GCH1 in early‐onset Parkinson's disease
Identifieur interne : 002426 ( Main/Corpus ); précédent : 002425; suivant : 002427GCH1 in early‐onset Parkinson's disease
Auteurs : Stephanie A. Cobb ; Christian Wider ; Owen A. Ross ; Ignacio F. Mata ; Charles H. Adler ; Alex Rajput ; Ali H. Rajput ; Ruey-Meei Wu ; Robert Hauser ; Keith A. Josephs ; Jonathan Carr ; Katrina Gwinn ; Michael G. Heckman ; Jan O. Aasly ; Timothy Lynch ; Ryan J. Uitti ; Zbigniew K. Wszolek ; Gregory Kapatos ; Matthew J. FarrerSource :
- Movement Disorders [ 0885-3185 ] ; 2009-10-30.
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Abstract
Mutations in GTP‐cyclohydrolase 1 (GCH1) cause autosomal dominant dopa‐responsive dystonia (DRD), characterized by childhood‐onset foot dystonia that later generalizes. DRD patients frequently present with associated Parkinsonism. Conversely, early‐onset Parkinson's disease (EOPD) patients commonly display dystonia. Herein, we investigated the frequency of GCH1 mutations in a series of 53 familial EOPD patients (21 with dystonia) and screened them for mutations in PRKN, PINK1, and DJ‐1. In addition, we examined a matched EOPD patient–control series for association of common variability at the GCH1 locus and EOPD susceptibility. No GCH1 coding change or copy‐number abnormality was identified in familial EOPD patients. A novel 18‐bp deletion was found in the proximal promoter (two patients, one control), which is expected to knock out two regulatory elements previously shown to regulate GCH1 transcription. No association was found between GCH1 variability and risk of EOPD. Fourteen (26.4%) familial EOPD patients had homozygous or compound heterozygous PRKN mutations. PRKN‐positive patients were 10 years younger than PRKN‐negative patients and had a twofold higher prevalence of dystonia. This study does not support a significant role for genetic variation at the GCH1 locus in EOPD. However, our results further highlight the relevance of PRKN screening in familial EOPD. © 2009 Movement Disorder Society
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DOI: 10.1002/mds.22729
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Cobb</name><affiliation><mods:affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</mods:affiliation></affiliation></author><author><name sortKey="Wider, Christian" sort="Wider, Christian" uniqKey="Wider C" first="Christian" last="Wider">Christian Wider</name><affiliation><mods:affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA</mods:affiliation></affiliation></author><author><name sortKey="Ross, Owen A" sort="Ross, Owen A" uniqKey="Ross O" first="Owen A." last="Ross">Owen A. Ross</name><affiliation><mods:affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</mods:affiliation></affiliation></author><author><name sortKey="Mata, Ignacio F" sort="Mata, Ignacio F" uniqKey="Mata I" first="Ignacio F." last="Mata">Ignacio F. Mata</name><affiliation><mods:affiliation>Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA</mods:affiliation></affiliation></author><author><name sortKey="Adler, Charles H" sort="Adler, Charles H" uniqKey="Adler C" first="Charles H." last="Adler">Charles H. Adler</name><affiliation><mods:affiliation>Department of Neurology, Mayo Clinic, Scottsdale, Arizona, USA</mods:affiliation></affiliation></author><author><name sortKey="Rajput, Alex" sort="Rajput, Alex" uniqKey="Rajput A" first="Alex" last="Rajput">Alex Rajput</name><affiliation><mods:affiliation>Division of Neurology, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, Canada</mods:affiliation></affiliation></author><author><name sortKey="Rajput, Ali H" sort="Rajput, Ali H" uniqKey="Rajput A" first="Ali H." last="Rajput">Ali H. Rajput</name><affiliation><mods:affiliation>Division of Neurology, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, Canada</mods:affiliation></affiliation></author><author><name sortKey="Wu, Ruey Eei" sort="Wu, Ruey Eei" uniqKey="Wu R" first="Ruey-Meei" last="Wu">Ruey-Meei Wu</name><affiliation><mods:affiliation>Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan</mods:affiliation></affiliation></author><author><name sortKey="Hauser, Robert" sort="Hauser, Robert" uniqKey="Hauser R" first="Robert" last="Hauser">Robert Hauser</name><affiliation><mods:affiliation>Department of Neurology, University of South Florida, Tampa, Florida, USA</mods:affiliation></affiliation></author><author><name sortKey="Josephs, Keith A" sort="Josephs, Keith A" uniqKey="Josephs K" first="Keith A." last="Josephs">Keith A. Josephs</name><affiliation><mods:affiliation>Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA</mods:affiliation></affiliation></author><author><name sortKey="Carr, Jonathan" sort="Carr, Jonathan" uniqKey="Carr J" first="Jonathan" last="Carr">Jonathan Carr</name><affiliation><mods:affiliation>Neurophysiology Laboratory, University of Stellenbosch, Tygerberg Hospital, Tygerberg, South Africa</mods:affiliation></affiliation></author><author><name sortKey="Gwinn, Katrina" sort="Gwinn, Katrina" uniqKey="Gwinn K" first="Katrina" last="Gwinn">Katrina Gwinn</name><affiliation><mods:affiliation>Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA</mods:affiliation></affiliation></author><author><name sortKey="Heckman, Michael G" sort="Heckman, Michael G" uniqKey="Heckman M" first="Michael G." last="Heckman">Michael