Genomic investigation of α‐synuclein multiplication and parkinsonism
Identifieur interne : 000322 ( Main/Corpus ); précédent : 000321; suivant : 000323Genomic investigation of α‐synuclein multiplication and parkinsonism
Auteurs : Owen A. Ross ; Adam T. Braithwaite ; Lisa M. Skipper ; Jennifer Kachergus ; Mary M. Hulihan ; Frank A. Middleton ; Kenya Nishioka ; Julia Fuchs ; Thomas Gasser ; Demetrius M. Maraganore ; Charles H. Adler ; Lydie Larvor ; Marie-Christine Chartier-Harlin ; Christer Nilsson ; J. William Langston ; Katrina Gwinn ; Nobutaka Hattori ; Matthew J. FarrerSource :
- Annals of Neurology [ 0364-5134 ] ; 2008-06.
Abstract
Objective: Copy number variation is a common polymorphic phenomenon within the human genome. Although the majority of these events are non‐deleterious they can also be highly pathogenic. Herein we characterize five families with parkinsonism that have been identified to harbor multiplication of the chromosomal 4q21 locus containing the α‐synuclein gene (SNCA). Methods: A methodological approach using fluorescent in situ hybridization and Affymetrix (Santa Clara, CA) 250K SNP microarrays was used to characterize the multiplication in each family and to identify the genes encoded within the region. The telomeric and centromeric breakpoints of each family were further narrowed using semiquantitative polymerase chain reaction with microsatellite markers and then screened for transposable repeat elements. Results: The severity of clinical presentation is correlated with SNCA dosage and does not appear to be overtly affected by the presence of other genes in the multiplicated region. With the exception of the Lister kindred, in each family the multiplication event appears de novo. The type and position of Alu/LINE repeats are also different at each breakpoint. Microsatellite analysis demonstrates two genomic mechanisms are responsible for chromosome 4q21 multiplications, including both SNCA duplication and recombination. Interpretation: SNCA dosage is responsible for parkinsonism, autonomic dysfunction, and dementia observed within each family. We hypothesize dysregulated expression of wild‐type α‐synuclein results in parkinsonism and may explain the recent association of common SNCA variants in sporadic Parkinson's disease. SNCA genomic duplication results from intraallelic (segmental duplication) or interallelic recombination with unequal crossing over, whereas both mechanisms appear to be required for genomic SNCA triplication. Ann Neurol 2008
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DOI: 10.1002/ana.21380
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William" last="Langston">J. William Langston</name><affiliation><mods:affiliation>Parkinson's Institute and Clinical Center, Sunnyvale, CA</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>Neurogenetics, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD</mods:affiliation></affiliation></author><author><name sortKey="Hattori, Nobutaka" sort="Hattori, Nobutaka" uniqKey="Hattori N" first="Nobutaka" last="Hattori">Nobutaka Hattori</name><affiliation><mods:affiliation>Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan</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, College of Medicine, Mayo Clinic, Jacksonville, FL</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:78C1348524C06C8DBBAD41A8533A9623D7595BC7</idno><date when="2008" year="2008">2008</date><idno type="doi">10.1002/ana.21380</idno><idno type="url">https://api.istex.fr/document/78C1348524C06C8DBBAD41A8533A9623D7595BC7/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">000322</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Genomic investigation of α‐synuclein multiplication and parkinsonism</title><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, College of Medicine, Mayo Clinic, Jacksonville, FL</mods:affiliation></affiliation></author><author><name sortKey="Braithwaite, Adam T" sort="Braithwaite, Adam T" uniqKey="Braithwaite A" first="Adam T." last="Braithwaite">Adam T. Braithwaite</name><affiliation><mods:affiliation>Division of Neurogenetics, Department of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville, FL</mods:affiliation></affiliation></author><author><name sortKey="Skipper, Lisa M" sort="Skipper, Lisa M" uniqKey="Skipper L" first="Lisa M." last="Skipper">Lisa M. Skipper</name><affiliation><mods:affiliation>Division of Neurogenetics, Department of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville, FL</mods:affiliation></affiliation></author><author><name sortKey="Kachergus, Jennifer" sort="Kachergus, Jennifer" uniqKey="Kachergus J" first="Jennifer" last="Kachergus">Jennifer Kachergus</name><affiliation><mods:affiliation>Division of Neurogenetics, Department of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville, FL</mods:affiliation></affiliation></author><author><name sortKey="Hulihan, Mary M" sort="Hulihan, Mary M" uniqKey="Hulihan M" first="Mary M." last="Hulihan">Mary M. Hulihan</name><affiliation><mods:affiliation>Division of Neurogenetics, Department of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville, FL</mods:affiliation></affiliation></author><author><name sortKey="Middleton, Frank A" sort="Middleton, Frank A" uniqKey="Middleton F" first="Frank A." last="Middleton">Frank A. Middleton</name><affiliation><mods:affiliation>Center for Neuropsychiatric Genetics, Microarray Core Facility, State University of New York Upstate Medical University, Syracuse, NY</mods:affiliation></affiliation></author><author><name