Variants in the estrogen receptor alpha gene and its mRNA contribute to risk for schizophrenia
Identifieur interne : 001536 ( Istex/Corpus ); précédent : 001535; suivant : 001537Variants in the estrogen receptor alpha gene and its mRNA contribute to risk for schizophrenia
Auteurs : Cynthia Shannon Weickert ; Ana L. Miranda-Angulo ; Jenny Wong ; William R. Perlman ; Sarah E. Ward ; Vakkalanka Radhakrishna ; Richard E. Straub ; Daniel R. Weinberger ; Joel E. KleinmanSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2008-08-01.
Abstract
Estrogen modifies human emotion and cognition and impacts symptoms of schizophrenia. We hypothesized that the variation in the estrogen receptor alpha (ESR1) gene and cortical ESR1 mRNA is associated with schizophrenia. In a small casecontrol genetic association analysis of postmortem brain tissue, genotype CC (rs2234693) and haplotypes containing the C allele of a single-nucleotide polymorphism (SNP) in intron1 (PvuII) were more frequent in African American schizophrenics (P 0.010.001). In a follow-up family-based association analysis, we found overtransmission of PvuII allele C and a PvuII C-containing haplotype (P 0.010.03) to African American and Caucasian patients with schizophrenia. Schizophrenics with the at risk PvuII genotype had lower ESR1 mRNA levels in the frontal cortex. Eighteen ESR1 splice variants and decreased frequencies of the wild-type ESR1 mRNA were detected in schizophrenia. In one patient, a unique ESR1 transcript with a genomic insert encoding a premature stop codon and a truncated ESR1 protein lacking most of the estrogen binding domain was the only transcript detected. Using a luciferase assay, we found that mRNA encoding a truncated ESR1 significantly attenuates gene expression at estrogen-response elements demonstrating a dominant negative function. An intron 6 SNP [rs2273207(G)] was associated with an ESR1 splice variant missing exon seven. The T allele of another intron 6 SNP was part of a 3 haplotype less common in schizophrenia [rs2273206(T), rs2273207(G), rs2228480(G)]. Thus, the variation in the ESR1 gene is associated with schizophrenia and the mechanism of this association may involve alternative gene regulation and transcript processing.
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DOI: 10.1093/hmg/ddn130
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We hypothesized that the variation in the estrogen receptor alpha (ESR1) gene and cortical ESR1 mRNA is associated with schizophrenia. In a small casecontrol genetic association analysis of postmortem brain tissue, genotype CC (rs2234693) and haplotypes containing the C allele of a single-nucleotide polymorphism (SNP) in intron1 (PvuII) were more frequent in African American schizophrenics (P 0.010.001). In a follow-up family-based association analysis, we found overtransmission of PvuII allele C and a PvuII C-containing haplotype (P 0.010.03) to African American and Caucasian patients with schizophrenia. Schizophrenics with the at risk PvuII genotype had lower ESR1 mRNA levels in the frontal cortex. Eighteen ESR1 splice variants and decreased frequencies of the wild-type ESR1 mRNA were detected in schizophrenia. In one patient, a unique ESR1 transcript with a genomic insert encoding a premature stop codon and a truncated ESR1 protein lacking most of the estrogen binding domain was the only transcript detected. Using a luciferase assay, we found that mRNA encoding a truncated ESR1 significantly attenuates gene expression at estrogen-response elements demonstrating a dominant negative function. An intron 6 SNP [rs2273207(G)] was associated with an ESR1 splice variant missing exon seven. The T allele of another intron 6 SNP was part of a 3 haplotype less common in schizophrenia [rs2273206(T), rs2273207(G), rs2228480(G)]. Thus, the variation in the ESR1 gene is associated with schizophrenia and the mechanism of this association may involve alternative gene regulation and transcript processing.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Cynthia Shannon Weickert</name><affiliations><json:string>MiNDS Unit, Section on Neuropathology</json:string><json:string>Schizophrenia Research Laboratory, Schizophrenia Research Institute, POWMRI, UNSW, Sydney, NSW 2031, Australia</json:string><json:string>E-mail: cyndi@powmri.edu.au</json:string></affiliations></json:item><json:item><name>Ana L. Miranda-Angulo</name><affiliations><json:string>MiNDS Unit, Section on Neuropathology</json:string></affiliations></json:item><json:item><name>Jenny Wong</name><affiliations><json:string>Schizophrenia Research Laboratory, Schizophrenia Research Institute, POWMRI, UNSW, Sydney, NSW 2031, Australia</json:string></affiliations></json:item><json:item><name>William R. 