G. Heckman</name><affiliation><mods:affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</mods:affiliation></affiliation></author><author><name sortKey="Aasly, Jan O" sort="Aasly, Jan O" uniqKey="Aasly J" first="Jan O." last="Aasly">Jan O. Aasly</name><affiliation><mods:affiliation>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</mods:affiliation></affiliation></author><author><name sortKey="Lynch, Timothy" sort="Lynch, Timothy" uniqKey="Lynch T" first="Timothy" last="Lynch">Timothy Lynch</name><affiliation><mods:affiliation>Dublin Neurological Institute at the Mater Misericordiae University Hospital, Dublin, Ireland</mods:affiliation></affiliation></author><author><name sortKey="Uitti, Ryan J" sort="Uitti, Ryan J" uniqKey="Uitti R" first="Ryan J." last="Uitti">Ryan J. Uitti</name><affiliation><mods:affiliation>Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA</mods:affiliation></affiliation></author><author><name sortKey="Wszolek, Zbigniew K" sort="Wszolek, Zbigniew K" uniqKey="Wszolek Z" first="Zbigniew K." last="Wszolek">Zbigniew K. Wszolek</name><affiliation><mods:affiliation>Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA</mods:affiliation></affiliation></author><author><name sortKey="Kapatos, Gregory" sort="Kapatos, Gregory" uniqKey="Kapatos G" first="Gregory" last="Kapatos">Gregory Kapatos</name><affiliation><mods:affiliation>Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan, USA</mods:affiliation></affiliation></author><author><name sortKey="Farrer, Matthew J" sort="Farrer, Matthew J" uniqKey="Farrer M" first="Matthew J." last="Farrer">Matthew J. Farrer</name><affiliation><mods:affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Movement Disorders</title><title level="j" type="sub">Official Journal of the Movement Disorder Society</title><title level="j" type="abbrev">Mov. Disord.</title><idno type="ISSN">0885-3185</idno><idno type="eISSN">1531-8257</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2009-10-30">2009-10-30</date><biblScope unit="volume">24</biblScope><biblScope unit="issue">14</biblScope><biblScope unit="page" from="2070">2070</biblScope><biblScope unit="page" to="2075">2075</biblScope></imprint><idno type="ISSN">0885-3185</idno></series><idno type="istex">E7C772768873F2B1C9F41CA093BBEBCB51710992</idno><idno type="DOI">10.1002/mds.22729</idno><idno type="ArticleID">MDS22729</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0885-3185</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>DRD</term><term>GCH1</term><term>PRKN</term><term>Parkinson's disease</term><term>dopa‐responsive dystonia</term><term>early‐onset Parkinson's disease</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Mutations in GTP‐cyclohydrolase 1 (GCH1) cause autosomal dominant dopa‐responsive dystonia (DRD), characterized by childhood‐onset foot dystonia that later generalizes. DRD patients frequently present with associated Parkinsonism. Conversely, early‐onset Parkinson's disease (EOPD) patients commonly display dystonia. Herein, we investigated the frequency of GCH1 mutations in a series of 53 familial EOPD patients (21 with dystonia) and screened them for mutations in PRKN, PINK1, and DJ‐1. In addition, we examined a matched EOPD patient–control series for association of common variability at the GCH1 locus and EOPD susceptibility. No GCH1 coding change or copy‐number abnormality was identified in familial EOPD patients. A novel 18‐bp deletion was found in the proximal promoter (two patients, one control), which is expected to knock out two regulatory elements previously shown to regulate GCH1 transcription. No association was found between GCH1 variability and risk of EOPD. Fourteen (26.4%) familial EOPD patients had homozygous or compound heterozygous PRKN mutations. PRKN‐positive patients were 10 years younger than PRKN‐negative patients and had a twofold higher prevalence of dystonia. This study does not support a significant role for genetic variation at the GCH1 locus in EOPD. However, our results further highlight the relevance of PRKN screening in familial EOPD. © 2009 Movement Disorder Society</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Stephanie A. Cobb BA</name><affiliations><json:string>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</json:string></affiliations></json:item><json:item><name>Christian Wider MD</name><affiliations><json:string>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</json:string><json:string>Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA</json:string></affiliations></json:item><json:item><name>Owen A. Ross PhD</name><affiliations><json:string>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</json:string></affiliations></json:item><json:item><name>Ignacio F. Mata PhD</name><affiliations><json:string>Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA</json:string></affiliations></json:item><json:item><name>Charles H. Adler MD, PhD</name><affiliations><json:string>Department of Neurology, Mayo Clinic, Scottsdale, Arizona, USA</json:string></affiliations></json:item><json:item><name>Alex Rajput FRCPC</name><affiliations><json:string>Division of Neurology, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, Canada</json:string></affiliations></json:item><json:item><name>Ali H. Rajput FRCPC</name><affiliations><json:string>Division of