Allelic imbalance of expression and epigenetic regulation within the alpha‐synuclein wild‐type and p.Ala53Thr alleles in Parkinson disease
Identifieur interne : 000617 ( Main/Corpus ); précédent : 000616; suivant : 000618Allelic imbalance of expression and epigenetic regulation within the alpha‐synuclein wild‐type and p.Ala53Thr alleles in Parkinson disease
Auteurs : Gerassimos E. Voutsinas ; Eleana F. Stavrou ; Gerassimos Karousos ; Aggeliki Dasoula ; Adamantia Papachatzopoulou ; Maria Syrrou ; Annemieke J. M. H. Verkerk ; Peter Van Der Spek ; George P. Patrinos ; Reinhard Stöger ; Aglaia AthanassiadouSource :
- Human Mutation [ 1059-7794 ] ; 2010-06.
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Abstract
Genetic alterations in the alpha‐synuclein (SNCA) gene have been implicated in Parkinson Disease (PD), including point mutations, gene multiplications, and sequence variations within the promoter. Such alterations may be involved in pathology through structural changes or overexpression of the protein leading to protein aggregation, as well as through impaired gene expression. It is, therefore, of importance to specify the parameters that regulate SNCA expression in its normal and mutated state. We studied the expression of SNCA alleles in a lymphoblastoid cell line and in the blood cells of a patient heterozygous for p.Ala53Thr, the first mutation to be implicated in PD pathogenesis. Here, we provide evidence that: (1) SNCA shows monoallelic expression in this patient, (2) epigenetic silencing of the mutated allele involves histone modifications but not DNA methylation, and (3) steady‐state mRNA levels deriving from the normal SNCA allele in this patient exceed those of the two normal SNCA alleles combined, in matching, control individuals. An imbalanced SNCA expression in this patient is thus documented, with silencing of the p.Ala53Thr allele and upregulation of the wild‐type‐allele. This phenomenon is demonstrated for a first time in the SNCA gene, and may have important implications for PD pathogenesis. Hum Mutat 31:1–7, 2010. © 2010 Wiley‐Liss, Inc.
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DOI: 10.1002/humu.21248
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Voutsinas</name><affiliation><mods:affiliation>Department of General Biology, School of Medicine, University of Patras, Patras, Greece</mods:affiliation></affiliation><affiliation><mods:affiliation>Laboratory of Environmental Mutagenesis and Carcinogenesis, Institute of Biology, NCSR “Demokritos,” GR‐15310 Athens, Greece</mods:affiliation></affiliation></author><author><name sortKey="Stavrou, Eleana F" sort="Stavrou, Eleana F" uniqKey="Stavrou E" first="Eleana F." last="Stavrou">Eleana F. 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Patrinos</name><affiliation><mods:affiliation>Erasmus University Medical Center, Faculty of Medicine and Health Sciences, Department of Bioinformatics, Rotterdam, The Netherlands</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Patras, School of Health Sciences, Department of Pharmacy, Patras, Greece</mods:affiliation></affiliation></author><author><name sortKey="Stoger, Reinhard" sort="Stoger, Reinhard" uniqKey="Stoger R" first="Reinhard" last="Stöger">Reinhard Stöger</name><affiliation><mods:affiliation>Department of Biology, University of Washington, Seattle, Washington</mods:affiliation></affiliation><affiliation><mods:affiliation>Current Address: School of Biosciences, University of Nottingham, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Athanassiadou, Aglaia" sort="Athanassiadou, Aglaia" uniqKey="Athanassiadou A" first="Aglaia" last="Athanassiadou">Aglaia Athanassiadou</name><affiliation><mods:affiliation>Department of General Biology, School of Medicine, University of Patras, Patras, Greece</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Human Mutation</title><title level="j" type="abbrev">Hum. 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Such alterations may be involved in pathology through structural changes or overexpression of the protein leading to protein aggregation, as well as through impaired gene expression. It is, therefore, of importance to specify the parameters that regulate SNCA expression in its normal and mutated state. We studied the expression of SNCA alleles in a lymphoblastoid cell line and in the blood cells of a patient heterozygous for p.Ala53Thr, the first mutation to be implicated in PD pathogenesis. Here, we provide evidence that: (1) SNCA shows monoallelic expression in this patient, (2) epigenetic silencing of the mutated allele involves histone modifications but not DNA methylation, and (3) steady‐state mRNA levels deriving from the normal SNCA allele in this patient exceed those of the two normal SNCA alleles combined, in matching, control individuals. An imbalanced SNCA expression in this patient is thus documented, with silencing of the p.Ala53Thr allele and upregulation of the wild‐type‐allele. This phenomenon is demonstrated for a first time in the SNCA gene, and may have important implications for PD pathogenesis. Hum Mutat 31:1–7, 2010. © 2010 Wiley‐Liss, Inc.