Genomic investigation of α‐synuclein multiplication and parkinsonism
Identifieur interne : 000D89 ( Main/Exploration ); précédent : 000D88; suivant : 000D90Genomic investigation of α‐synuclein multiplication and parkinsonism
Auteurs : Owen A. Ross [États-Unis] ; Adam T. Braithwaite [États-Unis] ; Lisa M. Skipper [États-Unis] ; Jennifer Kachergus [États-Unis] ; Mary M. Hulihan [États-Unis] ; Frank A. Middleton [États-Unis] ; Kenya Nishioka [Japon] ; Julia Fuchs [Allemagne] ; Thomas Gasser [Allemagne] ; Demetrius M. Maraganore [États-Unis] ; Charles H. Adler [États-Unis] ; Lydie Larvor [France] ; Marie-Christine Chartier-Harlin [France] ; Christer Nilsson [Suède] ; J. William Langston [États-Unis] ; Katrina Gwinn [États-Unis] ; Nobutaka Hattori [Japon] ; Matthew J. Farrer [États-Unis]Source :
- 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
Url:
DOI: 10.1002/ana.21380
Affiliations:
- Allemagne, France, Japon, Suède, États-Unis
- Arizona, Bade-Wurtemberg, Californie, District de Tübingen, Floride, Maryland, Minnesota, État de New York
- Tokyo, Tübingen
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Hulihan</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Floride</region></placeName><wicri:cityArea>Division of Neurogenetics, Department of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville</wicri:cityArea></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 wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>Center for Neuropsychiatric Genetics, Microarray Core Facility, State University of New York Upstate Medical University, Syracuse</wicri:cityArea></affiliation></author><author><name sortKey="Nishioka, Kenya" sort="Nishioka, Kenya" uniqKey="Nishioka K" first="Kenya" last="Nishioka">Kenya Nishioka</name><affiliation wicri:level="3"><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement></placeName></affiliation></author><author><name sortKey="Fuchs, Julia" sort="Fuchs, Julia" uniqKey="Fuchs J" first="Julia" last="Fuchs">Julia Fuchs</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Neurodegenerative Diseases, Center for Neurology, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation></author><author><name sortKey="Gasser, Thomas" sort="Gasser, Thomas" uniqKey="Gasser T" first="Thomas" last="Gasser">Thomas Gasser</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Neurodegenerative Diseases, Center for Neurology, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></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 wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Minnesota</region></placeName><wicri:cityArea>Department of Neurology, Mayo Clinic College of Medicine, Rochester</wicri:cityArea></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 wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Arizona</region></placeName><wicri:cityArea>Department of Neurology, Mayo Clinic College of Medicine, Scottsdale</wicri:cityArea></affiliation></author><author><name sortKey="Larvor, Lydie" sort="Larvor, Lydie" uniqKey="Larvor L" first="Lydie" last="Larvor">Lydie Larvor</name><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Lille Cedex</wicri:noRegion><wicri:noRegion>Lille Cedex</wicri:noRegion></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 wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Lille Cedex</wicri:noRegion><wicri:noRegion>Lille Cedex</wicri:noRegion></affiliation></author><author><name sortKey="Nilsson, Christer" sort="Nilsson, Christer" uniqKey="Nilsson C" first="Christer" last="Nilsson">Christer Nilsson</name><affiliation wicri:level="1"><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Clinical Medicine, Division of Geriatric Psychiatry, Lund University, Lund</wicri:regionArea><wicri:noRegion>Lund</wicri:noRegion></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 wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Parkinson's Institute and