Neurology, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, Canada</json:string></affiliations></json:item><json:item><name>Ruey‐Meei Wu MD, PhD</name><affiliations><json:string>Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan</json:string></affiliations></json:item><json:item><name>Robert Hauser MD</name><affiliations><json:string>Department of Neurology, University of South Florida, Tampa, Florida, USA</json:string></affiliations></json:item><json:item><name>Keith A. Josephs MD</name><affiliations><json:string>Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA</json:string></affiliations></json:item><json:item><name>Jonathan Carr MD</name><affiliations><json:string>Neurophysiology Laboratory, University of Stellenbosch, Tygerberg Hospital, Tygerberg, South Africa</json:string></affiliations></json:item><json:item><name>Katrina Gwinn MD</name><affiliations><json:string>Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA</json:string></affiliations></json:item><json:item><name>Michael G. Heckman MS</name><affiliations><json:string>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</json:string></affiliations></json:item><json:item><name>Jan O. Aasly MD, PhD</name><affiliations><json:string>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</json:string></affiliations></json:item><json:item><name>Timothy Lynch MD</name><affiliations><json:string>Dublin Neurological Institute at the Mater Misericordiae University Hospital, Dublin, Ireland</json:string></affiliations></json:item><json:item><name>Ryan J. Uitti MD</name><affiliations><json:string>Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA</json:string></affiliations></json:item><json:item><name>Zbigniew K. Wszolek MD</name><affiliations><json:string>Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA</json:string></affiliations></json:item><json:item><name>Gregory Kapatos PhD</name><affiliations><json:string>Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan, USA</json:string></affiliations></json:item><json:item><name>Matthew J. Farrer PhD</name><affiliations><json:string>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>GCH1</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Parkinson's disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>dopa‐responsive dystonia</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>DRD</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>PRKN</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>early‐onset Parkinson's disease</value></json:item></subject><articleId><json:string>MDS22729</json:string></articleId><language><json:string>eng</json:string></language><abstract>Mutations in GTP‐cyclohydrolase 1 (GCH1) cause autosomal dominant dopa‐responsive dystonia (DRD), characterized by childhood‐onset foot dystonia that later generalizes. DRD patients frequently present with associated Parkinsonism. Conversely, early‐onset Parkinson's disease (EOPD) patients commonly display dystonia. Herein, we investigated the frequency of GCH1 mutations in a series of 53 familial EOPD patients (21 with dystonia) and screened them for mutations in PRKN, PINK1, and DJ‐1. In addition, we examined a matched EOPD patient–control series for association of common variability at the GCH1 locus and EOPD susceptibility. No GCH1 coding change or copy‐number abnormality was identified in familial EOPD patients. A novel 18‐bp deletion was found in the proximal promoter (two patients, one control), which is expected to knock out two regulatory elements previously shown to regulate GCH1 transcription. No association was found between GCH1 variability and risk of EOPD. Fourteen (26.4%) familial EOPD patients had homozygous or compound heterozygous PRKN mutations. PRKN‐positive patients were 10 years younger than PRKN‐negative patients and had a twofold higher prevalence of dystonia. This study does not support a significant role for genetic variation at the GCH1 locus in EOPD. However, our results further highlight the relevance of PRKN screening in familial EOPD. © 2009 Movement Disorder Society</abstract><qualityIndicators><score>5.674</score><pdfVersion>1.3</pdfVersion><pdfPageSize>612 x 810 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>6</keywordCount><abstractCharCount>1421</abstractCharCount><pdfWordCount>3250</pdfWordCount><pdfCharCount>21622</pdfCharCount><pdfPageCount>6</pdfPageCount><abstractWordCount>202</abstractWordCount></qualityIndicators><title>GCH1 in early‐onset Parkinson's disease</title><genre><json:string>article</json:string></genre><host><volume>24</volume><publisherId><json:string>MDS</json:string></publisherId><pages><total>6</total><last>2075</last><first>2070</first></pages><issn><json:string>0885-3185</json:string></issn><issue>14</issue><subject><json:item><value>Research Article</value></json:item></subject><genre><json:string>Journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1531-8257</json:string></eissn><title>Movement Disorders</title><doi><json:string>10.1002/(ISSN)1531-8257</json:string></doi></host><publicationDate>2009</publicationDate><copyrightDate>2009</copyrightDate><doi><json:string>10.1002/mds.22729</json:string></doi><id>E7C772768873F2B1C9F41CA093BBEBCB51710992</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/E7C772768873F2B1C9F41CA093BBEBCB51710992/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/E7C772768873F2B1C9F41CA093BBEBCB51710992/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/E7C772768873F2B1C9F41CA093BBEBCB51710992/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">GCH1 in early‐onset Parkinson's disease</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><availability><p>WILEY</p></availability><date>2009</date></publicationStmt><notesStmt><note type="content">*Potential conflict of interest: Nothing to report.