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Gerassimos E. Voutsinas</name><affiliations><json:string>Department of General Biology, School of Medicine, University of Patras, Patras, Greece</json:string><json:string>Laboratory of Environmental Mutagenesis and Carcinogenesis, Institute of Biology, NCSR “Demokritos,” GR‐15310 Athens, Greece</json:string></affiliations></json:item><json:item><name>Eleana F. 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Verkerk</name><affiliations><json:string>Erasmus University Medical Center, Faculty of Medicine and Health Sciences, Department of Bioinformatics, Rotterdam, The Netherlands</json:string></affiliations></json:item><json:item><name>Peter van der Spek</name><affiliations><json:string>Erasmus University Medical Center, Faculty of Medicine and Health Sciences, Department of Bioinformatics, Rotterdam, The Netherlands</json:string></affiliations></json:item><json:item><name>George P. Patrinos</name><affiliations><json:string>Erasmus University Medical Center, Faculty of Medicine and Health Sciences, Department of Bioinformatics, Rotterdam, The Netherlands</json:string><json:string>University of Patras, School of Health Sciences, Department of Pharmacy, Patras, Greece</json:string></affiliations></json:item><json:item><name>Reinhard Stöger</name><affiliations><json:string>Department of Biology, University of Washington, Seattle, Washington</json:string><json:string>Current Address: School of Biosciences, University of Nottingham, United Kingdom</json:string></affiliations></json:item><json:item><name>Aglaia Athanassiadou</name><affiliations><json:string>Department of General Biology, School of Medicine, University of Patras, Patras, Greece</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Parkinson</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>alpha‐synuclein</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>SNCA</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>monoallelic</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>overexpression</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>epigenetic</value></json:item></subject><articleId><json:string>HUMU21248</json:string></articleId><language><json:string>eng</json:string></language><abstract>Genetic alterations in the alpha‐synuclein (SNCA) gene have been implicated in Parkinson Disease (PD), including point mutations, gene multiplications, and sequence variations within the promoter. Such alterations may be involved in pathology through structural changes or overexpression of the protein leading to protein aggregation, as well as through impaired gene expression. It is, therefore, of importance to specify the parameters that regulate SNCA expression in its normal and mutated state. We studied the expression of SNCA alleles in a lymphoblastoid cell line and in the blood cells of a patient heterozygous for p.Ala53Thr, the first mutation to be implicated in PD pathogenesis. Here, we provide evidence that: (1) SNCA shows monoallelic expression in this patient, (2) epigenetic silencing of the mutated allele involves histone modifications but not DNA methylation, and (3) steady‐state mRNA levels deriving from the normal SNCA allele in this patient exceed those of the two normal SNCA alleles combined, in matching, control individuals. An imbalanced SNCA expression in this patient is thus documented, with silencing of the p.Ala53Thr allele and upregulation of the wild‐type‐allele. This phenomenon is demonstrated for a first time in the SNCA gene, and may have important implications for PD pathogenesis. 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E.</forename><surname>Voutsinas</surname></persName><affiliation>Department of General Biology, School of Medicine, University of Patras, Patras, Greece</affiliation><affiliation>Laboratory of Environmental Mutagenesis and Carcinogenesis, Institute of Biology, NCSR “Demokritos,” GR‐15310 Athens, Greece</affiliation></author><author><persName><forename type="first">Eleana F.