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In a follow-up family-based association analysis, we found overtransmission of PvuII allele C and a PvuII C-containing haplotype (P 0.010.03) to African American and Caucasian patients with schizophrenia. Schizophrenics with the at risk PvuII genotype had lower ESR1 mRNA levels in the frontal cortex. Eighteen ESR1 splice variants and decreased frequencies of the wild-type ESR1 mRNA were detected in schizophrenia. In one patient, a unique ESR1 transcript with a genomic insert encoding a premature stop codon and a truncated ESR1 protein lacking most of the estrogen binding domain was the only transcript detected. Using a luciferase assay, we found that mRNA encoding a truncated ESR1 significantly attenuates gene expression at estrogen-response elements demonstrating a dominant negative function. An intron 6 SNP [rs2273207(G)] was associated with an ESR1 splice variant missing exon seven. The T allele of another intron 6 SNP was part of a 3 haplotype less common in schizophrenia [rs2273206(T), rs2273207(G), rs2228480(G)]. 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first two authors should be regarded as joint First Authors.</affiliation><affiliation>MiNDS Unit, Section on Neuropathology</affiliation><affiliation>Schizophrenia Research Laboratory, Schizophrenia Research Institute, POWMRI, UNSW, Sydney, NSW 2031, Australia</affiliation></author><author xml:id="author-2"><persName><forename type="first">Ana L.</forename><surname>Miranda-Angulo</surname></persName><note type="biography">The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</note><affiliation>The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</affiliation><affiliation>MiNDS Unit, Section on Neuropathology</affiliation></author><author xml:id="author-3"><persName><forename type="first">Jenny</forename><surname>Wong</surname></persName><affiliation>Schizophrenia Research Laboratory, Schizophrenia Research Institute, POWMRI, UNSW, Sydney, NSW 2031, Australia</affiliation></author><author xml:id="author-4"><persName><forename type="first">William R.</forename><surname>Perlman</surname></persName><affiliation>MiNDS Unit, Section on Neuropathology</affiliation></author><author xml:id="author-5"><persName><forename type="first">Sarah E.</forename><surname>Ward</surname></persName><affiliation>MiNDS Unit, Section on Neuropathology</affiliation></author><author xml:id="author-6"><persName><forename type="first">Vakkalanka</forename><surname>Radhakrishna</surname></persName><affiliation>Clinical Brain Disorders Branch, GCAP, NIMH, NIH, Bethesda, MD 20892, USA</affiliation></author><author xml:id="author-7"><persName><forename type="first">Richard E.</forename><surname>Straub</surname></persName><affiliation>Clinical Brain Disorders Branch, GCAP, NIMH, NIH, Bethesda, MD 20892, USA</affiliation></author><author xml:id="author-8"><persName><forename type="first">Daniel 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We hypothesized that the variation in the estrogen receptor alpha (ESR1) gene and cortical ESR1 mRNA is associated with schizophrenia. In a small casecontrol genetic association analysis of postmortem brain tissue, genotype CC (rs2234693) and haplotypes containing the C allele of a single-nucleotide polymorphism (SNP) in intron1 (PvuII) were more frequent in African American schizophrenics (P 0.010.001). In a follow-up family-based association analysis, we found overtransmission of PvuII allele C and a PvuII C-containing haplotype (P 0.010.03) to African American and Caucasian patients with schizophrenia. Schizophrenics with the at risk PvuII genotype had lower ESR1 mRNA levels in the frontal cortex. Eighteen ESR1 splice variants and decreased frequencies of the wild-type ESR1 mRNA were detected in schizophrenia. In one patient, a unique ESR1 transcript with a genomic insert encoding a premature stop codon and a truncated ESR1 protein lacking most of the estrogen binding domain was the only transcript detected. Using a luciferase assay, we found that mRNA encoding a truncated ESR1 significantly attenuates gene expression at estrogen-response elements demonstrating a dominant negative function. An intron 6 SNP [rs2273207(G)] was associated with an ESR1 splice variant missing exon seven. The T allele of another intron 6 SNP was part of a 3 haplotype less common in schizophrenia [rs2273206(T), rs2273207(G), rs2228480(G)]. Thus, the variation in the ESR1 gene is associated with schizophrenia and the mechanism of this association may involve alternative gene regulation and transcript processing.