</note><note>Swiss National Science Foundation - No. PBLAB‐115478;</note><note>Swiss Parkinson Foundation</note><note>Simpson Foundation Trust</note><note>Center of Excellence for Parkinson's disease Research - No. P50‐NS40256;</note><note>Pacific Alzheimer Research Foundation (PARF) - No. C06‐01;</note><note>NINDS - No. NS26081;</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">GCH1 in early‐onset Parkinson's disease</title><author><persName><forename type="first">Stephanie A.</forename><surname>Cobb</surname></persName><roleName type="degree">BA</roleName><affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</affiliation></author><author><persName><forename type="first">Christian</forename><surname>Wider</surname></persName><roleName type="degree">MD</roleName><affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</affiliation><affiliation>Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA</affiliation></author><author><persName><forename type="first">Owen A.</forename><surname>Ross</surname></persName><roleName type="degree">PhD</roleName><affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</affiliation></author><author><persName><forename type="first">Ignacio F.</forename><surname>Mata</surname></persName><roleName type="degree">PhD</roleName><affiliation>Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA</affiliation></author><author><persName><forename type="first">Charles H.</forename><surname>Adler</surname></persName><roleName type="degree">MD, PhD</roleName><affiliation>Department of Neurology, Mayo Clinic, Scottsdale, Arizona, USA</affiliation></author><author><persName><forename type="first">Alex</forename><surname>Rajput</surname></persName><roleName type="degree">FRCPC</roleName><affiliation>Division of Neurology, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, Canada</affiliation></author><author><persName><forename type="first">Ali H.</forename><surname>Rajput</surname></persName><roleName type="degree">FRCPC</roleName><affiliation>Division of Neurology, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, Canada</affiliation></author><author><persName><forename type="first">Ruey‐Meei</forename><surname>Wu</surname></persName><roleName type="degree">MD, PhD</roleName><affiliation>Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan</affiliation></author><author><persName><forename type="first">Robert</forename><surname>Hauser</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, University of South Florida, Tampa, Florida, USA</affiliation></author><author><persName><forename type="first">Keith A.</forename><surname>Josephs</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA</affiliation></author><author><persName><forename type="first">Jonathan</forename><surname>Carr</surname></persName><roleName type="degree">MD</roleName><affiliation>Neurophysiology Laboratory, University of Stellenbosch, Tygerberg Hospital, Tygerberg, South Africa</affiliation></author><author><persName><forename type="first">Katrina</forename><surname>Gwinn</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA</affiliation></author><author><persName><forename type="first">Michael G.</forename><surname>Heckman</surname></persName><roleName type="degree">MS</roleName><affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</affiliation></author><author><persName><forename type="first">Jan O.</forename><surname>Aasly</surname></persName><roleName type="degree">MD, PhD</roleName><affiliation>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</affiliation></author><author><persName><forename type="first">Timothy</forename><surname>Lynch</surname></persName><roleName type="degree">MD</roleName><affiliation>Dublin Neurological Institute at the Mater Misericordiae University Hospital, Dublin, Ireland</affiliation></author><author><persName><forename type="first">Ryan J.</forename><surname>Uitti</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA</affiliation></author><author><persName><forename type="first">Zbigniew K.</forename><surname>Wszolek</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA</affiliation></author><author><persName><forename type="first">Gregory</forename><surname>Kapatos</surname></persName><roleName type="degree">PhD</roleName><affiliation>Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan, USA</affiliation></author><author><persName><forename type="first">Matthew J.</forename><surname>Farrer</surname></persName><roleName type="degree">PhD</roleName><note type="correspondence"><p>Correspondence: Morris K. Udall Parkinson's Disease Research Center of Excellence, Mayo Clinic, Department of Neuroscience, 4500 San Pablo Road South, Jacksonville, Florida 32224</p></note><affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</affiliation></author></analytic><monogr><title level="j">Movement Disorders</title><title level="j" type="sub">Official Journal of the Movement Disorder Society</title><title level="j" type="abbrev">Mov. Disord.