SNCA locus duplication carriers: from genetics to Parkinson disease phenotypes
Identifieur interne : 000233 ( Main/Corpus ); précédent : 000232; suivant : 000234SNCA locus duplication carriers: from genetics to Parkinson disease phenotypes
Auteurs : Eugénie Mutez ; Frédéric Leprêtre ; Emilie Le Rhun ; Lydie Larvor ; Aurélie Duflot ; Vincent Mouroux ; Jean-Pierre Kerckaert ; Martin Figeac ; Kathy Dujardin ; Alain Destée ; Marie-Christine Chartier-HarlinSource :
- Human Mutation [ 1059-7794 ] ; 2011-04.
English descriptors
- KwdEn :
Abstract
Genomic multiplication of the alpha‐synuclein gene (SNCA) locus is one cause of familial Parkinson disease (PD). We performed detailed genomic, SNCA expression level, clinical, neuropsychological and functional imaging analyses of a parkinsonian kindred with a known duplication of the SNCA locus. We demonstrated that the duplication spanned 4.928 Mb (encompassing 31 known and putative genes) and was the largest to have been described at this locus. The presence of several repetitive long interspersed nuclear elements (LINEs) flanking the potential break area suggested that the duplication resulted from a genomic recombination between LINEs. We sequenced the break junction and confirmed the involvement of L1PA2 and L1PA4 in a non‐allelic, homologous recombination. An analysis of mRNA levels in immortalized lymphoblastoid cells and peripheral blood mononuclear cells showed SNCA overexpression in subjects with the duplication, as well as overexpression of 13 other genes highlighting the usefulness of such cell models to study this duplication. Interestingly, abnormal tracer uptake in DaTSCAN® imaging correlated with the severity of the clinical symptoms. Our detailed genomic analysis and clinical exploration enabled us to specify the genotype‐phenotype relationship, identify a case of presymptomatic PD and gain insight into the role of LINEs in SNCA locus duplication. © 2011 Wiley‐Liss, Inc.
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DOI: 10.1002/humu.21459
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France</mods:affiliation></affiliation><affiliation><mods:affiliation>Univ Lille Nord de France, Lille, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Functional Genomic Platform, UDSL, IRCL, Lille, France</mods:affiliation></affiliation></author><author><name sortKey="Le Rhun, Emilie" sort="Le Rhun, Emilie" uniqKey="Le Rhun E" first="Emilie" last="Le Rhun">Emilie Le Rhun</name><affiliation><mods:affiliation>Movement Disorders Unit, Lille University Hospital, Lille, France</mods:affiliation></affiliation></author><author><name sortKey="Larvor, Lydie" sort="Larvor, Lydie" uniqKey="Larvor L" first="Lydie" last="Larvor">Lydie Larvor</name><affiliation><mods:affiliation>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Univ Lille Nord de France, Lille, France</mods:affiliation></affiliation></author><author><name sortKey="Duflot, Aurelie" sort="Duflot, Aurelie" uniqKey="Duflot A" first="Aurélie" last="Duflot">Aurélie Duflot</name><affiliation><mods:affiliation>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Univ Lille Nord de France, Lille, France</mods:affiliation></affiliation></author><author><name sortKey="Mouroux, Vincent" sort="Mouroux, Vincent" uniqKey="Mouroux V" first="Vincent" last="Mouroux">Vincent Mouroux</name><affiliation><mods:affiliation>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Univ Lille Nord de France, Lille, France</mods:affiliation></affiliation></author><author><name sortKey="Kerckaert, Jean Ierre" sort="Kerckaert, Jean Ierre" uniqKey="Kerckaert J" first="Jean-Pierre" last="Kerckaert">Jean-Pierre Kerckaert</name><affiliation><mods:affiliation>Univ Lille Nord de France, Lille, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Functional Genomic Platform, UDSL, IRCL, Lille, France</mods:affiliation></affiliation></author><author><name sortKey="Figeac, Martin" sort="Figeac, Martin" uniqKey="Figeac M" first="Martin" last="Figeac">Martin Figeac</name><affiliation><mods:affiliation>Univ Lille Nord de France, Lille, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Functional Genomic Platform, UDSL, IRCL, Lille, France</mods:affiliation></affiliation></author><author><name sortKey="Dujardin, Kathy" sort="Dujardin, Kathy" uniqKey="Dujardin K" first="Kathy" last="Dujardin">Kathy Dujardin</name><affiliation><mods:affiliation>Univ Lille Nord de France, Lille, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Movement Disorders Unit, Lille University Hospital, Lille, France</mods:affiliation></affiliation></author><author><name