Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration
Identifieur interne : 000E55 ( Istex/Corpus ); précédent : 000E54; suivant : 000E56Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration
Auteurs : Claire L. Simpson ; Robin Lemmens ; Katarzyna Miskiewicz ; Wendy J. Broom ; Valerie K. Hansen ; Paul W. J. Van Vught ; John E. Landers ; Peter Sapp ; Ludo Van Den Bosch ; Joanne Knight ; Benjamin M. Neale ; Martin R. Turner ; Jan H. Veldink ; Roel A. Ophoff ; Vineeta B. Tripathi ; Ana Beleza ; Meera N. Shah ; Petroula Proitsi ; Annelies Van Hoecke ; Peter Carmeliet ; H. Robert Horvitz ; P. Nigel Leigh ; Christopher E. Shaw ; Leonard H. Van Den Berg ; Pak C. Sham ; John F. Powell ; Patrik Verstreken ; Robert H. Brown ; Wim Robberecht ; Ammar Al-ChalabiSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2009-02-01.
Abstract
Amyotrophic lateral sclerosis (ALS) is a spontaneous, relentlessly progressive motor neuron disease, usually resulting in death from respiratory failure within 3 years. Variation in the genes SOD1 and TARDBP accounts for a small percentage of cases, and other genes have shown association in both candidate gene and genome-wide studies, but the genetic causes remain largely unknown. We have performed two independent parallel studies, both implicating the RNA polymerase II component, ELP3, in axonal biology and neuronal degeneration. In the first, an association study of 1884 microsatellite markers, allelic variants of ELP3 were associated with ALS in three human populations comprising 1483 people (P 1.96 109). In the second, an independent mutagenesis screen in Drosophila for genes important in neuronal communication and survival identified two different loss of function mutations, both in ELP3 (R475K and R456K). Furthermore, knock down of ELP3 protein levels using antisense morpholinos in zebrafish embryos resulted in dose-dependent motor axonal abnormalities [Pearson correlation: 0.49, P 1.83 1012 (start codon morpholino) and 0.46, P 4.05 109 (splice-site morpholino), and in humans, risk-associated ELP3 genotypes correlated with reduced brain ELP3 expression (P 0.01). These findings add to the growing body of evidence implicating the RNA processing pathway in neurodegeneration and suggest a critical role for ELP3 in neuron biology and of ELP3 variants in ALS.
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DOI: 10.1093/hmg/ddn375
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Simpson</name><affiliation><mods:affiliation>Department of Neurology</mods:affiliation></affiliation></author><author><name sortKey="Lemmens, Robin" sort="Lemmens, Robin" uniqKey="Lemmens R" first="Robin" last="Lemmens">Robin Lemmens</name><affiliation><mods:affiliation>Service of Neurology (University Hospital Leuven) and Laboratory for Neurobiology, Section of Experimental Neurology, University of Leuven, Leuven B-3000, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Miskiewicz, Katarzyna" sort="Miskiewicz, Katarzyna" uniqKey="Miskiewicz K" first="Katarzyna" last="Miskiewicz">Katarzyna Miskiewicz</name><affiliation><mods:affiliation>Center for Human Genetics, Laboratory of Neuronal Communication, KU Leuven, Leuven B-3000, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Molecular and Developmental Genetics, VIB, Leuven B-3000, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Broom, Wendy J" sort="Broom, Wendy J" uniqKey="Broom W" first="Wendy J." last="Broom">Wendy J. Broom</name><affiliation><mods:affiliation>Cecil B Day Laboratory for Neuromuscular Research, Massachusetts General Hospital East, Charlestown, MA, USA</mods:affiliation></affiliation></author><author><name sortKey="Hansen, Valerie K" sort="Hansen, Valerie K" uniqKey="Hansen V" first="Valerie K." last="Hansen">Valerie K. Hansen</name><affiliation><mods:affiliation>Department of Neurology</mods:affiliation></affiliation></author><author><name sortKey="Van Vught, Paul W J" sort="Van Vught, Paul W J" uniqKey="Van Vught P" first="Paul W. J." last="Van Vught">Paul W. J. Van Vught</name><affiliation><mods:affiliation>Department of Neurology</mods:affiliation></affiliation></author><author><name sortKey="Landers, John E" sort="Landers, John E" uniqKey="Landers J" first="John E." last="Landers">John E. 