</title><idno type="pISSN">0885-3185</idno><idno type="eISSN">1531-8257</idno><idno type="DOI">10.1002/(ISSN)1531-8257</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2009-10-30"></date><biblScope unit="volume">24</biblScope><biblScope unit="issue">14</biblScope><biblScope unit="page" from="2070">2070</biblScope><biblScope unit="page" to="2075">2075</biblScope></imprint></monogr><idno type="istex">E7C772768873F2B1C9F41CA093BBEBCB51710992</idno><idno type="DOI">10.1002/mds.22729</idno><idno type="ArticleID">MDS22729</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2009</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Mutations in GTP‐cyclohydrolase 1 (GCH1) cause autosomal dominant dopa‐responsive dystonia (DRD), characterized by childhood‐onset foot dystonia that later generalizes. DRD patients frequently present with associated Parkinsonism. Conversely, early‐onset Parkinson's disease (EOPD) patients commonly display dystonia. Herein, we investigated the frequency of GCH1 mutations in a series of 53 familial EOPD patients (21 with dystonia) and screened them for mutations in PRKN, PINK1, and DJ‐1. In addition, we examined a matched EOPD patient–control series for association of common variability at the GCH1 locus and EOPD susceptibility. No GCH1 coding change or copy‐number abnormality was identified in familial EOPD patients. A novel 18‐bp deletion was found in the proximal promoter (two patients, one control), which is expected to knock out two regulatory elements previously shown to regulate GCH1 transcription. No association was found between GCH1 variability and risk of EOPD. Fourteen (26.4%) familial EOPD patients had homozygous or compound heterozygous PRKN mutations. PRKN‐positive patients were 10 years younger than PRKN‐negative patients and had a twofold higher prevalence of dystonia. This study does not support a significant role for genetic variation at the GCH1 locus in EOPD. However, our results further highlight the relevance of PRKN screening in familial EOPD. © 2009 Movement Disorder Society</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>GCH1</term></item><item><term>Parkinson's disease</term></item><item><term>dopa‐responsive dystonia</term></item><item><term>DRD</term></item><item><term>PRKN</term></item><item><term>early‐onset Parkinson's disease</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="2008-11-21">Received</change><change when="2009-06-08">Registration</change><change when="2009-10-30">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/E7C772768873F2B1C9F41CA093BBEBCB51710992/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)1531-8257</doi><issn type="print">0885-3185</issn><issn type="electronic">1531-8257</issn><idGroup><id type="product" value="MDS"></id></idGroup><titleGroup><title type="main" xml:lang="en" sort="MOVEMENT DISORDERS">Movement Disorders</title><title type="subtitle">Official Journal of the Movement Disorder Society</title><title type="short">Mov. Disord.</title></titleGroup></publicationMeta><publicationMeta level="part" position="140"><doi origin="wiley" registered="yes">10.1002/mds.v24:14</doi><numberingGroup><numbering type="journalVolume" number="24">24</numbering><numbering type="journalIssue">14</numbering></numberingGroup><coverDate startDate="2009-10-30">30 October 2009</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="50" status="forIssue"><doi origin="wiley" registered="yes">10.1002/mds.22729</doi><idGroup><id type="unit" value="MDS22729"></id></idGroup><countGroup><count type="pageTotal" number="6"></count></countGroup><titleGroup><title type="articleCategory">Research Article</title><title type="tocHeading1">Research Articles</title></titleGroup><copyright ownership="thirdParty">Copyright © 2009 Movement Disorder Society</copyright><eventGroup><event type="manuscriptReceived" date="2008-11-21"></event><event type="manuscriptRevised" date="2009-03-02"></event><event type="manuscriptAccepted" date="2009-06-08"></event><event type="publishedOnlineEarlyUnpaginated" date="2009-09-04"></event><event type="firstOnline" date="2009-09-04"></event><event type="publishedOnlineFinalForm" date="2009-10-28"></event><event type="xmlConverted" agent="Converter:JWSART34_TO_WML3G version:2.3.6 mode:FullText source:FullText result:FullText" date="2010-04-21"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-02-02"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-31"></event></eventGroup><numberingGroup><numbering type="pageFirst">2070</numbering><numbering type="pageLast">2075</numbering></numberingGroup><correspondenceTo>Morris K. Udall Parkinson's Disease Research Center of Excellence, Mayo Clinic, Department of Neuroscience, 4500 San Pablo Road South, Jacksonville, Florida 32224</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:MDS.MDS22729.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="2"></count><count type="tableTotal" number="3"></count><count type="referenceTotal" number="25"></count><count type="wordTotal" number="4281"></count></countGroup><titleGroup><title type="main" xml:lang="en"><i>GCH1</i> in early‐onset Parkinson's disease<link href="#fn3"></link></title><title type="short" xml:lang="en">GCH1 in Parkinson's Disease</title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Stephanie A.