sortKey="Destee, Alain" sort="Destee, Alain" uniqKey="Destee A" first="Alain" last="Destée">Alain Destée</name><affiliation><mods:affiliation>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Univ Lille Nord de France, Lille, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Movement Disorders Unit, Lille University Hospital, Lille, France</mods:affiliation></affiliation></author><author><name sortKey="Chartier Arlin, Marie Hristine" sort="Chartier Arlin, Marie Hristine" uniqKey="Chartier Arlin M" first="Marie-Christine" last="Chartier-Harlin">Marie-Christine Chartier-Harlin</name><affiliation><mods:affiliation>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Univ Lille Nord de France, Lille, France</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Human Mutation</title><title level="j" type="abbrev">Hum. Mutat.</title><idno type="ISSN">1059-7794</idno><idno type="eISSN">1098-1004</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2011-04">2011-04</date><biblScope unit="volume">32</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="E2079">E2079</biblScope><biblScope unit="page" to="E2090">E2090</biblScope></imprint><idno type="ISSN">1059-7794</idno></series><idno type="istex">243F2079A57EA35B36E0946D26003F3E82592C16</idno><idno type="DOI">10.1002/humu.21459</idno><idno type="ArticleID">HUMU21459</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1059-7794</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Parkinson</term><term>SNCA</term><term>alpha‐synuclein</term><term>duplication</term><term>overexpression</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Genomic multiplication of the alpha‐synuclein gene (SNCA) locus is one cause of familial Parkinson disease (PD). We performed detailed genomic, SNCA expression level, clinical, neuropsychological and functional imaging analyses of a parkinsonian kindred with a known duplication of the SNCA locus. We demonstrated that the duplication spanned 4.928 Mb (encompassing 31 known and putative genes) and was the largest to have been described at this locus. The presence of several repetitive long interspersed nuclear elements (LINEs) flanking the potential break area suggested that the duplication resulted from a genomic recombination between LINEs. We sequenced the break junction and confirmed the involvement of L1PA2 and L1PA4 in a non‐allelic, homologous recombination. An analysis of mRNA levels in immortalized lymphoblastoid cells and peripheral blood mononuclear cells showed SNCA overexpression in subjects with the duplication, as well as overexpression of 13 other genes highlighting the usefulness of such cell models to study this duplication. Interestingly, abnormal tracer uptake in DaTSCAN® imaging correlated with the severity of the clinical symptoms. Our detailed genomic analysis and clinical exploration enabled us to specify the genotype‐phenotype relationship, identify a case of presymptomatic PD and gain insight into the role of LINEs in SNCA locus duplication. © 2011 Wiley‐Liss, Inc.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Eugénie Mutez</name><affiliations><json:string>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</json:string><json:string>Univ Lille Nord de France, Lille, France</json:string><json:string>Movement Disorders Unit, Lille University Hospital, Lille, France</json:string></affiliations></json:item><json:item><name>Frédéric Leprêtre</name><affiliations><json:string>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</json:string><json:string>Univ Lille Nord de France, Lille, France</json:string><json:string>Functional Genomic Platform, UDSL, IRCL, Lille, France</json:string></affiliations></json:item><json:item><name>Emilie Le Rhun</name><affiliations><json:string>Movement Disorders Unit, Lille University Hospital, Lille, France</json:string></affiliations></json:item><json:item><name>Lydie Larvor</name><affiliations><json:string>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</json:string><json:string>Univ Lille Nord de France, Lille, France</json:string></affiliations></json:item><json:item><name>Aurélie Duflot</name><affiliations><json:string>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</json:string><json:string>Univ Lille Nord de France, Lille, France</json:string></affiliations></json:item><json:item><name>Vincent Mouroux</name><affiliations><json:string>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</json:string><json:string>Univ Lille Nord de France, Lille, France</json:string></affiliations></json:item><json:item><name>Jean‐Pierre Kerckaert</name><affiliations><json:string>Univ Lille Nord de