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Neale</name><affiliation><mods:affiliation>MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Kings College London, London SE5 8AF, UK</mods:affiliation></affiliation></author><author><name sortKey="Turner, Martin R" sort="Turner, Martin R" uniqKey="Turner M" first="Martin R." last="Turner">Martin R. Turner</name><affiliation><mods:affiliation>Department of Neurology</mods:affiliation></affiliation></author><author><name sortKey="Veldink, Jan H" sort="Veldink, Jan H" uniqKey="Veldink J" first="Jan H." last="Veldink">Jan H. Veldink</name><affiliation><mods:affiliation>Department of Neurology</mods:affiliation></affiliation></author><author><name sortKey="Ophoff, Roel A" sort="Ophoff, Roel A" uniqKey="Ophoff R" first="Roel A." last="Ophoff">Roel A. Ophoff</name><affiliation><mods:affiliation>Department of Medical Genetics, Rudolf Magnus Institute of Neuroscience, University Medical Center, Utrecht, the Netherlands</mods:affiliation></affiliation><affiliation><mods:affiliation>Neuropsychiatric Institute, University of California, Los Angeles, CA, USA</mods:affiliation></affiliation></author><author><name sortKey="Tripathi, Vineeta B" sort="Tripathi, Vineeta B" uniqKey="Tripathi V" first="Vineeta B." last="Tripathi">Vineeta B. Tripathi</name><affiliation><mods:affiliation>Department of Neurology</mods:affiliation></affiliation></author><author><name sortKey="Beleza, Ana" sort="Beleza, Ana" uniqKey="Beleza A" first="Ana" last="Beleza">Ana Beleza</name><affiliation><mods:affiliation>Department of Neurology</mods:affiliation></affiliation></author><author><name sortKey="Shah, Meera N" sort="Shah, Meera N" uniqKey="Shah M" first="Meera N." last="Shah">Meera N. Shah</name><affiliation><mods:affiliation>Department of Neurology</mods:affiliation></affiliation></author><author><name sortKey="Proitsi, Petroula" sort="Proitsi, Petroula" uniqKey="Proitsi P" first="Petroula" last="Proitsi">Petroula Proitsi</name><affiliation><mods:affiliation>Department of Neuroscience, MRC Centre for Neurodegeneration Research</mods:affiliation></affiliation></author><author><name sortKey="Van Hoecke, Annelies" sort="Van Hoecke, Annelies" uniqKey="Van Hoecke A" first="Annelies" last="Van Hoecke">Annelies Van Hoecke</name><affiliation><mods:affiliation>Service of Neurology (University Hospital Leuven) and Laboratory for Neurobiology, Section of Experimental Neurology, University of Leuven, Leuven B-3000, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Vesalius Research Center, Flanders Institute for Biotechnology (VIB)</mods:affiliation></affiliation></author><author><name sortKey="Carmeliet, Peter" sort="Carmeliet, Peter" uniqKey="Carmeliet P" first="Peter" last="Carmeliet">Peter Carmeliet</name><affiliation><mods:affiliation>Vesalius Research Center, Flanders Institute for Biotechnology (VIB)</mods:affiliation></affiliation></author><author><name sortKey="Horvitz, H Robert" sort="Horvitz, H Robert" uniqKey="Horvitz H" first="H. Robert" last="Horvitz">H. Robert Horvitz</name><affiliation><mods:affiliation>Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA</mods:affiliation></affiliation></author><author><name sortKey="Leigh, P Nigel" sort="Leigh, P Nigel" uniqKey="Leigh P" first="P. Nigel" last="Leigh">P. Nigel Leigh</name><affiliation><mods:affiliation>Department of Neurology</mods:affiliation></affiliation></author><author><name sortKey="Shaw, Christopher E" sort="Shaw, Christopher E" uniqKey="Shaw C" first="Christopher E." last="Shaw">Christopher E. Shaw</name><affiliation><mods:affiliation>Department of Neurology</mods:affiliation></affiliation></author><author><name sortKey="Van Den Berg, Leonard H" sort="Van Den Berg, Leonard H" uniqKey="Van Den Berg L" first="Leonard H." last="Van Den Berg">Leonard H. Van Den Berg</name><affiliation><mods:affiliation>Department of Neurology</mods:affiliation></affiliation></author><author><name sortKey="Sham, Pak C" sort="Sham, Pak C" uniqKey="Sham P" first="Pak C." last="Sham">Pak C. Sham</name><affiliation><mods:affiliation>Department of Psychiatry and Genome Centre, University of Hong Kong, Hong Kong</mods:affiliation></affiliation></author><author><name sortKey="Powell, John F" sort="Powell, John F" uniqKey="Powell J" first="John F." last="Powell">John F. Powell</name><affiliation><mods:affiliation>Department of Neuroscience, MRC Centre for Neurodegeneration Research</mods:affiliation></affiliation></author><author><name sortKey="Verstreken, Patrik" sort="Verstreken, Patrik" uniqKey="Verstreken P" first="Patrik" last="Verstreken">Patrik Verstreken</name><affiliation><mods:affiliation>Center for Human Genetics, Laboratory of Neuronal Communication, KU Leuven, Leuven B-3000, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Molecular and Developmental Genetics, VIB, Leuven B-3000, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Brown, Robert H" sort="Brown, Robert H" uniqKey="Brown R" first="Robert H." last="Brown">Robert H. Brown</name><affiliation><mods:affiliation>Cecil B Day Laboratory for Neuromuscular Research, Massachusetts General Hospital East, Charlestown, MA, USA</mods:affiliation></affiliation></author><author><name sortKey="Robberecht, Wim" sort="Robberecht, Wim" uniqKey="Robberecht