</forename><surname>Stavrou</surname></persName><affiliation>Department of General Biology, School of Medicine, University of Patras, Patras, Greece</affiliation></author><author><persName><forename type="first">Gerassimos</forename><surname>Karousos</surname></persName><affiliation>Department of General Biology, School of Medicine, University of Patras, Patras, Greece</affiliation></author><author><persName><forename type="first">Aggeliki</forename><surname>Dasoula</surname></persName><affiliation>Laboratory of General Biology, School of Medicine, University of Ioannina, Ioannina, Greece</affiliation></author><author><persName><forename type="first">Adamantia</forename><surname>Papachatzopoulou</surname></persName><affiliation>Department of General Biology, School of Medicine, University of Patras, Patras, Greece</affiliation></author><author><persName><forename type="first">Maria</forename><surname>Syrrou</surname></persName><affiliation>Laboratory of General Biology, School of Medicine, University of Ioannina, Ioannina, Greece</affiliation></author><author><persName><forename type="first">Annemieke J.M.H.</forename><surname>Verkerk</surname></persName><affiliation>Erasmus University Medical Center, Faculty of Medicine and Health Sciences, Department of Bioinformatics, Rotterdam, The Netherlands</affiliation></author><author><persName><forename type="first">Peter</forename><surname>van der Spek</surname></persName><affiliation>Erasmus University Medical Center, Faculty of Medicine and Health Sciences, Department of Bioinformatics, Rotterdam, The Netherlands</affiliation></author><author><persName><forename type="first">George P.</forename><surname>Patrinos</surname></persName><affiliation>Erasmus University Medical Center, Faculty of Medicine and Health Sciences, Department of Bioinformatics, Rotterdam, The Netherlands</affiliation><affiliation>University of Patras, School of Health Sciences, Department of Pharmacy, Patras, Greece</affiliation></author><author><persName><forename type="first">Reinhard</forename><surname>Stöger</surname></persName><affiliation>Department of Biology, University of Washington, Seattle, Washington</affiliation><affiliation>Current Address: School of Biosciences, University of Nottingham, United Kingdom</affiliation></author><author><persName><forename type="first">Aglaia</forename><surname>Athanassiadou</surname></persName><note type="correspondence"><p>Correspondence: Department of General Biology, Faculty of Medicine, University of Patras, Rion, Patras, GR‐26500, Greece</p></note><affiliation>Department of General Biology, School of Medicine, University of Patras, Patras, Greece</affiliation></author></analytic><monogr><title level="j">Human Mutation</title><title level="j" type="abbrev">Hum. Mutat.</title><idno type="pISSN">1059-7794</idno><idno type="eISSN">1098-1004</idno><idno type="DOI">10.1002/(ISSN)1098-1004</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2010-06"></date><biblScope unit="volume">31</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="685">685</biblScope><biblScope unit="page" to="691">691</biblScope></imprint></monogr><idno type="istex">0780772AEDD857BDB4A67C3DC98CFF472926E7B0</idno><idno type="DOI">10.1002/humu.21248</idno><idno type="ArticleID">HUMU21248</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2010</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Genetic alterations in the alpha‐synuclein (SNCA) gene have been implicated in Parkinson Disease (PD), including point mutations, gene multiplications, and sequence variations within the promoter. Such alterations may be involved in pathology through structural changes or overexpression of the protein leading to protein aggregation, as well as through impaired gene expression. It is, therefore, of importance to specify the parameters that regulate SNCA expression in its normal and mutated state. We studied the expression of SNCA alleles in a lymphoblastoid cell line and in the blood cells of a patient heterozygous for p.Ala53Thr, the first mutation to be implicated in PD pathogenesis. Here, we provide evidence that: (1) SNCA shows monoallelic expression in this patient, (2) epigenetic silencing of the mutated allele involves histone modifications but not DNA methylation, and (3) steady‐state mRNA levels deriving from the normal SNCA allele in this patient exceed those of the two normal SNCA alleles combined, in matching, control individuals. An imbalanced SNCA expression in this patient is thus documented, with silencing of the p.Ala53Thr allele and upregulation of the wild‐type‐allele. This phenomenon is demonstrated for a first time in the SNCA gene, and may have important implications for PD pathogenesis. Hum Mutat 31:1–7, 2010. © 2010 Wiley‐Liss, Inc.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>Parkinson</term></item><item><term>alpha‐synuclein</term></item><item><term>SNCA</term></item><item><term>monoallelic</term></item><item><term>overexpression</term></item><item><term>epigenetic</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>article category</head><item><term>Research Article</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2009-11-23">Received</change><change when="2010-03-03">Registration</change><change when="2010-06">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/0780772AEDD857BDB4A67C3DC98CFF472926E7B0/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Wiley Subscription Services, Inc., A Wiley Company</publisherName><publisherLoc>Hoboken</publisherLoc></publisherInfo><doi registered="yes">10.1002/(ISSN)1098-1004</doi><issn type="print">1059-7794</issn><issn type="electronic">1098-1004</issn><idGroup><id type="product" value="HUMU"></id></idGroup><titleGroup><title type="main" xml:lang="en" sort="HUMAN MUTATION">Human Mutation</title><title type="short">Hum. Mutat.