sortKey="Nishioka, Kenya" sort="Nishioka, Kenya" uniqKey="Nishioka K" first="Kenya" last="Nishioka">Kenya Nishioka</name><affiliation><mods:affiliation>Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan</mods:affiliation></affiliation></author><author><name sortKey="Fuchs, Julia" sort="Fuchs, Julia" uniqKey="Fuchs J" first="Julia" last="Fuchs">Julia Fuchs</name><affiliation><mods:affiliation>Department of Neurodegenerative Diseases, Center for Neurology, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</mods:affiliation></affiliation></author><author><name sortKey="Gasser, Thomas" sort="Gasser, Thomas" uniqKey="Gasser T" first="Thomas" last="Gasser">Thomas Gasser</name><affiliation><mods:affiliation>Department of Neurodegenerative Diseases, Center for Neurology, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</mods:affiliation></affiliation></author><author><name sortKey="Maraganore, Demetrius M" sort="Maraganore, Demetrius M" uniqKey="Maraganore D" first="Demetrius M." last="Maraganore">Demetrius M. Maraganore</name><affiliation><mods:affiliation>Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN</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 College of Medicine, Scottsdale, AZ</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>EA2683 ministère de l' éducation nationale de la recherche et de la technologie (MENRT), Diagnostic and Physiopathology of Parkinson's Disease, Institut de Recherches sur le Cancer de Lille (IRCL), Lille Cedex, 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>EA2683 ministère de l' éducation nationale de la recherche et de la technologie (MENRT), Diagnostic and Physiopathology of Parkinson's Disease, Institut de Recherches sur le Cancer de Lille (IRCL), Lille Cedex, France</mods:affiliation></affiliation></author><author><name sortKey="Nilsson, Christer" sort="Nilsson, Christer" uniqKey="Nilsson C" first="Christer" last="Nilsson">Christer Nilsson</name><affiliation><mods:affiliation>Department of Clinical Medicine, Division of Geriatric Psychiatry, Lund University, Lund, Sweden</mods:affiliation></affiliation></author><author><name sortKey="Langston, J William" sort="Langston, J William" uniqKey="Langston J" first="J. William" last="Langston">J. William Langston</name><affiliation><mods:affiliation>Parkinson's Institute and Clinical Center, Sunnyvale, CA</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>Neurogenetics, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD</mods:affiliation></affiliation></author><author><name sortKey="Hattori, Nobutaka" sort="Hattori, Nobutaka" uniqKey="Hattori N" first="Nobutaka" last="Hattori">Nobutaka Hattori</name><affiliation><mods:affiliation>Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan</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, College of Medicine, Mayo Clinic, Jacksonville, FL</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Annals of Neurology</title><title level="j" type="sub">Official Journal of the American Neurological Association and the Child Neurology Society</title><title level="j" type="abbrev">Ann Neurol.</title><idno type="ISSN">0364-5134</idno><idno type="eISSN">1531-8249</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2008-06">2008-06</date><biblScope unit="volume">63</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="743">743</biblScope><biblScope unit="page" to="750">750</biblScope></imprint><idno type="ISSN">0364-5134</idno></series><idno type="istex">78C1348524C06C8DBBAD41A8533A9623D7595BC7</idno><idno type="DOI">10.1002/ana.21380</idno><idno type="ArticleID">ANA21380</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0364-5134</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Objective: Copy number variation is a common polymorphic phenomenon within the human genome. Although the majority of these events are non‐deleterious they can also be highly pathogenic. Herein we characterize five families with parkinsonism that have been identified to harbor multiplication of the chromosomal 4q21 locus containing the α‐synuclein gene (SNCA). Methods: A methodological approach using fluorescent in situ hybridization and Affymetrix (Santa Clara, CA) 250K SNP microarrays was used to characterize the multiplication in each family and to identify the genes encoded within the region. The telomeric and centromeric breakpoints of each family were further narrowed using semiquantitative polymerase chain reaction with microsatellite markers and then screened for transposable repeat elements. Results: The severity of clinical presentation is correlated with SNCA dosage and does not appear to be overtly affected by the presence of other genes in the multiplicated region. With the exception of the Lister kindred, in each family the multiplication event appears de novo. The type and position of Alu/LINE repeats are also different at each breakpoint. Microsatellite analysis demonstrates two genomic mechanisms are responsible for chromosome 4q21 multiplications, including both SNCA duplication and recombination. Interpretation: SNCA dosage is responsible for parkinsonism, autonomic dysfunction, and dementia observed within each family. We hypothesize dysregulated expression of wild‐type α‐synuclein results in parkinsonism and may explain the recent association of common SNCA variants in sporadic Parkinson's disease. SNCA genomic duplication results from intraallelic (segmental duplication) or interallelic recombination with unequal crossing over, whereas both mechanisms appear to be required for