Clinical Center, Sunnyvale</wicri:cityArea></affiliation></author><author><name sortKey="Gwinn, Katrina" sort="Gwinn, Katrina" uniqKey="Gwinn K" first="Katrina" last="Gwinn">Katrina Gwinn</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Neurogenetics, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Hattori, Nobutaka" sort="Hattori, Nobutaka" uniqKey="Hattori N" first="Nobutaka" last="Hattori">Nobutaka Hattori</name><affiliation wicri:level="3"><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement></placeName></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 wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Floride</region></placeName><wicri:cityArea>Division of Neurogenetics, Department of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville</wicri:cityArea></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><affiliations><list><country><li>Allemagne</li><li>France</li><li>Japon</li><li>Suède</li><li>États-Unis</li></country><region><li>Arizona</li><li>Bade-Wurtemberg</li><li>Californie</li><li>District de Tübingen</li><li>Floride</li><li>Maryland</li><li>Minnesota</li><li>État de New York</li></region><settlement><li>Tokyo</li><li>Tübingen</li></settlement></list><tree><country name="États-Unis"><region name="Floride"><name sortKey="Ross, Owen A" sort="Ross, Owen A" uniqKey="Ross O" first="Owen A." last="Ross">Owen A. Ross</name></region><name sortKey="Adler, Charles H" sort="Adler, Charles H" uniqKey="Adler C" first="Charles H." last="Adler">Charles H. Adler</name><name sortKey="Braithwaite, Adam T" sort="Braithwaite, Adam T" uniqKey="Braithwaite A" first="Adam T." last="Braithwaite">Adam T. Braithwaite</name><name sortKey="Farrer, Matthew J" sort="Farrer, Matthew J" uniqKey="Farrer M" first="Matthew J." last="Farrer">Matthew J. Farrer</name><name sortKey="Gwinn, Katrina" sort="Gwinn, Katrina" uniqKey="Gwinn K" first="Katrina" last="Gwinn">Katrina Gwinn</name><name sortKey="Hulihan, Mary M" sort="Hulihan, Mary M" uniqKey="Hulihan M" first="Mary M." last="Hulihan">Mary M. Hulihan</name><name sortKey="Kachergus, Jennifer" sort="Kachergus, Jennifer" uniqKey="Kachergus J" first="Jennifer" last="Kachergus">Jennifer Kachergus</name><name sortKey="Langston, J William" sort="Langston, J William" uniqKey="Langston J" first="J. William" last="Langston">J. William Langston</name><name sortKey="Maraganore, Demetrius M" sort="Maraganore, Demetrius M" uniqKey="Maraganore D" first="Demetrius M." last="Maraganore">Demetrius M. Maraganore</name><name sortKey="Middleton, Frank A" sort="Middleton, Frank A" uniqKey="Middleton F" first="Frank A." last="Middleton">Frank A. Middleton</name><name sortKey="Skipper, Lisa M" sort="Skipper, Lisa M" uniqKey="Skipper L" first="Lisa M." last="Skipper">Lisa M. Skipper</name></country><country name="Japon"><noRegion><name sortKey="Nishioka, Kenya" sort="Nishioka, Kenya" uniqKey="Nishioka K" first="Kenya" last="Nishioka">Kenya Nishioka</name></noRegion><name sortKey="Hattori, Nobutaka" sort="Hattori, Nobutaka" uniqKey="Hattori N" first="Nobutaka" last="Hattori">Nobutaka Hattori</name></country><country name="Allemagne"><region name="Bade-Wurtemberg"><name sortKey="Fuchs, Julia" sort="Fuchs, Julia" uniqKey="Fuchs J" first="Julia" last="Fuchs">Julia Fuchs</name></region><name sortKey="Gasser, Thomas" sort="Gasser, Thomas" uniqKey="Gasser T" first="Thomas" last="Gasser">Thomas Gasser</name></country><country name="France"><noRegion><name sortKey="Larvor, Lydie" sort="Larvor, Lydie" uniqKey="Larvor L" first="Lydie" last="Larvor">Lydie Larvor</name></noRegion><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></country><country name="Suède"><noRegion><name sortKey="Nilsson, Christer" sort="Nilsson, Christer" uniqKey="Nilsson C" first="Christer" last="Nilsson">Christer Nilsson</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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