</givenNames><familyName>Cobb</familyName><degrees>BA</degrees></personName></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Christian</givenNames><familyName>Wider</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Owen A.</givenNames><familyName>Ross</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Ignacio F.</givenNames><familyName>Mata</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au5" creatorRole="author" affiliationRef="#af4"><personName><givenNames>Charles H.</givenNames><familyName>Adler</familyName><degrees>MD, PhD</degrees></personName></creator><creator xml:id="au6" creatorRole="author" affiliationRef="#af5"><personName><givenNames>Alex</givenNames><familyName>Rajput</familyName><degrees>FRCPC</degrees></personName></creator><creator xml:id="au7" creatorRole="author" affiliationRef="#af5"><personName><givenNames>Ali H.</givenNames><familyName>Rajput</familyName><degrees>FRCPC</degrees></personName></creator><creator xml:id="au8" creatorRole="author" affiliationRef="#af6"><personName><givenNames>Ruey‐Meei</givenNames><familyName>Wu</familyName><degrees>MD, PhD</degrees></personName></creator><creator xml:id="au9" creatorRole="author" affiliationRef="#af7"><personName><givenNames>Robert</givenNames><familyName>Hauser</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au10" creatorRole="author" affiliationRef="#af8"><personName><givenNames>Keith A.</givenNames><familyName>Josephs</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au11" creatorRole="author" affiliationRef="#af9"><personName><givenNames>Jonathan</givenNames><familyName>Carr</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au12" creatorRole="author" affiliationRef="#af10"><personName><givenNames>Katrina</givenNames><familyName>Gwinn</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au13" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Michael G.</givenNames><familyName>Heckman</familyName><degrees>MS</degrees></personName></creator><creator xml:id="au14" creatorRole="author" affiliationRef="#af11"><personName><givenNames>Jan O.</givenNames><familyName>Aasly</familyName><degrees>MD, PhD</degrees></personName></creator><creator xml:id="au15" creatorRole="author" affiliationRef="#af12"><personName><givenNames>Timothy</givenNames><familyName>Lynch</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au16" creatorRole="author" affiliationRef="#af2"><personName><givenNames>Ryan J.</givenNames><familyName>Uitti</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au17" creatorRole="author" affiliationRef="#af2"><personName><givenNames>Zbigniew K.</givenNames><familyName>Wszolek</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au18" creatorRole="author" affiliationRef="#af13"><personName><givenNames>Gregory</givenNames><familyName>Kapatos</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au19" creatorRole="author" affiliationRef="#af1" corresponding="yes"><personName><givenNames>Matthew J.</givenNames><familyName>Farrer</familyName><degrees>PhD</degrees></personName><contactDetails><email>farrer.matthew@mayo.edu</email></contactDetails></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="US" type="organization"><unparsedAffiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="US" type="organization"><unparsedAffiliation>Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA</unparsedAffiliation></affiliation><affiliation xml:id="af3" countryCode="US" type="organization"><unparsedAffiliation>Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA</unparsedAffiliation></affiliation><affiliation xml:id="af4" countryCode="US" type="organization"><unparsedAffiliation>Department of Neurology, Mayo Clinic, Scottsdale, Arizona, USA</unparsedAffiliation></affiliation><affiliation xml:id="af5" countryCode="CA" type="organization"><unparsedAffiliation>Division of Neurology, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, Canada</unparsedAffiliation></affiliation><affiliation xml:id="af6" countryCode="TW" type="organization"><unparsedAffiliation>Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan</unparsedAffiliation></affiliation><affiliation xml:id="af7" countryCode="US" type="organization"><unparsedAffiliation>Department of Neurology, University of South Florida, Tampa, Florida, USA</unparsedAffiliation></affiliation><affiliation xml:id="af8" countryCode="US" type="organization"><unparsedAffiliation>Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA</unparsedAffiliation></affiliation><affiliation xml:id="af9" countryCode="ZA" type="organization"><unparsedAffiliation>Neurophysiology Laboratory, University of Stellenbosch, Tygerberg Hospital, Tygerberg, South Africa</unparsedAffiliation></affiliation><affiliation xml:id="af10" countryCode="US" type="organization"><unparsedAffiliation>Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA</unparsedAffiliation></affiliation><affiliation xml:id="af11" countryCode="NO" type="organization"><unparsedAffiliation>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</unparsedAffiliation></affiliation><affiliation xml:id="af12" countryCode="IE" type="organization"><unparsedAffiliation>Dublin Neurological Institute at the Mater Misericordiae University Hospital, Dublin, Ireland</unparsedAffiliation></affiliation><affiliation xml:id="af13" countryCode="US" type="organization"><unparsedAffiliation>Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan, USA</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en" type="author"><keyword