genomic SNCA triplication. Ann Neurol 2008</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Owen A. Ross PhD</name><affiliations><json:string>Division of Neurogenetics, Department of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville, FL</json:string></affiliations></json:item><json:item><name>Adam T. Braithwaite BSc</name><affiliations><json:string>Division of Neurogenetics, Department of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville, FL</json:string></affiliations></json:item><json:item><name>Lisa M. Skipper PhD</name><affiliations><json:string>Division of Neurogenetics, Department of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville, FL</json:string></affiliations></json:item><json:item><name>Jennifer Kachergus BSc, MBA</name><affiliations><json:string>Division of Neurogenetics, Department of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville, FL</json:string></affiliations></json:item><json:item><name>Mary M. Hulihan MPH</name><affiliations><json:string>Division of Neurogenetics, Department of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville, FL</json:string></affiliations></json:item><json:item><name>Frank A. Middleton PhD</name><affiliations><json:string>Center for Neuropsychiatric Genetics, Microarray Core Facility, State University of New York Upstate Medical University, Syracuse, NY</json:string></affiliations></json:item><json:item><name>Kenya Nishioka MD</name><affiliations><json:string>Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan</json:string></affiliations></json:item><json:item><name>Julia Fuchs MD</name><affiliations><json:string>Department of Neurodegenerative Diseases, Center for Neurology, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</json:string></affiliations></json:item><json:item><name>Thomas Gasser MD</name><affiliations><json:string>Department of Neurodegenerative Diseases, Center for Neurology, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</json:string></affiliations></json:item><json:item><name>Demetrius M. Maraganore MD</name><affiliations><json:string>Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN</json:string></affiliations></json:item><json:item><name>Charles H. Adler MD</name><affiliations><json:string>Department of Neurology, Mayo Clinic College of Medicine, Scottsdale, AZ</json:string></affiliations></json:item><json:item><name>Lydie Larvor PhD</name><affiliations><json:string>EA2683 ministère de l' éducation nationale de la recherche et de la technologie (MENRT), Diagnostic and Physiopathology of Parkinson's Disease, Institut de Recherches sur le Cancer de Lille (IRCL), Lille Cedex, France</json:string></affiliations></json:item><json:item><name>Marie‐Christine Chartier‐Harlin MD</name><affiliations><json:string>EA2683 ministère de l' éducation nationale de la recherche et de la technologie (MENRT), Diagnostic and Physiopathology of Parkinson's Disease, Institut de Recherches sur le Cancer de Lille (IRCL), Lille Cedex, France</json:string></affiliations></json:item><json:item><name>Christer Nilsson MD</name><affiliations><json:string>Department of Clinical Medicine, Division of Geriatric Psychiatry, Lund University, Lund, Sweden</json:string></affiliations></json:item><json:item><name>J. William Langston MD</name><affiliations><json:string>Parkinson's Institute and Clinical Center, Sunnyvale, CA</json:string></affiliations></json:item><json:item><name>Katrina Gwinn MD</name><affiliations><json:string>Neurogenetics, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD</json:string></affiliations></json:item><json:item><name>Nobutaka Hattori MD</name><affiliations><json:string>Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan</json:string></affiliations></json:item><json:item><name>Matthew J. Farrer PhD</name><affiliations><json:string>Division of Neurogenetics, Department of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville, FL</json:string></affiliations></json:item></author><articleId><json:string>ANA21380</json:string></articleId><language><json:string>eng</json:string></language><abstract>Objective: Copy number variation is a common polymorphic phenomenon within the human genome. Although the majority of these events are non‐deleterious they can also be highly pathogenic. Herein we characterize five families with parkinsonism that have been identified to harbor multiplication of the chromosomal 4q21 locus containing the α‐synuclein gene (SNCA). Methods: A methodological approach using fluorescent in situ hybridization and Affymetrix (Santa Clara, CA) 250K SNP microarrays was used to characterize the multiplication in each family and to identify the genes encoded within the region. The telomeric and centromeric breakpoints of each family were further narrowed using semiquantitative polymerase chain reaction with microsatellite markers and then screened for transposable repeat elements. Results: The severity of clinical presentation is correlated with SNCA dosage and does not appear to be overtly affected by the presence of other genes in the multiplicated region. With the exception of the Lister kindred, in each family the multiplication event appears de novo. The type and position of Alu/LINE repeats are also different at each breakpoint. Microsatellite analysis demonstrates two genomic mechanisms are responsible for chromosome 4q21 multiplications, including both SNCA duplication and recombination. Interpretation: SNCA dosage is responsible for parkinsonism, autonomic dysfunction, and dementia observed within