</title></titleGroup></publicationMeta><publicationMeta level="part" position="60"><doi origin="wiley" registered="yes">10.1002/humu.v31:6</doi><numberingGroup><numbering type="journalVolume" number="31">31</numbering><numbering type="journalIssue">6</numbering></numberingGroup><coverDate startDate="2010-06">June 2010</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="8" status="forIssue"><doi origin="wiley" registered="yes">10.1002/humu.21248</doi><idGroup><id type="unit" value="HUMU21248"></id></idGroup><countGroup><count type="pageTotal" number="7"></count></countGroup><titleGroup><title type="articleCategory">Research Article</title><title type="tocHeading1">Research Articles</title></titleGroup><copyright ownership="publisher">© 2010 Wiley‐Liss, Inc.</copyright><eventGroup><event type="manuscriptReceived" date="2009-11-23"></event><event type="manuscriptAccepted" date="2010-03-03"></event><event type="publishedOnlineAccepted" date="2010-03-25"></event><event type="publishedOnlineEarlyUnpaginated" date="2010-04-28"></event><event type="firstOnline" date="2010-03-25"></event><event type="publishedOnlineFinalForm" date="2010-05-25"></event><event type="xmlConverted" agent="Converter:JWSART34_TO_WML3G version:2.3.15 mode:FullText source:HeaderRef result:HeaderRef" date="2010-07-19"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-01-27"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-23"></event></eventGroup><numberingGroup><numbering type="pageFirst">685</numbering><numbering type="pageLast">691</numbering></numberingGroup><correspondenceTo>Department of General Biology, Faculty of Medicine, University of Patras, Rion, Patras, GR‐26500, Greece</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:HUMU.HUMU21248.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="3"></count><count type="tableTotal" number="0"></count><count type="referenceTotal" number="38"></count></countGroup><titleGroup><title type="main" xml:lang="en">Allelic imbalance of expression and epigenetic regulation within the alpha‐synuclein wild‐type and p.Ala53Thr alleles in Parkinson disease<link href="#fn1"></link></title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Gerassimos E.</givenNames><familyName>Voutsinas</familyName></personName></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Eleana F.</givenNames><familyName>Stavrou</familyName></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Gerassimos</givenNames><familyName>Karousos</familyName></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Aggeliki</givenNames><familyName>Dasoula</familyName></personName></creator><creator xml:id="au5" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Adamantia</givenNames><familyName>Papachatzopoulou</familyName></personName></creator><creator xml:id="au6" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Maria</givenNames><familyName>Syrrou</familyName></personName></creator><creator xml:id="au7" creatorRole="author" affiliationRef="#af4"><personName><givenNames>Annemieke J.M.H.</givenNames><familyName>Verkerk</familyName></personName></creator><creator xml:id="au8" creatorRole="author" affiliationRef="#af4"><personName><givenNames>Peter</givenNames><familyName>van der Spek</familyName></personName></creator><creator xml:id="au9" creatorRole="author" affiliationRef="#af4 #af5"><personName><givenNames>George P.</givenNames><familyName>Patrinos</familyName></personName></creator><creator xml:id="au10" creatorRole="author" affiliationRef="#af6" currentRef="#curr1"><personName><givenNames>Reinhard</givenNames><familyName>Stöger</familyName></personName></creator><creator xml:id="au11" creatorRole="author" affiliationRef="#af1" corresponding="yes"><personName><givenNames>Aglaia</givenNames><familyName>Athanassiadou</familyName></personName><contactDetails><email>athanass@med.upatras.gr</email></contactDetails></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="GR" type="organization"><unparsedAffiliation>Department of General Biology, School of Medicine, University of Patras, Patras, Greece</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="GR" type="organization"><unparsedAffiliation>Laboratory of Environmental Mutagenesis and Carcinogenesis, Institute of Biology, NCSR “Demokritos,” GR‐15310 Athens, Greece</unparsedAffiliation></affiliation><affiliation