xml:id="kwd1"><i>GCH1</i></keyword><keyword xml:id="kwd2">Parkinson's disease</keyword><keyword xml:id="kwd3">dopa‐responsive dystonia</keyword><keyword xml:id="kwd4">DRD</keyword><keyword xml:id="kwd5">PRKN</keyword><keyword xml:id="kwd6">early‐onset Parkinson's disease</keyword></keywordGroup><fundingInfo><fundingAgency>Swiss National Science Foundation</fundingAgency><fundingNumber>PBLAB‐115478</fundingNumber></fundingInfo><fundingInfo><fundingAgency>Swiss Parkinson Foundation</fundingAgency></fundingInfo><fundingInfo><fundingAgency>Simpson Foundation Trust</fundingAgency></fundingInfo><fundingInfo><fundingAgency>Center of Excellence for Parkinson's disease Research</fundingAgency><fundingNumber>P50‐NS40256</fundingNumber></fundingInfo><fundingInfo><fundingAgency>Pacific Alzheimer Research Foundation (PARF)</fundingAgency><fundingNumber>C06‐01</fundingNumber></fundingInfo><fundingInfo><fundingAgency>NINDS</fundingAgency><fundingNumber>NS26081</fundingNumber></fundingInfo><supportingInformation><p> Additional supporting information may be found in the online version of this article. </p><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:08853185:media:mds22729:MDS_22729_sm_suppinfotable1"></mediaResource><caption>Supplemental Table 1. Linkage disequilibrium between GCH1 SNPs measured in control subjects and expressed as r2 values</caption></supportingInfoItem></supportingInformation><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>Mutations in <i>GTP‐cyclohydrolase 1</i> (<i>GCH1</i>) cause autosomal dominant dopa‐responsive dystonia (DRD), characterized by childhood‐onset foot dystonia that later generalizes. DRD patients frequently present with associated Parkinsonism. Conversely, early‐onset Parkinson's disease (EOPD) patients commonly display dystonia. Herein, we investigated the frequency of <i>GCH1</i> mutations in a series of 53 familial EOPD patients (21 with dystonia) and screened them for mutations in <i>PRKN</i>, <i>PINK1</i>, and <i>DJ‐1</i>. In addition, we examined a matched EOPD patient–control series for association of common variability at the <i>GCH1</i> locus and EOPD susceptibility. No <i>GCH1</i> coding change or copy‐number abnormality was identified in familial EOPD patients. A novel 18‐bp deletion was found in the proximal promoter (two patients, one control), which is expected to knock out two regulatory elements previously shown to regulate <i>GCH1</i> transcription. No association was found between <i>GCH1</i> variability and risk of EOPD. Fourteen (26.4%) familial EOPD patients had homozygous or compound heterozygous <i>PRKN</i> mutations. <i>PRKN</i>‐positive patients were 10 years younger than <i>PRKN</i>‐negative patients and had a twofold higher prevalence of dystonia. This study does not support a significant role for genetic variation at the <i>GCH1</i> locus in EOPD. However, our results further highlight the relevance of <i>PRKN</i> screening in familial EOPD. © 2009 Movement Disorder Society</p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="fn3"><p>Potential conflict of interest: Nothing to report.</p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>GCH1 in early‐onset Parkinson's disease</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>GCH1 in Parkinson's Disease</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>in early‐onset Parkinson's disease</title></titleInfo><name type="personal"><namePart type="given">Stephanie A.</namePart><namePart type="family">Cobb</namePart><namePart type="termsOfAddress">BA</namePart><affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christian</namePart><namePart type="family">Wider</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</affiliation><affiliation>Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Owen A.</namePart><namePart type="family">Ross</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ignacio F.</namePart><namePart type="family">Mata</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Charles H.</namePart><namePart type="family">Adler</namePart><namePart type="termsOfAddress">MD, PhD</namePart><affiliation>Department of Neurology, Mayo Clinic, Scottsdale, Arizona, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alex</namePart><namePart type="family">Rajput</namePart><namePart type="termsOfAddress">FRCPC</namePart><affiliation>Division of Neurology, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ali H.</namePart><namePart type="family">Rajput</namePart><namePart type="termsOfAddress">FRCPC</namePart><affiliation>Division of Neurology, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ruey‐Meei</namePart><namePart type="family">Wu</namePart><namePart type="termsOfAddress">MD, PhD</namePart><affiliation>Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Robert</namePart><namePart type="family">Hauser</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, University of South Florida, Tampa, Florida, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Keith A.</namePart><namePart type="family">Josephs</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jonathan</namePart><namePart type="family">Carr</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Neurophysiology Laboratory, University of Stellenbosch, Tygerberg Hospital, Tygerberg, South Africa</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Katrina</namePart><namePart type="family">Gwinn</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Michael G.