France, Lille, France</json:string><json:string>Functional Genomic Platform, UDSL, IRCL, Lille, France</json:string></affiliations></json:item><json:item><name>Martin Figeac</name><affiliations><json:string>Univ Lille Nord de France, Lille, France</json:string><json:string>Functional Genomic Platform, UDSL, IRCL, Lille, France</json:string></affiliations></json:item><json:item><name>Kathy Dujardin</name><affiliations><json:string>Univ Lille Nord de France, Lille, France</json:string><json:string>Movement Disorders Unit, Lille University Hospital, Lille, France</json:string></affiliations></json:item><json:item><name>Alain Destée</name><affiliations><json:string>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</json:string><json:string>Univ Lille Nord de France, Lille, France</json:string><json:string>Movement Disorders Unit, Lille University Hospital, Lille, France</json:string></affiliations></json:item><json:item><name>Marie‐Christine Chartier‐Harlin</name><affiliations><json:string>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</json:string><json:string>Univ Lille Nord de France, Lille, France</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>duplication</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>overexpression</value></json:item></subject><articleId><json:string>HUMU21459</json:string></articleId><language><json:string>eng</json:string></language><abstract>Genomic multiplication of the alpha‐synuclein gene (SNCA) locus is one cause of familial Parkinson disease (PD). We performed detailed genomic, SNCA expression level, clinical, neuropsychological and functional imaging analyses of a parkinsonian kindred with a known duplication of the SNCA locus. We demonstrated that the duplication spanned 4.928 Mb (encompassing 31 known and putative genes) and was the largest to have been described at this locus. The presence of several repetitive long interspersed nuclear elements (LINEs) flanking the potential break area suggested that the duplication resulted from a genomic recombination between LINEs. We sequenced the break junction and confirmed the involvement of L1PA2 and L1PA4 in a non‐allelic, homologous recombination. An analysis of mRNA levels in immortalized lymphoblastoid cells and peripheral blood mononuclear cells showed SNCA overexpression in subjects with the duplication, as well as overexpression of 13 other genes highlighting the usefulness of such cell models to study this duplication. Interestingly, abnormal tracer uptake in DaTSCAN® imaging correlated with the severity of the clinical symptoms. Our detailed genomic analysis and clinical exploration enabled us to specify the genotype‐phenotype relationship, identify a case of presymptomatic PD and gain insight into the role of LINEs in SNCA locus duplication. © 2011 Wiley‐Liss, Inc.</abstract><qualityIndicators><score>7.924</score><pdfVersion>1.4</pdfVersion><pdfPageSize>612 x 792 pts (letter)</pdfPageSize><refBibsNative>false</refBibsNative><keywordCount>5</keywordCount><abstractCharCount>1411</abstractCharCount><pdfWordCount>5751</pdfWordCount><pdfCharCount>37130</pdfCharCount><pdfPageCount>12</pdfPageCount><abstractWordCount>202</abstractWordCount></qualityIndicators><title>SNCA locus duplication carriers: from genetics to Parkinson disease phenotypes</title><genre><json:string>brief communication</json:string></genre><host><volume>32</volume><publisherId><json:string>HUMU</json:string></publisherId><pages><total>12</total><last>E2090</last><first>E2079</first></pages><issn><json:string>1059-7794</json:string></issn><issue>4</issue><subject><json:item><value>Mutation in Brief</value></json:item></subject><genre><json:string>Journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1098-1004</json:string></eissn><title>Human Mutation</title><doi><json:string>10.1002/(ISSN)1098-1004</json:string></doi></host><publicationDate>2011</publicationDate><copyrightDate>2011</copyrightDate><doi><json:string>10.1002/humu.21459</json:string></doi><id>243F2079A57EA35B36E0946D26003F3E82592C16</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/243F2079A57EA35B36E0946D26003F3E82592C16/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/243F2079A57EA35B36E0946D26003F3E82592C16/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/243F2079A57EA35B36E0946D26003F3E82592C16/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">SNCA locus duplication carriers: from genetics to Parkinson disease phenotypes</title><respStmt xml:id="ISTEX-API" resp="Références bibliographiques récupérées via GROBID" name="ISTEX-API (INIST-CNRS)"></respStmt></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><availability><p>WILEY</p></availability><date>2011</date></publicationStmt><notesStmt><note type="content">*Communicated by Christine Van Broeckhoven</note><note>Univ Lille Nord de France, INSERM, Lille University Hospital, French Ministry of Research - No. PHRC PARKFANORD (2005/1914).;</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">SNCA locus duplication carriers: from genetics to Parkinson disease phenotypes</title><author><persName><forename type="first">Eugénie</forename><surname>Mutez</surname></persName><note type="biography">These authors contributed equally to the study</note><affiliation>These authors contributed equally to the study</affiliation><affiliation>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</affiliation><affiliation>Univ Lille Nord de France, Lille, France</affiliation><affiliation>Movement Disorders Unit, Lille University Hospital, Lille, France</affiliation></author><author><persName><forename type="first">Frédéric</forename><surname>Leprêtre</surname></persName><note type="biography">These authors contributed equally to the study</note><affiliation>These authors contributed equally to the study</affiliation><affiliation>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</affiliation><affiliation>Univ Lille Nord de France, Lille, France</affiliation><affiliation>Functional Genomic Platform, UDSL, IRCL, Lille, France</affiliation></author><author><persName><forename type="first">Emilie</forename><surname>Le Rhun</surname></persName><note type="biography">These authors contributed equally to the study</note><affiliation>These authors contributed equally to the study</affiliation><affiliation>Movement Disorders Unit, Lille University Hospital, Lille, France</affiliation></author><author><persName><forename type="first">Lydie</forename><surname>Larvor</surname></persName><note type="biography">These authors contributed equally to the study</note><affiliation>These authors contributed equally to the study</affiliation><affiliation>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</affiliation><affiliation>Univ Lille Nord de France, Lille, France</affiliation></author><author><persName><forename type="first">Aurélie</forename><surname>Duflot</surname></persName><affiliation>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</affiliation><affiliation>Univ Lille Nord de France, Lille, France</affiliation></author><author><persName><forename type="first">Vincent</forename><surname>Mouroux</surname></persName><affiliation>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</affiliation><affiliation>Univ Lille Nord de France, Lille, France</affiliation></author><author><persName><forename type="first">Jean‐Pierre</forename><surname>Kerckaert</surname></persName><affiliation>Univ Lille Nord de France, Lille, France</affiliation><affiliation>Functional Genomic Platform, UDSL, IRCL, Lille, France</affiliation></author><author><persName><forename type="first">Martin</forename><surname>Figeac</surname></persName><affiliation>Univ Lille Nord de France, Lille, France</affiliation><affiliation>Functional Genomic Platform, UDSL, IRCL, Lille, France</affiliation></author><author><persName><forename type="first">Kathy</forename><surname>Dujardin</surname></persName><affiliation>Univ Lille Nord de France, Lille, France</affiliation><affiliation>Movement Disorders Unit, Lille University Hospital, Lille, France</affiliation></author><author><persName><forename type="first">Alain</forename><surname>Destée</surname></persName><affiliation>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</affiliation><affiliation>Univ Lille Nord de France, Lille, France</affiliation><affiliation>Movement Disorders Unit, Lille University Hospital, Lille, France</affiliation></author><author><persName><forename type="first">Marie‐Christine</forename><surname>Chartier‐Harlin</surname></persName><note type="correspondence"><p>Correspondence: UMR 837 INSERM, Team 6, JParc, IRCL, Place de Verdun, 59045 Lille Cedex, France</p></note><affiliation>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</affiliation><affiliation>Univ Lille Nord de France, Lille, France</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="2011-04"></date><biblScope unit="volume">32</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="E2079">E2079</biblScope><biblScope unit="page" to="E2090">E2090</biblScope></imprint></monogr><idno type="istex">243F2079A57EA35B36E0946D26003F3E82592C16</idno><idno type="DOI">10.1002/humu.21459</idno><idno