each family. We hypothesize dysregulated expression of wild‐type α‐synuclein results in parkinsonism and may explain the recent association of common SNCA variants in sporadic Parkinson's disease. SNCA genomic duplication results from intraallelic (segmental duplication) or interallelic recombination with unequal crossing over, whereas both mechanisms appear to be required for genomic SNCA triplication. Ann Neurol 2008</abstract><qualityIndicators><score>7.235</score><pdfVersion>1.3</pdfVersion><pdfPageSize>594 x 783 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>0</keywordCount><abstractCharCount>1872</abstractCharCount><pdfWordCount>4235</pdfWordCount><pdfCharCount>29202</pdfCharCount><pdfPageCount>8</pdfPageCount><abstractWordCount>256</abstractWordCount></qualityIndicators><title>Genomic investigation of α‐synuclein multiplication and parkinsonism</title><genre><json:string>article</json:string></genre><host><volume>63</volume><publisherId><json:string>ANA</json:string></publisherId><pages><total>8</total><last>750</last><first>743</first></pages><issn><json:string>0364-5134</json:string></issn><issue>6</issue><subject><json:item><value>Original Article</value></json:item></subject><genre><json:string>Journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1531-8249</json:string></eissn><title>Annals of Neurology</title><doi><json:string>10.1002/(ISSN)1531-8249</json:string></doi></host><publicationDate>2008</publicationDate><copyrightDate>2008</copyrightDate><doi><json:string>10.1002/ana.21380</json:string></doi><id>78C1348524C06C8DBBAD41A8533A9623D7595BC7</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/78C1348524C06C8DBBAD41A8533A9623D7595BC7/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/78C1348524C06C8DBBAD41A8533A9623D7595BC7/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/78C1348524C06C8DBBAD41A8533A9623D7595BC7/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Genomic investigation of α‐synuclein multiplication and parkinsonism</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><availability><p>WILEY</p></availability><date>2008</date></publicationStmt><notesStmt><note>American Parkinson Disease Association</note><note>Morris K. Udall Parkinson's Disease Research Center of Excellence (National Institute of Neurological Disorders and Stroke) - No. P50 #NS40256;</note><note>NIH (National Institute of Aging) - No. P01 #AG17216;</note><note>German National Genome Network (NGFN) - No. 01GS0116;</note><note>PHRC 2005/1914 the Universite de Lille 2 and Institut National de la Sante et de la Recherche Medicale</note><note>Draper Family Foundation</note><note>NIH (National Institute of Neurological Disorders and Stroke) - No. #N01‐NS‐2‐2349;</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Genomic investigation of α‐synuclein multiplication and parkinsonism</title><author><persName><forename type="first">Owen A.</forename><surname>Ross</surname></persName><roleName type="degree">PhD</roleName><affiliation>Division of Neurogenetics, Department of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville, FL</affiliation></author><author><persName><forename type="first">Adam T.</forename><surname>Braithwaite</surname></persName><roleName type="degree">BSc</roleName><affiliation>Division of Neurogenetics, Department of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville, FL</affiliation></author><author><persName><forename type="first">Lisa M.</forename><surname>Skipper</surname></persName><roleName type="degree">PhD</roleName><affiliation>Division of Neurogenetics, Department of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville, FL</affiliation></author><author><persName><forename type="first">Jennifer</forename><surname>Kachergus</surname></persName><roleName type="degree">BSc, MBA</roleName><affiliation>Division of Neurogenetics, Department of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville, FL</affiliation></author><author><persName><forename type="first">Mary M.</forename><surname>Hulihan</surname></persName><roleName type="degree">MPH</roleName><affiliation>Division of Neurogenetics, Department of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville, FL</affiliation></author><author><persName><forename type="first">Frank A.</forename><surname>Middleton</surname></persName><roleName type="degree">PhD</roleName><affiliation>Center for Neuropsychiatric Genetics, Microarray Core Facility, State University of New York Upstate Medical University, Syracuse, NY</affiliation></author><author><persName><forename type="first">Kenya</forename><surname>Nishioka</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan</affiliation></author><author><persName><forename type="first">Julia</forename><surname>Fuchs</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurodegenerative Diseases, Center for Neurology, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</affiliation></author><author><persName><forename type="first">Thomas</forename><surname>Gasser</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurodegenerative Diseases, Center for Neurology, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</affiliation></author><author><persName><forename type="first">Demetrius M.</forename><surname>Maraganore</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN</affiliation></author><author><persName><forename type="first">Charles H.