</namePart><namePart type="family">Heckman</namePart><namePart type="termsOfAddress">MS</namePart><affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jan O.</namePart><namePart type="family">Aasly</namePart><namePart type="termsOfAddress">MD, PhD</namePart><affiliation>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Timothy</namePart><namePart type="family">Lynch</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Dublin Neurological Institute at the Mater Misericordiae University Hospital, Dublin, Ireland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ryan J.</namePart><namePart type="family">Uitti</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Zbigniew K.</namePart><namePart type="family">Wszolek</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Gregory</namePart><namePart type="family">Kapatos</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Matthew J.</namePart><namePart type="family">Farrer</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</affiliation><description>Correspondence: Morris K. Udall Parkinson's Disease Research Center of Excellence, Mayo Clinic, Department of Neuroscience, 4500 San Pablo Road South, Jacksonville, Florida 32224</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">2009-10-30</dateIssued><dateCaptured encoding="w3cdtf">2008-11-21</dateCaptured><dateValid encoding="w3cdtf">2009-06-08</dateValid><copyrightDate encoding="w3cdtf">2009</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">2</extent><extent unit="tables">3</extent><extent unit="references">25</extent><extent unit="words">4281</extent></physicalDescription><abstract lang="en">Mutations in GTP‐cyclohydrolase 1 (GCH1) cause autosomal dominant dopa‐responsive dystonia (DRD), characterized by childhood‐onset foot dystonia that later generalizes. DRD patients frequently present with associated Parkinsonism. Conversely, early‐onset Parkinson's disease (EOPD) patients commonly display dystonia. Herein, we investigated the frequency of GCH1 mutations in a series of 53 familial EOPD patients (21 with dystonia) and screened them for mutations in PRKN, PINK1, and DJ‐1. In addition, we examined a matched EOPD patient–control series for association of common variability at the GCH1 locus and EOPD susceptibility. No GCH1 coding change or copy‐number abnormality was identified in familial EOPD patients. A novel 18‐bp deletion was found in the proximal promoter (two patients, one control), which is expected to knock out two regulatory elements previously shown to regulate GCH1 transcription. No association was found between GCH1 variability and risk of EOPD. Fourteen (26.4%) familial EOPD patients had homozygous or compound heterozygous PRKN mutations. PRKN‐positive patients were 10 years younger than PRKN‐negative patients and had a twofold higher prevalence of dystonia. This study does not support a significant role for genetic variation at the GCH1 locus in EOPD. However, our results further highlight the relevance of PRKN screening in familial EOPD. © 2009 Movement Disorder Society</abstract><note type="content">*Potential conflict of interest: Nothing to report.</note><note type="funding">Swiss National Science Foundation - No. PBLAB‐115478; </note><note type="funding">Swiss Parkinson Foundation</note><note type="funding">Simpson Foundation Trust</note><note type="funding">Center of Excellence for Parkinson's disease Research - No. P50‐NS40256; </note><note type="funding">Pacific Alzheimer Research Foundation (PARF) - No. C06‐01; </note><note type="funding">NINDS - No. NS26081; </note><subject lang="en"><genre>Keywords</genre><topic>GCH1</topic><topic>Parkinson's disease</topic><topic>dopa‐responsive dystonia</topic><topic>DRD</topic><topic>PRKN</topic><topic>early‐onset Parkinson's disease</topic></subject><relatedItem type="host"><titleInfo><title>Movement Disorders</title><subTitle>Official Journal of the Movement Disorder Society</subTitle></titleInfo><titleInfo type="abbreviated"><title>Mov. Disord.</title></titleInfo><genre type="Journal">journal</genre><note type="content"> Additional supporting information may be found in the online version of this article.Supporting Info Item: Supplemental Table 1. Linkage disequilibrium between GCH1 SNPs measured in control subjects and expressed as r2 values - </note><subject><genre>article category</genre><topic>Research Article</topic></subject><identifier type="ISSN">0885-3185</identifier><identifier type="eISSN">1531-8257</identifier><identifier type="DOI">10.1002/(ISSN)1531-8257</identifier><identifier type="PublisherID">MDS</identifier><part><date>2009</date><detail type="volume"><caption>vol.</caption><number>24</number></detail><detail type="issue"><caption>no.</caption><number>14</number></detail><extent unit="pages"><start>2070</start><end>2075</end><total>6</total></extent></part></relatedItem><identifier type="istex">E7C772768873F2B1C9F41CA093BBEBCB51710992</identifier><identifier type="DOI">10.1002/mds.22729</identifier><identifier type="ArticleID">MDS22729</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2009 Movement Disorder Society</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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