinic and Department of Neurology, Middelheim General Hospital Antwerpen, Belgium</affiliation><affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</affiliation></author><author xml:id="author-4"><persName><forename type="first">Veerle</forename><surname>Bogaerts</surname></persName><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</affiliation><affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</affiliation><affiliation>University of Antwerp Antwerpen, Belgium</affiliation><affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</affiliation></author><author xml:id="author-5"><persName><forename type="first">Sally</forename><surname>Serneels</surname></persName><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</affiliation><affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</affiliation><affiliation>University of Antwerp Antwerpen, Belgium</affiliation><affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</affiliation></author><author xml:id="author-6"><persName><forename type="first">Kenan</forename><surname>Kamali</surname></persName><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</affiliation><affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</affiliation><affiliation>University of Antwerp Antwerpen, Belgium</affiliation><affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</affiliation></author><author xml:id="author-7"><persName><forename type="first">Ellen</forename><surname>Corsmit</surname></persName><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</affiliation><affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</affiliation><affiliation>University of Antwerp Antwerpen, Belgium</affiliation><affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</affiliation></author><author xml:id="author-8"><persName><forename type="first">Evelyn De</forename><surname>Leenheir</surname></persName><affiliation>Laboratory of Neuropathology, Institute Born-Bunge Antwerpen, Belgium</affiliation><affiliation>University of Antwerp Antwerpen, Belgium</affiliation><affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</affiliation></author><author xml:id="author-9"><persName><forename type="first">Jean-Jacques</forename><surname>Martin</surname></persName><affiliation>Laboratory of Neuropathology, Institute Born-Bunge Antwerpen, Belgium</affiliation><affiliation>University of Antwerp Antwerpen, Belgium</affiliation><affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</affiliation></author><author xml:id="author-10"><persName><forename type="first">Peter P.</forename><surname>De Deyn</surname></persName><affiliation>Laboratory of Neurochemistry and Behavior, Institute Born-Bunge Antwerpen, Belgium</affiliation><affiliation>University of Antwerp Antwerpen, Belgium</affiliation><affiliation>Memory Clinic and Department of Neurology, Middelheim General Hospital Antwerpen, Belgium</affiliation><affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</affiliation></author><author xml:id="author-11"><persName><forename type="first">Christine Van</forename><surname>Broeckhoven</surname></persName><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</affiliation><affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</affiliation><affiliation>University of Antwerp Antwerpen, Belgium</affiliation><affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</affiliation></author><author xml:id="author-12"><persName><forename type="first">Jessie</forename><surname>Theuns</surname></persName><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</affiliation><affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</affiliation><affiliation>University of Antwerp Antwerpen, Belgium</affiliation><affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</affiliation></author></analytic><monogr><title level="j">Brain</title><idno type="pISSN">0006-8950</idno><idno type="eISSN">1460-2156</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2006-08-24"></date><biblScope unit="volume">129</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="2984">2984</biblScope><biblScope unit="page" to="2991">2991</biblScope></imprint></monogr><idno type="istex">8CB76E05CE193825F03AE95403936458E957D393</idno><idno type="DOI">10.1093/brain/awl212</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2006-08-24</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>It is well established that Alzheimer's disease causing mutations in APP, PSEN1 and PSEN2 lead to a relative increased production of Aβ42, thereby fostering its deposition in plaques. Recently others and we showed that amyloid precursor protein (APP) overproduction, either as a result of genomic locus duplication or altered regulatory sequences in the APP promoter region, leads to early-onset disease. Here, we have expanded our study of genetic variability in the APP promoter to a large group of well-documented Belgian patients (n = 750, mean onset age = 75.0 ± 8.6, range = 37–96). We identified three different APP promoter mutations (−369C→G, −534G→A and −479C→T) in seven patients. In patients with onset ≤70 years (n = 204), we identified one patient carrying the London APP V717I mutation while no patients carried an APP locus duplication, indicating that APP promoter mutations (n = 2) were more frequently associated with increased risk for early-onset Alzheimer's disease. The two mutations (−369C→G and −534G→A) increasing APP promoter activity by nearly 2-fold and mimicking an APP duplication, appeared in probands of families with multiple patients with dementia. The −479C→T mutation that increased APP expression only mildly (1.2-fold), was observed in four patients with onset ages ranging from 62 to 79 years (mean 71.5 years), suggesting that its contribution to disease risk is more pronounced at later age due to modulating factors. In conclusion, we provided evidence that mutations in APP regulatory sequences are more frequent than APP coding mutations, and that increased APP transcriptional activity constitutes a risk factor for Alzheimer's disease with onset ages inversely correlated with levels of APP expression.