</forename><surname>Adler</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, Mayo Clinic College of Medicine, Scottsdale, AZ</affiliation></author><author><persName><forename type="first">Lydie</forename><surname>Larvor</surname></persName><roleName type="degree">PhD</roleName><affiliation>EA2683 ministère de l' éducation nationale de la recherche et de la technologie (MENRT), Diagnostic and Physiopathology of Parkinson's Disease, Institut de Recherches sur le Cancer de Lille (IRCL), Lille Cedex, France</affiliation></author><author><persName><forename type="first">Marie‐Christine</forename><surname>Chartier‐Harlin</surname></persName><roleName type="degree">MD</roleName><affiliation>EA2683 ministère de l' éducation nationale de la recherche et de la technologie (MENRT), Diagnostic and Physiopathology of Parkinson's Disease, Institut de Recherches sur le Cancer de Lille (IRCL), Lille Cedex, France</affiliation></author><author><persName><forename type="first">Christer</forename><surname>Nilsson</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Clinical Medicine, Division of Geriatric Psychiatry, Lund University, Lund, Sweden</affiliation></author><author><persName><forename type="first">J. William</forename><surname>Langston</surname></persName><roleName type="degree">MD</roleName><affiliation>Parkinson's Institute and Clinical Center, Sunnyvale, CA</affiliation></author><author><persName><forename type="first">Katrina</forename><surname>Gwinn</surname></persName><roleName type="degree">MD</roleName><affiliation>Neurogenetics, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD</affiliation></author><author><persName><forename type="first">Nobutaka</forename><surname>Hattori</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan</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, FL 32224</p></note><affiliation>Division of Neurogenetics, Department of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville, FL</affiliation></author></analytic><monogr><title level="j">Annals of Neurology</title><title level="j" type="sub">Official Journal of the American Neurological Association and the Child Neurology Society</title><title level="j" type="abbrev">Ann Neurol.</title><idno type="pISSN">0364-5134</idno><idno type="eISSN">1531-8249</idno><idno type="DOI">10.1002/(ISSN)1531-8249</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2008-06"></date><biblScope unit="volume">63</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="743">743</biblScope><biblScope unit="page" to="750">750</biblScope></imprint></monogr><idno type="istex">78C1348524C06C8DBBAD41A8533A9623D7595BC7</idno><idno type="DOI">10.1002/ana.21380</idno><idno type="ArticleID">ANA21380</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2008</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Objective: Copy number variation is a common polymorphic phenomenon within the human genome. Although the majority of these events are non‐deleterious they can also be highly pathogenic. Herein we characterize five families with parkinsonism that have been identified to harbor multiplication of the chromosomal 4q21 locus containing the α‐synuclein gene (SNCA). Methods: A methodological approach using fluorescent in situ hybridization and Affymetrix (Santa Clara, CA) 250K SNP microarrays was used to characterize the multiplication in each family and to identify the genes encoded within the region. The telomeric and centromeric breakpoints of each family were further narrowed using semiquantitative polymerase chain reaction with microsatellite markers and then screened for transposable repeat elements. Results: The severity of clinical presentation is correlated with SNCA dosage and does not appear to be overtly affected by the presence of other genes in the multiplicated region. With the exception of the Lister kindred, in each family the multiplication event appears de novo. The type and position of Alu/LINE repeats are also different at each breakpoint. Microsatellite analysis demonstrates two genomic mechanisms are responsible for chromosome 4q21 multiplications, including both SNCA duplication and recombination. Interpretation: SNCA dosage is responsible for parkinsonism, autonomic dysfunction, and dementia observed within each family. We hypothesize dysregulated expression of wild‐type α‐synuclein results in parkinsonism and may explain the recent association of common SNCA variants in sporadic Parkinson's disease. SNCA genomic duplication results from intraallelic (segmental duplication) or interallelic recombination with unequal crossing over, whereas both mechanisms appear to be required for genomic SNCA triplication. 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Udall Parkinson's Disease Research Center of Excellence, Mayo Clinic, Department of Neuroscience, 4500 San Pablo Road South, Jacksonville, FL 32224</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:ANA.ANA21380.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="3"></count><count type="tableTotal" number="1"></count><count type="referenceTotal" number="43"></count><count type="wordTotal" number="4844"></count></countGroup><titleGroup><title type="main" xml:lang="en">Genomic investigation of α‐synuclein multiplication and parkinsonism</title><title type="short" xml:lang="en">SNCA and Parkinsonism</title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Owen A.</givenNames><familyName>Ross</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Adam T.</givenNames><familyName>Braithwaite</familyName><degrees>BSc</degrees></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Lisa M.