xml:id="af3" countryCode="GR" type="organization"><unparsedAffiliation>Laboratory of General Biology, School of Medicine, University of Ioannina, Ioannina, Greece</unparsedAffiliation></affiliation><affiliation xml:id="af4" countryCode="NL" type="organization"><unparsedAffiliation>Erasmus University Medical Center, Faculty of Medicine and Health Sciences, Department of Bioinformatics, Rotterdam, The Netherlands</unparsedAffiliation></affiliation><affiliation xml:id="af5" countryCode="GR" type="organization"><unparsedAffiliation>University of Patras, School of Health Sciences, Department of Pharmacy, Patras, Greece</unparsedAffiliation></affiliation><affiliation xml:id="af6" countryCode="US" type="organization"><unparsedAffiliation>Department of Biology, University of Washington, Seattle, Washington</unparsedAffiliation></affiliation><affiliation xml:id="curr1" countryCode="GB"><unparsedAffiliation>School of Biosciences, University of Nottingham, United Kingdom</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en" type="author"><keyword xml:id="kwd1">Parkinson</keyword><keyword xml:id="kwd2">alpha‐synuclein</keyword><keyword xml:id="kwd3"><i>SNCA</i></keyword><keyword xml:id="kwd4">monoallelic</keyword><keyword xml:id="kwd5">overexpression</keyword><keyword xml:id="kwd6">epigenetic</keyword></keywordGroup><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>Genetic alterations in the alpha‐synuclein (<i>SNCA</i>) gene have been implicated in Parkinson Disease (PD), including point mutations, gene multiplications, and sequence variations within the promoter. Such alterations may be involved in pathology through structural changes or overexpression of the protein leading to protein aggregation, as well as through impaired gene expression. It is, therefore, of importance to specify the parameters that regulate <i>SNCA</i> expression in its normal and mutated state. We studied the expression of <i>SNCA</i> alleles in a lymphoblastoid cell line and in the blood cells of a patient heterozygous for p.Ala53Thr, the first mutation to be implicated in PD pathogenesis. Here, we provide evidence that: (1) <i>SNCA</i> shows monoallelic expression in this patient, (2) epigenetic silencing of the mutated allele involves histone modifications but not DNA methylation, and (3) steady‐state mRNA levels deriving from the normal <i>SNCA</i> allele in this patient exceed those of the two normal <i>SNCA</i> alleles combined, in matching, control individuals. An imbalanced <i>SNCA</i> expression in this patient is thus documented, with silencing of the p.Ala53Thr allele and upregulation of the wild‐type‐allele. This phenomenon is demonstrated for a first time in the <i>SNCA</i> gene, and may have important implications for PD pathogenesis. Hum Mutat 31:1–7, 2010. © 2010 Wiley‐Liss, Inc.</p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="fn1"><p>Communicated by Christine Van Broeckhoven</p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Allelic imbalance of expression and epigenetic regulation within the alpha‐synuclein wild‐type and p.Ala53Thr alleles in Parkinson disease</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Allelic imbalance of expression and epigenetic regulation within the alpha‐synuclein wild‐type and p.Ala53Thr alleles in Parkinson disease</title></titleInfo><name type="personal"><namePart type="given">Gerassimos E.</namePart><namePart type="family">Voutsinas</namePart><affiliation>Department of General Biology, School of Medicine, University of Patras, Patras, Greece</affiliation><affiliation>Laboratory of Environmental Mutagenesis and Carcinogenesis, Institute of Biology, NCSR “Demokritos,” GR‐15310 Athens, Greece</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Eleana F.</namePart><namePart type="family">Stavrou</namePart><affiliation>Department of General Biology, School of Medicine, University of Patras, Patras, Greece</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Gerassimos</namePart><namePart type="family">Karousos</namePart><affiliation>Department of General Biology, School of Medicine, University of Patras, Patras, Greece</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Aggeliki</namePart><namePart type="family">Dasoula</namePart><affiliation>Laboratory of General Biology, School of Medicine, University of Ioannina, Ioannina, Greece</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Adamantia</namePart><namePart type="family">Papachatzopoulou</namePart><affiliation>Department of General Biology, School of Medicine, University of Patras, Patras, Greece</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Maria</namePart><namePart type="family">Syrrou</namePart><affiliation>Laboratory of General Biology, School of Medicine, University of Ioannina, Ioannina, Greece</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Annemieke J.M.H.