</p></abstract></profileDesc><revisionDesc><change when="2008-04-18">Created</change><change when="2008-08-01">Published</change><change xml:id="refBibs-istex" who="#ISTEX-API" when="2016-10-14">References added</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/AA892FC2C18B2237CE2E273477FF27FB7DC22A39/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</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 article-type="research-article"><front><journal-meta><journal-id journal-id-type="publisher-id">hmg</journal-id><journal-id journal-id-type="hwp">hmg</journal-id><journal-title>Human Molecular Genetics</journal-title><issn pub-type="ppub">0964-6906</issn><issn pub-type="epub">1460-2083</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1093/hmg/ddn130</article-id><article-id pub-id-type="publisher-id">ddn130</article-id><article-categories><subj-group subj-group-type="heading"><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title>Variants in the estrogen receptor alpha gene and its mRNA contribute to risk for schizophrenia</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Weickert</surname><given-names>Cynthia Shannon</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af4">4</xref><xref ref-type="author-notes" rid="FN1">†</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib><contrib contrib-type="author"><name><surname>Miranda-Angulo</surname><given-names>Ana L.</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="author-notes" rid="FN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Wong</surname><given-names>Jenny</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Perlman</surname><given-names>William R.</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Ward</surname><given-names>Sarah E.</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Radhakrishna</surname><given-names>Vakkalanka</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Straub</surname><given-names>Richard E.</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Weinberger</surname><given-names>Daniel R.</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Kleinman</surname><given-names>Joel E.</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib></contrib-group><aff id="af1"><label>1</label><addr-line>MiNDS Unit, Section on Neuropathology</addr-line></aff><aff id="af2"><label>2</label><institution>Section on Neuropathology</institution>, <addr-line>CBDB</addr-line></aff><aff id="af3"><label>3</label><addr-line>Clinical Brain Disorders Branch, GCAP</addr-line>, <institution>NIMH, NIH</institution>, <addr-line>Bethesda, MD 20892</addr-line>, <country>USA</country></aff><aff id="af4"><label>4</label><institution>Schizophrenia Research Laboratory, Schizophrenia Research Institute</institution>, <addr-line>POWMRI, UNSW, Sydney, NSW 2031</addr-line>, <country>Australia</country></aff><author-notes><fn id="FN1"><label>†</label><p>The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</p></fn><corresp id="cor1"><label>*</label>To whom correspondence should be addressed at: <institution>Maquarie Group Foundation Chair of Schizophrenia Research, UNSW Department of Psychiatry, Prince of Wales Medical Research Institute</institution>, <addr-line>Corner of Barker and Easy Street, Randwick, Sydney NSW 2031</addr-line>, <country>Australia.</country> Tel: <phone>+61 293991117</phone>; Fax: <fax>+61 293991005</fax>; Email: <email>cyndi@powmri.edu.au</email> or <email>c.shannonweickert@unsw.edu.au</email></corresp></author-notes><pub-date pub-type="ppub"><day>1</day><month>8</month><year>2008</year></pub-date><pub-date pub-type="epub"><day>18</day><month>4</month><year>2008</year></pub-date><volume>17</volume><issue>15</issue><fpage>2293</fpage><lpage>2309</lpage><history><date date-type="received"><day>3</day><month>1</month><year>2008</year></date><date date-type="rev-recd"><day>12</day><month>3</month><year>2008</year></date><date date-type="accepted"><day>15</day><month>4</month><year>2008</year></date></history><copyright-statement>Published by Oxford University Press 2008</copyright-statement><copyright-year>2008</copyright-year><license license-type="creative-commons" xlink:href="http://creativecommons.org/licenses/by-nc/2.0/uk/"><p>This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.