</givenNames><familyName>Skipper</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Jennifer</givenNames><familyName>Kachergus</familyName><degrees>BSc, MBA</degrees></personName></creator><creator xml:id="au5" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Mary M.</givenNames><familyName>Hulihan</familyName><degrees>MPH</degrees></personName></creator><creator xml:id="au6" creatorRole="author" affiliationRef="#af2"><personName><givenNames>Frank A.</givenNames><familyName>Middleton</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au7" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Kenya</givenNames><familyName>Nishioka</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au8" creatorRole="author" affiliationRef="#af4"><personName><givenNames>Julia</givenNames><familyName>Fuchs</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au9" creatorRole="author" affiliationRef="#af4"><personName><givenNames>Thomas</givenNames><familyName>Gasser</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au10" creatorRole="author" affiliationRef="#af5"><personName><givenNames>Demetrius M.</givenNames><familyName>Maraganore</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au11" creatorRole="author" affiliationRef="#af6"><personName><givenNames>Charles H.</givenNames><familyName>Adler</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au12" creatorRole="author" affiliationRef="#af7"><personName><givenNames>Lydie</givenNames><familyName>Larvor</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au13" creatorRole="author" affiliationRef="#af7"><personName><givenNames>Marie‐Christine</givenNames><familyName>Chartier‐Harlin</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au14" creatorRole="author" affiliationRef="#af8"><personName><givenNames>Christer</givenNames><familyName>Nilsson</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au15" creatorRole="author" affiliationRef="#af9"><personName><givenNames>J. William</givenNames><familyName>Langston</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au16" creatorRole="author" affiliationRef="#af10"><personName><givenNames>Katrina</givenNames><familyName>Gwinn</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au17" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Nobutaka</givenNames><familyName>Hattori</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au18" 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, College of Medicine, Mayo Clinic, Jacksonville, FL</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="US" type="organization"><unparsedAffiliation>Center for Neuropsychiatric Genetics, Microarray Core Facility, State University of New York Upstate Medical University, Syracuse, NY</unparsedAffiliation></affiliation><affiliation xml:id="af3" countryCode="JP" type="organization"><unparsedAffiliation>Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan</unparsedAffiliation></affiliation><affiliation xml:id="af4" countryCode="DE" type="organization"><unparsedAffiliation>Department of Neurodegenerative Diseases, Center for Neurology, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</unparsedAffiliation></affiliation><affiliation xml:id="af5" countryCode="US" type="organization"><unparsedAffiliation>Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN</unparsedAffiliation></affiliation><affiliation xml:id="af6" countryCode="US" type="organization"><unparsedAffiliation>Department of Neurology, Mayo Clinic College of Medicine, Scottsdale, AZ</unparsedAffiliation></affiliation><affiliation xml:id="af7" countryCode="FR" type="organization"><unparsedAffiliation>EA2683 ministère de l' éducation nationale de la recherche et de la technologie (MENRT), Diagnostic and Physiopathology of Parkinson's Disease, Institut de Recherches sur le Cancer de Lille (IRCL), Lille Cedex, France</unparsedAffiliation></affiliation><affiliation xml:id="af8" countryCode="SE" type="organization"><unparsedAffiliation>Department of Clinical Medicine, Division of Geriatric Psychiatry, Lund University, Lund, Sweden</unparsedAffiliation></affiliation><affiliation xml:id="af9" countryCode="US" type="organization"><unparsedAffiliation>Parkinson's Institute and Clinical Center, Sunnyvale, CA</unparsedAffiliation></affiliation><affiliation xml:id="af10" countryCode="US" type="organization"><unparsedAffiliation>Neurogenetics, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD</unparsedAffiliation></affiliation></affiliationGroup><fundingInfo><fundingAgency>American Parkinson Disease Association</fundingAgency></fundingInfo><fundingInfo><fundingAgency>Morris K. Udall Parkinson's Disease Research Center of Excellence (National Institute of Neurological Disorders and Stroke)</fundingAgency><fundingNumber>P50 #NS40256</fundingNumber></fundingInfo><fundingInfo><fundingAgency>NIH (National Institute of Aging)</fundingAgency><fundingNumber>P01 #AG17216</fundingNumber></fundingInfo><fundingInfo><fundingAgency>German National Genome Network (NGFN)</fundingAgency><fundingNumber>01GS0116</fundingNumber></fundingInfo><fundingInfo><fundingAgency>PHRC 2005/1914 the Universite de Lille 2 and Institut National de la Sante et de la Recherche Medicale</fundingAgency></fundingInfo><fundingInfo><fundingAgency>Draper Family Foundation</fundingAgency></fundingInfo><fundingInfo><fundingAgency>NIH (National Institute of Neurological Disorders and Stroke)</fundingAgency><fundingNumber>#N01‐NS‐2‐2349</fundingNumber></fundingInfo><supportingInformation><p> This article includes supplementary materials available via the Internet at <url href="http://www.interscience.wiley.com/jpages/0364-5134/suppmat"> http://www.interscience.wiley.com/jpages/0364‐5134/suppmat </url></p></supportingInformation><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><section xml:id="abs1-1"><title type="main">Objective</title><p>Copy number variation is a common polymorphic phenomenon within the human genome. Although the majority of these events are non‐deleterious they can also be highly pathogenic. Herein we characterize five families with parkinsonism that have been identified to harbor multiplication of the chromosomal 4q21 locus containing the α‐<i>synuclein</i> gene (<i>SNCA</i>).