</namePart><namePart type="family">Verkerk</namePart><affiliation>Erasmus University Medical Center, Faculty of Medicine and Health Sciences, Department of Bioinformatics, Rotterdam, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Peter</namePart><namePart type="family">van der Spek</namePart><affiliation>Erasmus University Medical Center, Faculty of Medicine and Health Sciences, Department of Bioinformatics, Rotterdam, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">George P.</namePart><namePart type="family">Patrinos</namePart><affiliation>Erasmus University Medical Center, Faculty of Medicine and Health Sciences, Department of Bioinformatics, Rotterdam, The Netherlands</affiliation><affiliation>University of Patras, School of Health Sciences, Department of Pharmacy, Patras, Greece</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Reinhard</namePart><namePart type="family">Stöger</namePart><affiliation>Department of Biology, University of Washington, Seattle, Washington</affiliation><affiliation>Current Address: School of Biosciences, University of Nottingham, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Aglaia</namePart><namePart type="family">Athanassiadou</namePart><affiliation>Department of General Biology, School of Medicine, University of Patras, Patras, Greece</affiliation><description>Correspondence: Department of General Biology, Faculty of Medicine, University of Patras, Rion, Patras, GR‐26500, Greece</description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><place><placeTerm type="text">Hoboken</placeTerm></place><dateIssued encoding="w3cdtf">2010-06</dateIssued><dateCaptured encoding="w3cdtf">2009-11-23</dateCaptured><dateValid encoding="w3cdtf">2010-03-03</dateValid><copyrightDate encoding="w3cdtf">2010</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">3</extent><extent unit="references">38</extent></physicalDescription><abstract lang="en">Genetic alterations in the alpha‐synuclein (SNCA) gene have been implicated in Parkinson Disease (PD), including point mutations, gene multiplications, and sequence variations within the promoter. Such alterations may be involved in pathology through structural changes or overexpression of the protein leading to protein aggregation, as well as through impaired gene expression. It is, therefore, of importance to specify the parameters that regulate SNCA expression in its normal and mutated state. We studied the expression of SNCA alleles in a lymphoblastoid cell line and in the blood cells of a patient heterozygous for p.Ala53Thr, the first mutation to be implicated in PD pathogenesis. Here, we provide evidence that: (1) SNCA shows monoallelic expression in this patient, (2) epigenetic silencing of the mutated allele involves histone modifications but not DNA methylation, and (3) steady‐state mRNA levels deriving from the normal SNCA allele in this patient exceed those of the two normal SNCA alleles combined, in matching, control individuals. An imbalanced SNCA expression in this patient is thus documented, with silencing of the p.Ala53Thr allele and upregulation of the wild‐type‐allele. This phenomenon is demonstrated for a first time in the SNCA gene, and may have important implications for PD pathogenesis. Hum Mutat 31:1–7, 2010. © 2010 Wiley‐Liss, Inc.</abstract><note type="content">*Communicated by Christine Van Broeckhoven</note><subject lang="en"><genre>Keywords</genre><topic>Parkinson</topic><topic>alpha‐synuclein</topic><topic>SNCA</topic><topic>monoallelic</topic><topic>overexpression</topic><topic>epigenetic</topic></subject><relatedItem type="host"><titleInfo><title>Human Mutation</title></titleInfo><titleInfo type="abbreviated"><title>Hum. Mutat.</title></titleInfo><genre type="Journal">journal</genre><subject><genre>article category</genre><topic>Research Article</topic></subject><identifier type="ISSN">1059-7794</identifier><identifier type="eISSN">1098-1004</identifier><identifier type="DOI">10.1002/(ISSN)1098-1004</identifier><identifier type="PublisherID">HUMU</identifier><part><date>2010</date><detail type="volume"><caption>vol.</caption><number>31</number></detail><detail type="issue"><caption>no.</caption><number>6</number></detail><extent unit="pages"><start>685</start><end>691</end><total>7</total></extent></part></relatedItem><identifier type="istex">0780772AEDD857BDB4A67C3DC98CFF472926E7B0</identifier><identifier type="DOI">10.1002/humu.21248</identifier><identifier type="ArticleID">HUMU21248</identifier><accessCondition type="use and reproduction" contentType="copyright">© 2010 Wiley‐Liss, Inc.</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Wiley Subscription Services, Inc., A Wiley Company</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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