Gain-of-function haplotypes in the vesicular monoamine transporter promoter are protective for Parkinson disease in women
Identifieur interne : 001293 ( Main/Exploration ); précédent : 001292; suivant : 001294Gain-of-function haplotypes in the vesicular monoamine transporter promoter are protective for Parkinson disease in women
Auteurs : Charles E. Glatt [États-Unis] ; Angelika D. Wahner ; Daniel J. White [Royaume-Uni] ; Andres Ruiz-Linares [Royaume-Uni] ; Beate RitzSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2006-01-15.
Abstract
The vesicular monoamine transporter can protect against toxins that induce an acute parkinsonian syndrome. It has been hypothesized that cytoplasmic dopamine has subacute toxic effects in Parkinson Disease (PD) leading to neuronal death and clinical symptoms. Regulatory polymorphisms in the brain form of the vesicular monoamine transporter (VMAT2) which affect its quantitative expression might therefore serve as genetic risk factors for PD. We have screened the promoter region of the gene for VMAT2 (SLC18A2) and identified several novel polymorphisms that form discrete haplotypes. We have tested the common halpotypes in SLC18A2 for functional effects in reporter gene assays and found that there are several gain-of-function haplotypes that display significantly increased transcriptional activity from the reference element. These gain-of-function haplotypes were tested for association with PD and found to confer a protective effect that was selective for females. This finding is consistent with the prediction that increased sequestration of dopamine in secretory vesicles by VMAT2 is protective for PD.
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DOI: 10.1093/hmg/ddi445
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White</name></author><author><name sortKey="Ruiz Linares, Andres" sort="Ruiz Linares, Andres" uniqKey="Ruiz Linares A" first="Andres" last="Ruiz-Linares">Andres Ruiz-Linares</name></author><author><name sortKey="Ritz, Beate" sort="Ritz, Beate" uniqKey="Ritz B" first="Beate" last="Ritz">Beate Ritz</name></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:5E7FE2E890C8951FF68E507D361AA487E6142A2C</idno><date when="2006" year="2006">2006</date><idno type="doi">10.1093/hmg/ddi445</idno><idno type="url">https://api.istex.fr/document/5E7FE2E890C8951FF68E507D361AA487E6142A2C/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">001B29</idno><idno type="wicri:Area/Main/Curation">001866</idno><idno type="wicri:Area/Main/Exploration">001293</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Gain-of-function haplotypes in the vesicular monoamine transporter promoter are protective for Parkinson disease in women</title><author><name sortKey="Glatt, Charles E" sort="Glatt, Charles E" uniqKey="Glatt C" first="Charles E." last="Glatt">Charles E. Glatt</name><affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation><affiliation wicri:level="1"><country wicri:rule="url">États-Unis</country></affiliation></author><author><name sortKey="Wahner, Angelika D" sort="Wahner, Angelika D" uniqKey="Wahner A" first="Angelika D." last="Wahner">Angelika D. Wahner</name><affiliation><wicri:noCountry code="subField">USA and</wicri:noCountry></affiliation></author><author><name sortKey="White, Daniel J" sort="White, Daniel J" uniqKey="White D" first="Daniel J." last="White">Daniel J. 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Genet.</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2006-01-15">2006-01-15</date><biblScope unit="volume">15</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="299">299</biblScope><biblScope unit="page" to="305">305</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">5E7FE2E890C8951FF68E507D361AA487E6142A2C</idno><idno type="DOI">10.1093/hmg/ddi445</idno><idno type="href">ddi445</idno><idno type="local">ddi445</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The vesicular monoamine transporter can protect against toxins that induce an acute parkinsonian syndrome. It has been hypothesized that cytoplasmic dopamine has subacute toxic effects in Parkinson Disease (PD) leading to neuronal death and clinical symptoms. Regulatory polymorphisms in the brain form of the vesicular monoamine transporter (VMAT2) which affect its quantitative expression might therefore serve as genetic risk factors for PD. We have screened the promoter region of the gene for VMAT2 (SLC18A2) and identified several novel polymorphisms that form discrete haplotypes. We have tested the common halpotypes in SLC18A2 for functional effects in reporter gene assays and found that there are several gain-of-function haplotypes that display significantly increased transcriptional activity from the reference element. These gain-of-function haplotypes were tested for association with PD and found to confer a protective effect that was selective for females. This finding is consistent with the prediction that increased sequestration of dopamine in secretory vesicles by VMAT2 is protective for PD.</div></front></TEI><affiliations><list><country><li>Royaume-Uni</li><li>États-Unis</li></country></list><tree><noCountry><name sortKey="Ritz, Beate" sort="Ritz, Beate" uniqKey="Ritz B" first="Beate" last="Ritz">Beate Ritz</name><name sortKey="Wahner, Angelika D" sort="Wahner, Angelika D" uniqKey="Wahner A" first="Angelika D." last="Wahner">Angelika D. Wahner</name></noCountry><country name="États-Unis"><noRegion><name sortKey="Glatt, Charles E" sort="Glatt, Charles E" uniqKey="Glatt C" first="Charles E." last="Glatt">Charles E. Glatt</name></noRegion></country><country name="Royaume-Uni"><noRegion><name sortKey="White, Daniel J" sort="White, Daniel J" uniqKey="White D" first="Daniel J." last="White">Daniel J. White</name></noRegion><name sortKey="Ruiz Linares, Andres" sort="Ruiz Linares, Andres" uniqKey="Ruiz Linares A" first="Andres" last="Ruiz-Linares">Andres Ruiz-Linares</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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