</p></abstract><textClass><keywords scheme="keyword"><list><item><term>Original Articles</term></item></list></keywords></textClass><textClass><keywords scheme="keyword"><list><head>keywords</head><item><term>Alzheimer disease</term></item><item><term>risk factor</term></item><item><term>amyloid precursor protein</term></item><item><term>promoter</term></item><item><term>mutations</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2006-08-24">Created</change><change when="2006-08-24">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/8CB76E05CE193825F03AE95403936458E957D393/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="hwp">brain</journal-id><journal-id journal-id-type="publisher-id">brainj</journal-id><journal-id journal-id-type="pmc">brain</journal-id><journal-title>Brain</journal-title><issn pub-type="epub">1460-2156</issn><issn pub-type="ppub">0006-8950</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1093/brain/awl212</article-id><article-categories><subj-group><subject>Original Articles</subject></subj-group></article-categories><title-group><article-title>Genetic risk and transcriptional variability of amyloid precursor protein in Alzheimer's disease</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Brouwers</surname><given-names>Nathalie</given-names></name><xref ref-type="aff" rid="au1">1</xref><xref ref-type="aff" rid="au2">2</xref><xref ref-type="aff" rid="au5">5</xref></contrib><contrib contrib-type="author"><name><surname>Sleegers</surname><given-names>Kristel</given-names></name><xref ref-type="aff" rid="au1">1</xref><xref ref-type="aff" rid="au2">2</xref><xref ref-type="aff" rid="au5">5</xref></contrib><contrib contrib-type="author"><name><surname>Engelborghs</surname><given-names>Sebastiaan</given-names></name><xref ref-type="aff" rid="au3">3</xref><xref ref-type="aff" rid="au5">5</xref><xref ref-type="aff" rid="au6">6</xref></contrib><contrib contrib-type="author"><name><surname>Bogaerts</surname><given-names>Veerle</given-names></name><xref ref-type="aff" rid="au1">1</xref><xref ref-type="aff" rid="au2">2</xref><xref ref-type="aff" rid="au5">5</xref></contrib><contrib contrib-type="author"><name><surname>Serneels</surname><given-names>Sally</given-names></name><xref ref-type="aff" rid="au1">1</xref><xref ref-type="aff" rid="au2">2</xref><xref ref-type="aff" rid="au5">5</xref></contrib><contrib contrib-type="author"><name><surname>Kamali</surname><given-names>Kenan</given-names></name><xref ref-type="aff" rid="au1">1</xref><xref ref-type="aff" rid="au2">2</xref><xref ref-type="aff" rid="au5">5</xref></contrib><contrib contrib-type="author"><name><surname>Corsmit</surname><given-names>Ellen</given-names></name><xref ref-type="aff" rid="au1">1</xref><xref ref-type="aff" rid="au2">2</xref><xref ref-type="aff" rid="au5">5</xref></contrib><contrib contrib-type="author"><name><surname>Leenheir</surname><given-names>Evelyn De</given-names></name><xref ref-type="aff" rid="au4">4</xref><xref ref-type="aff" rid="au5">5</xref></contrib><contrib contrib-type="author"><name><surname>Martin</surname><given-names>Jean-Jacques</given-names></name><xref ref-type="aff" rid="au4">4</xref><xref ref-type="aff" rid="au5">5</xref></contrib><contrib contrib-type="author"><name><surname>De Deyn</surname><given-names>Peter P.</given-names></name><xref ref-type="aff" rid="au3">3</xref><xref ref-type="aff" rid="au5">5</xref><xref ref-type="aff" rid="au6">6</xref></contrib><contrib contrib-type="author"><name><surname>Broeckhoven</surname><given-names>Christine Van</given-names></name><xref ref-type="aff" rid="au1">1</xref><xref ref-type="aff" rid="au2">2</xref><xref ref-type="aff" rid="au5">5</xref></contrib><contrib contrib-type="author"><name><surname>Theuns</surname><given-names>Jessie</given-names></name><xref ref-type="aff" rid="au1">1</xref><xref ref-type="aff" rid="au2">2</xref><xref ref-type="aff" rid="au5">5</xref></contrib><aff id="au1"><sup>1</sup><institution>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics</institution> <addr-line>Flanders Interuniversity Institute for Biotechnology</addr-line> <addr-line>Antwerpen, Belgium</addr-line></aff><aff id="au2"><sup>2</sup><institution>Laboratory of Neurogenetics, Institute Born-Bunge</institution> <addr-line>Antwerpen, Belgium</addr-line></aff><aff id="au3"><sup>3</sup><institution>Laboratory of Neurochemistry and Behavior, Institute Born-Bunge</institution> <addr-line>Antwerpen, Belgium</addr-line></aff><aff id="au4"><sup>4</sup><institution>Laboratory of Neuropathology, Institute Born-Bunge</institution> <addr-line>Antwerpen, Belgium</addr-line></aff><aff id="au5"><sup>5</sup><institution>University of Antwerp</institution> <addr-line>Antwerpen, Belgium</addr-line></aff><aff id="au6"><sup>6</sup><institution>Memory Clinic and Department of Neurology, Middelheim General