</p></section><section xml:id="abs1-2"><title type="main">Methods</title><p>A methodological approach using fluorescent in situ hybridization and Affymetrix (Santa Clara, CA) 250K SNP microarrays was used to characterize the multiplication in each family and to identify the genes encoded within the region. The telomeric and centromeric breakpoints of each family were further narrowed using semiquantitative polymerase chain reaction with microsatellite markers and then screened for transposable repeat elements.</p></section><section xml:id="abs1-3"><title type="main">Results</title><p>The severity of clinical presentation is correlated with <i>SNCA</i> dosage and does not appear to be overtly affected by the presence of other genes in the multiplicated region. With the exception of the Lister kindred, in each family the multiplication event appears de novo. The type and position of Alu/LINE repeats are also different at each breakpoint. Microsatellite analysis demonstrates two genomic mechanisms are responsible for chromosome 4q21 multiplications, including both <i>SNCA</i> duplication and recombination.</p></section><section xml:id="abs1-4"><title type="main">Interpretation</title><p><i>SNCA</i> dosage is responsible for parkinsonism, autonomic dysfunction, and dementia observed within each family. We hypothesize dysregulated expression of wild‐type α‐synuclein results in parkinsonism and may explain the recent association of common <i>SNCA</i> variants in sporadic Parkinson's disease. <i>SNCA</i> genomic duplication results from intraallelic (segmental duplication) or interallelic recombination with unequal crossing over, whereas both mechanisms appear to be required for genomic <i>SNCA</i> triplication. Ann Neurol 2008</p></section></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Genomic investigation of α‐synuclein multiplication and parkinsonism</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>SNCA and Parkinsonism</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Genomic investigation of α‐synuclein multiplication and parkinsonism</title></titleInfo><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, College of Medicine, Mayo Clinic, Jacksonville, FL</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Adam T.</namePart><namePart type="family">Braithwaite</namePart><namePart type="termsOfAddress">BSc</namePart><affiliation>Division of Neurogenetics, Department of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville, FL</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Lisa M.</namePart><namePart type="family">Skipper</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Division of Neurogenetics, Department of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville, FL</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jennifer</namePart><namePart type="family">Kachergus</namePart><namePart type="termsOfAddress">BSc, MBA</namePart><affiliation>Division of Neurogenetics, Department of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville, FL</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mary M.</namePart><namePart type="family">Hulihan</namePart><namePart type="termsOfAddress">MPH</namePart><affiliation>Division of Neurogenetics, Department of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville, FL</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Frank A.</namePart><namePart type="family">Middleton</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Center for Neuropsychiatric Genetics, Microarray Core Facility, State University of New York Upstate Medical University, Syracuse, NY</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kenya</namePart><namePart type="family">Nishioka</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Julia</namePart><namePart type="family">Fuchs</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurodegenerative Diseases, Center for Neurology, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Thomas</namePart><namePart type="family">Gasser</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurodegenerative Diseases, Center for Neurology, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Demetrius M.