</p></license><abstract><p>Estrogen modifies human emotion and cognition and impacts symptoms of schizophrenia. We hypothesized that the variation in the estrogen receptor alpha (ESR1) gene and cortical ESR1 mRNA is associated with schizophrenia. In a small case–control genetic association analysis of postmortem brain tissue, genotype CC (rs2234693) and haplotypes containing the C allele of a single-nucleotide polymorphism (SNP) in intron1 (PvuII) were more frequent in African American schizophrenics (<italic>P</italic> = 0.01–0.001). In a follow-up family-based association analysis, we found overtransmission of PvuII allele C and a PvuII C-containing haplotype (<italic>P</italic> = 0.01–0.03) to African American and Caucasian patients with schizophrenia. Schizophrenics with the ‘at risk’ PvuII genotype had lower ESR1 mRNA levels in the frontal cortex. Eighteen ESR1 splice variants and decreased frequencies of the wild-type ESR1 mRNA were detected in schizophrenia. In one patient, a unique ESR1 transcript with a genomic insert encoding a premature stop codon and a truncated ESR1 protein lacking most of the estrogen binding domain was the only transcript detected. Using a luciferase assay, we found that mRNA encoding a truncated ESR1 significantly attenuates gene expression at estrogen-response elements demonstrating a dominant negative function. An intron 6 SNP [rs2273207(G)] was associated with an ESR1 splice variant missing exon seven. The T allele of another intron 6 SNP was part of a 3′ haplotype less common in schizophrenia [rs2273206(T), rs2273207(G), rs2228480(G)]. Thus, the variation in the ESR1 gene is associated with schizophrenia and the mechanism of this association may involve alternative gene regulation and transcript processing.</p></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Variants in the estrogen receptor alpha gene and its mRNA contribute to risk for schizophrenia</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Variants in the estrogen receptor alpha gene and its mRNA contribute to risk for schizophrenia</title></titleInfo><name type="personal"><namePart type="given">Cynthia Shannon</namePart><namePart type="family">Weickert</namePart><affiliation>MiNDS Unit, Section on Neuropathology</affiliation><affiliation>Schizophrenia Research Laboratory, Schizophrenia Research Institute, POWMRI, UNSW, Sydney, NSW 2031, Australia</affiliation><affiliation>E-mail: cyndi@powmri.edu.au</affiliation><description>The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ana L.</namePart><namePart type="family">Miranda-Angulo</namePart><affiliation>MiNDS Unit, Section on Neuropathology</affiliation><description>The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jenny</namePart><namePart type="family">Wong</namePart><affiliation>Schizophrenia Research Laboratory, Schizophrenia Research Institute, POWMRI, UNSW, Sydney, NSW 2031, Australia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">William R.</namePart><namePart type="family">Perlman</namePart><affiliation>MiNDS Unit, Section on Neuropathology</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sarah E.</namePart><namePart type="family">Ward</namePart><affiliation>MiNDS Unit, Section on Neuropathology</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Vakkalanka</namePart><namePart type="family">Radhakrishna</namePart><affiliation>Clinical Brain Disorders Branch, GCAP, NIMH, NIH, Bethesda, MD 20892, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Richard E.</namePart><namePart type="family">Straub</namePart><affiliation>Clinical Brain Disorders Branch, GCAP, NIMH, NIH, Bethesda, MD 20892, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Daniel R.</namePart><namePart type="family">Weinberger</namePart><affiliation>Clinical Brain Disorders Branch, GCAP, NIMH, NIH, Bethesda, MD 20892, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Joel E.