Hospital</institution> <addr-line>Antwerpen, Belgium</addr-line></aff></contrib-group><author-notes><corresp>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium E-mail: <email>christine.vanbroeckhoven@ua.ac.be</email></corresp></author-notes><pub-date pub-type="collection"><month>11</month><year>2006</year></pub-date><pub-date pub-type="epub"><day>24</day><month>8</month><year>2006</year></pub-date><volume>129</volume><issue>11</issue><fpage>2984</fpage><lpage>2991</lpage><history><date date-type="received"><day>22</day><month>5</month><year>2006</year></date><date date-type="rev-recd"><day>26</day><month>6</month><year>2006</year></date><date date-type="accepted"><day>19</day><month>7</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="openaccess"><p>The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org</p></license><abstract><p>It is well established that Alzheimer's disease causing mutations in <italic>APP</italic>, <italic>PSEN1</italic> and <italic>PSEN2</italic> lead to a relative increased production of Aβ<sub>42</sub>, thereby fostering its deposition in plaques. Recently others and we showed that amyloid precursor protein (APP) overproduction, either as a result of genomic locus duplication or altered regulatory sequences in the <italic>APP</italic> promoter region, leads to early-onset disease. Here, we have expanded our study of genetic variability in the <italic>APP</italic> promoter to a large group of well-documented Belgian patients (<italic>n</italic> = 750, mean onset age = 75.0 ± 8.6, range = 37–96). We identified three different <italic>APP</italic> promoter mutations (−369C→G, −534G→A and −479C→T) in seven patients. In patients with onset ≤70 years (<italic>n</italic> = 204), we identified one patient carrying the London <italic>APP</italic> V717I mutation while no patients carried an <italic>APP</italic> locus duplication, indicating that <italic>APP</italic> promoter mutations (<italic>n</italic> = 2) were more frequently associated with increased risk for early-onset Alzheimer's disease. The two mutations (−369C→G and −534G→A) increasing <italic>APP</italic> promoter activity by nearly 2-fold and mimicking an <italic>APP</italic> duplication, appeared in probands of families with multiple patients with dementia. The −479C→T mutation that increased <italic>APP</italic> expression only mildly (1.2-fold), was observed in four patients with onset ages ranging from 62 to 79 years (mean 71.5 years), suggesting that its contribution to disease risk is more pronounced at later age due to modulating factors. In conclusion, we provided evidence that mutations in <italic>APP</italic> regulatory sequences are more frequent than <italic>APP</italic> coding mutations, and that increased <italic>APP</italic> transcriptional activity constitutes a risk factor for Alzheimer's disease with onset ages inversely correlated with levels of <italic>APP</italic> expression.</p></abstract><kwd-group><kwd>Alzheimer disease</kwd><kwd>risk factor</kwd><kwd>amyloid precursor protein</kwd><kwd>promoter</kwd><kwd>mutations</kwd></kwd-group></article-meta><notes><def-list><title>Abbreviations</title><def-item><term>AAO</term><def><p>age at onset in patients</p></def></def-item><def-item><term>Aβ</term><def><p>amyloid β</p></def></def-item><def-item><term>APP</term><def><p>amyloid precursor protein</p></def></def-item><def-item><term>MAQ</term><def><p>multiplex amplicon quantification</p></def></def-item><def-item><term>MMSE</term><def><p>Mini-Mental State Examination</p></def></def-item><def-item><term>SPECT</term><def><p>single photon emission computed tomography</p></def></def-item><def-item><term>STR</term><def><p>short tandem repeat</p></def></def-item></def-list></notes></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Genetic risk and transcriptional variability of amyloid precursor protein in Alzheimer's disease</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Genetic risk and transcriptional variability of amyloid precursor protein in Alzheimer's disease</title></titleInfo><name type="personal"><namePart type="given">Nathalie</namePart><namePart type="family">Brouwers</namePart><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</affiliation><affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</affiliation><affiliation>University of Antwerp Antwerpen, Belgium</affiliation><affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kristel</namePart><namePart type="family">Sleegers</namePart><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</affiliation><affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</affiliation><affiliation>University of Antwerp Antwerpen, Belgium</affiliation><affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</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, Institute Born-Bunge Antwerpen, Belgium</affiliation><affiliation>University of Antwerp Antwerpen, Belgium</affiliation><affiliation>Memory Clinic and Department of Neurology, Middelheim General Hospital Antwerpen, Belgium</affiliation><affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</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 Antwerpen, Belgium</affiliation><affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</affiliation><affiliation>University of Antwerp Antwerpen, Belgium</affiliation><affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sally</namePart><namePart