type="ArticleID">HUMU21459</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2011</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Genomic multiplication of the alpha‐synuclein gene (SNCA) locus is one cause of familial Parkinson disease (PD). We performed detailed genomic, SNCA expression level, clinical, neuropsychological and functional imaging analyses of a parkinsonian kindred with a known duplication of the SNCA locus. We demonstrated that the duplication spanned 4.928 Mb (encompassing 31 known and putative genes) and was the largest to have been described at this locus. The presence of several repetitive long interspersed nuclear elements (LINEs) flanking the potential break area suggested that the duplication resulted from a genomic recombination between LINEs. We sequenced the break junction and confirmed the involvement of L1PA2 and L1PA4 in a non‐allelic, homologous recombination. An analysis of mRNA levels in immortalized lymphoblastoid cells and peripheral blood mononuclear cells showed SNCA overexpression in subjects with the duplication, as well as overexpression of 13 other genes highlighting the usefulness of such cell models to study this duplication. Interestingly, abnormal tracer uptake in DaTSCAN® imaging correlated with the severity of the clinical symptoms. Our detailed genomic analysis and clinical exploration enabled us to specify the genotype‐phenotype relationship, identify a case of presymptomatic PD and gain insight into the role of LINEs in SNCA locus duplication. © 2011 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>duplication</term></item><item><term>overexpression</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>article category</head><item><term>Mutation in Brief</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2010-10-18">Received</change><change when="2011-01-12">Registration</change><change when="2011-04">Published</change><change xml:id="refBibs-istex" who="#ISTEX-API" when="2016-3-3">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/243F2079A57EA35B36E0946D26003F3E82592C16/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley component found"><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. 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type="referenceTotal" number="29"></count></countGroup><titleGroup><title type="main" xml:lang="en">SNCA locus duplication carriers: from genetics to Parkinson disease phenotypes<link href="#fn1"></link></title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1 #af2 #af3" noteRef="#fn2"><personName><givenNames>Eugénie</givenNames><familyName>Mutez</familyName></personName></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af1 #af2 #af4" noteRef="#fn2"><personName><givenNames>Frédéric</givenNames><familyName>Leprêtre</familyName></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af3" noteRef="#fn2"><personName><givenNames>Emilie</givenNames><familyName>Le Rhun</familyName></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af1 #af2" noteRef="#fn2"><personName><givenNames>Lydie</givenNames><familyName>Larvor</familyName></personName></creator><creator xml:id="au5" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Aurélie</givenNames><familyName>Duflot</familyName></personName></creator><creator xml:id="au6" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Vincent</givenNames><familyName>Mouroux</familyName></personName></creator><creator xml:id="au7" creatorRole="author" affiliationRef="#af2 #af4"><personName><givenNames>Jean‐Pierre</givenNames><familyName>Kerckaert</familyName></personName></creator><creator xml:id="au8" creatorRole="author" affiliationRef="#af2 #af4"><personName><givenNames>Martin</givenNames><familyName>Figeac</familyName></personName></creator><creator xml:id="au9" creatorRole="author" affiliationRef="#af2 #af3"><personName><givenNames>Kathy</givenNames><familyName>Dujardin</familyName></personName></creator><creator xml:id="au10" creatorRole="author" affiliationRef="#af1 #af2 #af3"><personName><givenNames>Alain</givenNames><familyName>Destée</familyName></personName></creator><creator xml:id="au11" creatorRole="author" affiliationRef="#af1 #af2" corresponding="yes"><personName><givenNames>Marie‐Christine</givenNames><familyName>Chartier‐Harlin</familyName></personName><contactDetails><email normalForm="marie-christine.chartier-harlin@inserm.fr">marie‐christine.chartier‐harlin@inserm.fr</email></contactDetails></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="FR" type="organization"><unparsedAffiliation>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="FR" type="organization"><unparsedAffiliation>Univ Lille Nord