</namePart><namePart type="family">Kleinman</namePart><affiliation>Section on Neuropathology, CBDB</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">2008-08-01</dateIssued><dateCreated encoding="w3cdtf">2008-04-18</dateCreated><copyrightDate encoding="w3cdtf">2008</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>Estrogen modifies human emotion and cognition and impacts symptoms of schizophrenia. We hypothesized that the variation in the estrogen receptor alpha (ESR1) gene and cortical ESR1 mRNA is associated with schizophrenia. In a small casecontrol genetic association analysis of postmortem brain tissue, genotype CC (rs2234693) and haplotypes containing the C allele of a single-nucleotide polymorphism (SNP) in intron1 (PvuII) were more frequent in African American schizophrenics (P 0.010.001). In a follow-up family-based association analysis, we found overtransmission of PvuII allele C and a PvuII C-containing haplotype (P 0.010.03) to African American and Caucasian patients with schizophrenia. Schizophrenics with the at risk PvuII genotype had lower ESR1 mRNA levels in the frontal cortex. Eighteen ESR1 splice variants and decreased frequencies of the wild-type ESR1 mRNA were detected in schizophrenia. In one patient, a unique ESR1 transcript with a genomic insert encoding a premature stop codon and a truncated ESR1 protein lacking most of the estrogen binding domain was the only transcript detected. Using a luciferase assay, we found that mRNA encoding a truncated ESR1 significantly attenuates gene expression at estrogen-response elements demonstrating a dominant negative function. An intron 6 SNP [rs2273207(G)] was associated with an ESR1 splice variant missing exon seven. The T allele of another intron 6 SNP was part of a 3 haplotype less common in schizophrenia [rs2273206(T), rs2273207(G), rs2228480(G)]. Thus, the variation in the ESR1 gene is associated with schizophrenia and the mechanism of this association may involve alternative gene regulation and transcript processing.</abstract><note type="footnotes">The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</note><relatedItem type="host"><titleInfo><title>Human Molecular Genetics</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">0964-6906</identifier><identifier type="eISSN">1460-2083</identifier><identifier type="PublisherID">hmg</identifier><identifier type="PublisherID-hwp">hmg</identifier><part><date>2008</date><detail type="volume"><caption>vol.</caption><number>17</number></detail><detail type="issue"><caption>no.</caption><number>15</number></detail><extent unit="pages"><start>2293</start><end>2309</end></extent></part></relatedItem><identifier type="istex">AA892FC2C18B2237CE2E273477FF27FB7DC22A39</identifier><identifier type="DOI">10.1093/hmg/ddn130</identifier><identifier type="ArticleID">ddn130</identifier><accessCondition type="use and reproduction" contentType="copyright">Published by Oxford University Press 2008</accessCondition><recordInfo><recordContentSource>OUP</recordContentSource></recordInfo></mods></metadata><covers><json:item><original>true</original><mimetype>image/tiff</mimetype><extension>tiff</extension><uri>https://api.istex.fr/document/AA892FC2C18B2237CE2E273477FF27FB7DC22A39/covers/tiff</uri></json:item><json:item><original>true</original><mimetype>text/html</mimetype><extension>html</extension><uri>https://api.istex.fr/document/AA892FC2C18B2237CE2E273477FF27FB7DC22A39/covers/html</uri></json:item></covers><annexes><json:item><original>true</original><mimetype>image/jpeg</mimetype><extension>jpeg</extension><uri>https://api.istex.fr/document/AA892FC2C18B2237CE2E273477FF27FB7DC22A39/annexes/jpeg</uri></json:item><json:item><original>true</original><mimetype>image/gif</mimetype><extension>gif</extension><uri>https://api.istex.fr/document/AA892FC2C18B2237CE2E273477FF27FB7DC22A39/annexes/gif</uri></json:item><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/AA892FC2C18B2237CE2E273477FF27FB7DC22A39/annexes/pdf</uri></json:item></annexes><enrichments><istex:catWosTEI uri="https://api.istex.fr/document/AA892FC2C18B2237CE2E273477FF27FB7DC22A39/enrichments/catWos"><teiHeader><profileDesc><textClass><classCode scheme="WOS">BIOCHEMISTRY & MOLECULAR BIOLOGY</classCode><classCode scheme="WOS">GENETICS & HEREDITY</classCode></textClass></profileDesc></teiHeader></istex:catWosTEI><json:item><type>refBibs</type><uri>https://api.istex.fr/document/AA892FC2C18B2237CE2E273477FF27FB7DC22A39/enrichments/refBibs</uri></json:item></enrichments><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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