type="family">Serneels</namePart><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</affiliation><affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</affiliation><affiliation>University of Antwerp Antwerpen, Belgium</affiliation><affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kenan</namePart><namePart type="family">Kamali</namePart><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</affiliation><affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</affiliation><affiliation>University of Antwerp Antwerpen, Belgium</affiliation><affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ellen</namePart><namePart type="family">Corsmit</namePart><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</affiliation><affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</affiliation><affiliation>University of Antwerp Antwerpen, Belgium</affiliation><affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Evelyn De</namePart><namePart type="family">Leenheir</namePart><affiliation>Laboratory of Neuropathology, Institute Born-Bunge Antwerpen, Belgium</affiliation><affiliation>University of Antwerp Antwerpen, Belgium</affiliation><affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</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 Antwerpen, Belgium</affiliation><affiliation>University of Antwerp Antwerpen, Belgium</affiliation><affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</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, Institute Born-Bunge Antwerpen, Belgium</affiliation><affiliation>University of Antwerp Antwerpen, Belgium</affiliation><affiliation>Memory Clinic and Department of Neurology, Middelheim General Hospital Antwerpen, Belgium</affiliation><affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christine Van</namePart><namePart type="family">Broeckhoven</namePart><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</affiliation><affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</affiliation><affiliation>University of Antwerp Antwerpen, Belgium</affiliation><affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jessie</namePart><namePart type="family">Theuns</namePart><affiliation>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium</affiliation><affiliation>Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium</affiliation><affiliation>University of Antwerp Antwerpen, Belgium</affiliation><affiliation>Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><subject><topic>Original Articles</topic></subject><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2006-08-24</dateIssued><dateCreated encoding="w3cdtf">2006-08-24</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>It is well established that Alzheimer's disease causing mutations in APP, PSEN1 and PSEN2 lead to a relative increased production of Aβ42, thereby fostering its deposition in plaques. Recently others and we showed that amyloid precursor protein (APP) overproduction, either as a result of genomic locus duplication or altered regulatory sequences in the APP promoter region, leads to early-onset disease. Here, we have expanded our study of genetic variability in the APP promoter to a large group of well-documented Belgian patients (n = 750, mean onset age = 75.0 ± 8.6, range = 37–96). We identified three different APP promoter mutations (−369C→G, −534G→A and −479C→T) in seven patients. In patients with onset ≤70 years (n = 204), we identified one patient carrying the London APP V717I mutation while no patients carried an APP locus duplication, indicating that APP promoter mutations (n = 2) were more frequently associated with increased risk for early-onset Alzheimer's disease. The two mutations (−369C→G and −534G→A) increasing APP promoter activity by nearly 2-fold and mimicking an APP duplication, appeared in probands of families with multiple patients with dementia. The −479C→T mutation that increased APP expression only mildly (1.2-fold), was observed in four patients with onset ages ranging from 62 to 79 years (mean 71.5 years), suggesting that its contribution to disease risk is more pronounced at later age due to modulating factors. In conclusion, we provided evidence that mutations in APP regulatory sequences are more frequent than APP coding mutations, and that increased APP transcriptional activity constitutes a risk factor for Alzheimer's disease with onset ages inversely correlated with levels of APP expression.</abstract><note>Abbreviations AAOage at onset in patients Aβamyloid β APPamyloid precursor protein MAQmultiplex amplicon quantification MMSEMini-Mental State Examination SPECTsingle photon emission computed tomography STRshort tandem repeat</note><subject><genre>keywords</genre><topic>Alzheimer disease</topic><topic>risk factor</topic><topic>amyloid precursor protein</topic><topic>promoter</topic><topic>mutations</topic></subject><relatedItem type="host"><titleInfo><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><part><date>2006</date><detail type="volume"><caption>vol.</caption><number>129</number></detail><detail type="issue"><caption>no.</caption><number>11</number></detail><extent unit="pages"><start>2984</start><end>2991</end></extent></part></relatedItem><identifier type="istex">8CB76E05CE193825F03AE95403936458E957D393</identifier><identifier type="DOI">10.1093/brain/awl212</identifier><accessCondition type="use and reproduction" contentType="copyright">© The Author (2006). Published by Oxford University Press. All rights reserved. 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