de France, Lille, France</unparsedAffiliation></affiliation><affiliation xml:id="af3" countryCode="FR" type="organization"><unparsedAffiliation>Movement Disorders Unit, Lille University Hospital, Lille, France</unparsedAffiliation></affiliation><affiliation xml:id="af4" countryCode="FR" type="organization"><unparsedAffiliation>Functional Genomic Platform, UDSL, IRCL, Lille, France</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">duplication</keyword><keyword xml:id="kwd5">overexpression</keyword></keywordGroup><fundingInfo><fundingAgency>Univ Lille Nord de France, INSERM, Lille University Hospital, French Ministry of Research</fundingAgency><fundingNumber>PHRC PARKFANORD (2005/1914).</fundingNumber></fundingInfo><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>Genomic multiplication of the alpha‐synuclein gene (<i>SNCA</i>) locus is one cause of familial Parkinson disease (PD). We performed detailed genomic, <i>SNCA</i> expression level, clinical, neuropsychological and functional imaging analyses of a parkinsonian kindred with a known duplication of the <i>SNCA</i> locus. We demonstrated that the duplication spanned 4.928 Mb (encompassing 31 known and putative genes) and was the largest to have been described at this locus. The presence of several repetitive long interspersed nuclear elements (LINEs) flanking the potential break area suggested that the duplication resulted from a genomic recombination between LINEs. We sequenced the break junction and confirmed the involvement of L1PA2 and L1PA4 in a non‐allelic, homologous recombination. An analysis of mRNA levels in immortalized lymphoblastoid cells and peripheral blood mononuclear cells showed <i>SNCA</i> overexpression in subjects with the duplication, as well as overexpression of 13 other genes highlighting the usefulness of such cell models to study this duplication. Interestingly, abnormal tracer uptake in DaTSCAN<sup>®</sup> imaging correlated with the severity of the clinical symptoms. Our detailed genomic analysis and clinical exploration enabled us to specify the genotype‐phenotype relationship, identify a case of presymptomatic PD and gain insight into the role of LINEs in <i>SNCA</i> locus duplication. © 2011 Wiley‐Liss, Inc.</p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="fn1"><p>Communicated by Christine Van Broeckhoven</p></note><note xml:id="fn2"><p>These authors contributed equally to the study</p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>SNCA locus duplication carriers: from genetics to Parkinson disease phenotypes</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>SNCA locus duplication carriers: from genetics to Parkinson disease phenotypes</title></titleInfo><name type="personal"><namePart type="given">Eugénie</namePart><namePart type="family">Mutez</namePart><affiliation>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</affiliation><affiliation>Univ Lille Nord de France, Lille, France</affiliation><affiliation>Movement Disorders Unit, Lille University Hospital, Lille, France</affiliation><description>These authors contributed equally to the study</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Frédéric</namePart><namePart type="family">Leprêtre</namePart><affiliation>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</affiliation><affiliation>Univ Lille Nord de France, Lille, France</affiliation><affiliation>Functional Genomic Platform, UDSL, IRCL, Lille, France</affiliation><description>These authors contributed equally to the study</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Emilie</namePart><namePart type="family">Le Rhun</namePart><affiliation>Movement Disorders Unit, Lille University Hospital, Lille, France</affiliation><description>These authors contributed equally to the study</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Lydie</namePart><namePart type="family">Larvor</namePart><affiliation>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</affiliation><affiliation>Univ Lille Nord de France, Lille, France</affiliation><description>These authors contributed equally to the study</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Aurélie</namePart><namePart type="family">Duflot</namePart><affiliation>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</affiliation><affiliation>Univ Lille Nord de France, Lille, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Vincent</namePart><namePart type="family">Mouroux</namePart><affiliation>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</affiliation><affiliation>Univ Lille Nord de