</namePart><namePart type="family">Maraganore</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN</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</namePart><affiliation>Department of Neurology, Mayo Clinic College of Medicine, Scottsdale, AZ</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Lydie</namePart><namePart type="family">Larvor</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>EA2683 ministère de l' éducation nationale de la recherche et de la technologie (MENRT), Diagnostic and Physiopathology of Parkinson's Disease, Institut de Recherches sur le Cancer de Lille (IRCL), Lille Cedex, 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><namePart type="termsOfAddress">MD</namePart><affiliation>EA2683 ministère de l' éducation nationale de la recherche et de la technologie (MENRT), Diagnostic and Physiopathology of Parkinson's Disease, Institut de Recherches sur le Cancer de Lille (IRCL), Lille Cedex, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christer</namePart><namePart type="family">Nilsson</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Clinical Medicine, Division of Geriatric Psychiatry, Lund University, Lund, Sweden</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">J. William</namePart><namePart type="family">Langston</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Parkinson's Institute and Clinical Center, Sunnyvale, CA</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>Neurogenetics, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Nobutaka</namePart><namePart type="family">Hattori</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan</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, College of Medicine, Mayo Clinic, Jacksonville, FL</affiliation><description>Correspondence: Morris K. Udall Parkinson's Disease Research Center of Excellence, Mayo Clinic, Department of Neuroscience, 4500 San Pablo Road South, Jacksonville, FL 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">2008-06</dateIssued><dateCaptured encoding="w3cdtf">2007-11-08</dateCaptured><dateValid encoding="w3cdtf">2008-02-11</dateValid><copyrightDate encoding="w3cdtf">2008</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="tables">1</extent><extent unit="references">43</extent><extent unit="words">4844</extent></physicalDescription><abstract lang="en">Objective: Copy number variation is a common polymorphic phenomenon within the human genome. Although the majority of these events are non‐deleterious they can also be highly pathogenic. Herein we characterize five families with parkinsonism that have been identified to harbor multiplication of the chromosomal 4q21 locus containing the α‐synuclein gene (SNCA). Methods: A methodological approach using fluorescent in situ hybridization and Affymetrix (Santa Clara, CA) 250K SNP microarrays was used to characterize the multiplication in each family and to identify the genes encoded within the region. The telomeric and centromeric breakpoints of each family were further narrowed using semiquantitative polymerase chain reaction with microsatellite markers and then screened for transposable repeat elements. Results: The severity of clinical presentation is correlated with SNCA dosage and does not appear to be overtly affected by the presence of other genes in the multiplicated region. With the exception of the Lister kindred, in each family the multiplication event appears de novo. The type and position of Alu/LINE repeats are also different at each breakpoint. Microsatellite analysis demonstrates two genomic mechanisms are responsible for chromosome 4q21 multiplications, including both SNCA duplication and recombination. Interpretation: SNCA dosage is responsible for parkinsonism, autonomic dysfunction, and dementia observed within each family. We hypothesize dysregulated expression of wild‐type α‐synuclein results in parkinsonism and may explain the recent association of common SNCA variants in sporadic Parkinson's disease. SNCA genomic duplication results from intraallelic (segmental duplication) or interallelic recombination with unequal crossing over, whereas both mechanisms appear to be required for genomic SNCA triplication. Ann Neurol 2008</abstract><note type="funding">American Parkinson Disease Association</note><note type="funding">Morris K. Udall Parkinson's Disease Research Center of Excellence (National Institute of Neurological Disorders and Stroke) - No. P50 #NS40256; </note><note type="funding">NIH (National Institute of Aging) - No. P01 #AG17216; </note><note type="funding">German National Genome Network (NGFN) - No. 01GS0116; </note><note type="funding">PHRC 2005/1914 the Universite de Lille 2 and Institut National de la Sante et de la Recherche Medicale</note><note type="funding">Draper Family Foundation</note><note type="funding">NIH (National Institute of Neurological Disorders and Stroke) - No. #N01‐NS‐2‐2349; </note><relatedItem type="host"><titleInfo><title>Annals of Neurology</title><subTitle>Official Journal of the American Neurological Association and the Child Neurology Society</subTitle></titleInfo><titleInfo type="abbreviated"><title>Ann Neurol.</title></titleInfo><genre type="Journal">journal</genre><note type="content"> This article includes supplementary materials available via the Internet at http://www.interscience.wiley.com/jpages/0364‐5134/suppmat</note><subject><genre>article category</genre><topic>Original Article</topic></subject><identifier type="ISSN">0364-5134</identifier><identifier type="eISSN">1531-8249</identifier><identifier type="DOI">10.1002/(ISSN)1531-8249</identifier><identifier type="PublisherID">ANA</identifier><part><date>2008</date><detail type="volume"><caption>vol.</caption><number>63</number></detail><detail type="issue"><caption>no.</caption><number>6</number></detail><extent unit="pages"><start>743</start><end>750</end><total>8</total></extent></part></relatedItem><identifier type="istex">78C1348524C06C8DBBAD41A8533A9623D7595BC7</identifier><identifier type="DOI">10.1002/ana.21380</identifier><identifier type="ArticleID">ANA21380</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2008 American Neurological Association</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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