France, Lille, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jean‐Pierre</namePart><namePart type="family">Kerckaert</namePart><affiliation>Univ Lille Nord de France, Lille, France</affiliation><affiliation>Functional Genomic Platform, UDSL, IRCL, Lille, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Martin</namePart><namePart type="family">Figeac</namePart><affiliation>Univ Lille Nord de France, Lille, France</affiliation><affiliation>Functional Genomic Platform, UDSL, IRCL, Lille, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kathy</namePart><namePart type="family">Dujardin</namePart><affiliation>Univ Lille Nord de France, Lille, France</affiliation><affiliation>Movement Disorders Unit, Lille University Hospital, Lille, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alain</namePart><namePart type="family">Destée</namePart><affiliation>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</affiliation><affiliation>Univ Lille Nord de France, Lille, France</affiliation><affiliation>Movement Disorders Unit, Lille University Hospital, Lille, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Marie‐Christine</namePart><namePart type="family">Chartier‐Harlin</namePart><affiliation>UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France</affiliation><affiliation>Univ Lille Nord de France, Lille, France</affiliation><description>Correspondence: UMR 837 INSERM, Team 6, JParc, IRCL, Place de Verdun, 59045 Lille Cedex, France</description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="brief communication" displayLabel="shortCommunication"></genre><originInfo><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><place><placeTerm type="text">Hoboken</placeTerm></place><dateIssued encoding="w3cdtf">2011-04</dateIssued><dateCaptured encoding="w3cdtf">2010-10-18</dateCaptured><dateValid encoding="w3cdtf">2011-01-12</dateValid><copyrightDate encoding="w3cdtf">2011</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">4</extent><extent unit="tables">1</extent><extent unit="references">29</extent></physicalDescription><abstract lang="en">Genomic multiplication of the alpha‐synuclein gene (SNCA) locus is one cause of familial Parkinson disease (PD). We performed detailed genomic, SNCA expression level, clinical, neuropsychological and functional imaging analyses of a parkinsonian kindred with a known duplication of the SNCA locus. We demonstrated that the duplication spanned 4.928 Mb (encompassing 31 known and putative genes) and was the largest to have been described at this locus. The presence of several repetitive long interspersed nuclear elements (LINEs) flanking the potential break area suggested that the duplication resulted from a genomic recombination between LINEs. We sequenced the break junction and confirmed the involvement of L1PA2 and L1PA4 in a non‐allelic, homologous recombination. An analysis of mRNA levels in immortalized lymphoblastoid cells and peripheral blood mononuclear cells showed SNCA overexpression in subjects with the duplication, as well as overexpression of 13 other genes highlighting the usefulness of such cell models to study this duplication. Interestingly, abnormal tracer uptake in DaTSCAN® imaging correlated with the severity of the clinical symptoms. Our detailed genomic analysis and clinical exploration enabled us to specify the genotype‐phenotype relationship, identify a case of presymptomatic PD and gain insight into the role of LINEs in SNCA locus duplication. © 2011 Wiley‐Liss, Inc.</abstract><note type="content">*Communicated by Christine Van Broeckhoven</note><note type="funding">Univ Lille Nord de France, INSERM, Lille University Hospital, French Ministry of Research - No. PHRC PARKFANORD (2005/1914).; </note><subject lang="en"><genre>Keywords</genre><topic>Parkinson</topic><topic>alpha‐synuclein</topic><topic>SNCA</topic><topic>duplication</topic><topic>overexpression</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>Mutation in Brief</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>2011</date><detail type="volume"><caption>vol.</caption><number>32</number></detail><detail type="issue"><caption>no.</caption><number>4</number></detail><extent unit="pages"><start>E2079</start><end>E2090</end><total>12</total></extent></part></relatedItem><identifier type="istex">243F2079A57EA35B36E0946D26003F3E82592C16</identifier><identifier type="DOI">10.1002/humu.21459</identifier><identifier type="ArticleID">HUMU21459</identifier><accessCondition type="use and reproduction" contentType="copyright">© 2011 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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