W" first="Wim" last="Robberecht">Wim Robberecht</name><affiliation><mods:affiliation>Service of Neurology (University Hospital Leuven) and Laboratory for Neurobiology, Section of Experimental Neurology, University of Leuven, Leuven B-3000, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Vesalius Research Center, Flanders Institute for Biotechnology (VIB)</mods:affiliation></affiliation></author><author><name sortKey="Al Chalabi, Ammar" sort="Al Chalabi, Ammar" uniqKey="Al Chalabi A" first="Ammar" last="Al-Chalabi">Ammar Al-Chalabi</name><affiliation><mods:affiliation>Department of Neurology</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: ammar@iop.kcl.ac.uk</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:A978A982B22444802EEEFD36FB8A8351D048E4B3</idno><date when="2009" year="2009">2009</date><idno type="doi">10.1093/hmg/ddn375</idno><idno type="url">https://api.istex.fr/document/A978A982B22444802EEEFD36FB8A8351D048E4B3/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">000E55</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration</title><author><name sortKey="Simpson, Claire L" sort="Simpson, Claire L" uniqKey="Simpson C" first="Claire L." last="Simpson">Claire L. Simpson</name><affiliation><mods:affiliation>Department of Neurology</mods:affiliation></affiliation></author><author><name sortKey="Lemmens, Robin" sort="Lemmens, Robin" uniqKey="Lemmens R" first="Robin" last="Lemmens">Robin Lemmens</name><affiliation><mods:affiliation>Service of Neurology (University Hospital Leuven) and Laboratory for Neurobiology, Section of Experimental Neurology, University of Leuven, Leuven B-3000, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Miskiewicz, Katarzyna" sort="Miskiewicz, Katarzyna" uniqKey="Miskiewicz K" first="Katarzyna" last="Miskiewicz">Katarzyna Miskiewicz</name><affiliation><mods:affiliation>Center for Human Genetics, Laboratory of Neuronal Communication, KU Leuven, Leuven B-3000, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Molecular and Developmental Genetics, VIB, Leuven B-3000, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Broom, Wendy J" sort="Broom, Wendy J" uniqKey="Broom W" first="Wendy J." last="Broom">Wendy J. Broom</name><affiliation><mods:affiliation>Cecil B Day Laboratory for Neuromuscular Research, Massachusetts General Hospital East, Charlestown, MA, USA</mods:affiliation></affiliation></author><author><name sortKey="Hansen, Valerie K" sort="Hansen, Valerie K" uniqKey="Hansen V" first="Valerie K." last="Hansen">Valerie K. Hansen</name><affiliation><mods:affiliation>Department of Neurology</mods:affiliation></affiliation></author><author><name sortKey="Van Vught, Paul W J" sort="Van Vught, Paul W J" uniqKey="Van Vught P" first="Paul W. J." last="Van Vught">Paul W. J. Van Vught</name><affiliation><mods:affiliation>Department of Neurology</mods:affiliation></affiliation></author><author><name sortKey="Landers, John E" sort="Landers, John E" uniqKey="Landers J" first="John E." last="Landers">John E. Landers</name><affiliation><mods:affiliation>Cecil B Day Laboratory for Neuromuscular Research, Massachusetts General Hospital East, Charlestown, MA, USA</mods:affiliation></affiliation></author><author><name sortKey="Sapp, Peter" sort="Sapp, Peter" uniqKey="Sapp P" first="Peter" last="Sapp">Peter Sapp</name><affiliation><mods:affiliation>Cecil B Day Laboratory for Neuromuscular Research, Massachusetts General Hospital East, Charlestown, MA, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA</mods:affiliation></affiliation></author><author><name sortKey="Van Den Bosch, Ludo" sort="Van Den Bosch, Ludo" uniqKey="Van Den Bosch L" first="Ludo" last="Van Den Bosch">Ludo Van Den Bosch</name><affiliation><mods:affiliation>Service of Neurology (University Hospital Leuven) and Laboratory for Neurobiology, Section of Experimental Neurology, University of Leuven, Leuven B-3000, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Vesalius Research Center, Flanders Institute for Biotechnology (VIB)</mods:affiliation></affiliation></author><author><name sortKey="Knight, Joanne" sort="Knight, Joanne" uniqKey="Knight J" first="Joanne" last="Knight">Joanne Knight</name><affiliation><mods:affiliation>MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Kings College London, London SE5 8AF, UK</mods:affiliation></affiliation></author><author><name sortKey="Neale, Benjamin M" sort="Neale, Benjamin M" uniqKey="Neale B" first="Benjamin M." last="Neale">Benjamin M. Neale</name><affiliation><mods:affiliation>MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Kings College London, London SE5 8AF, UK</mods:affiliation></affiliation></author><author><name sortKey="Turner, Martin R" sort="Turner, Martin R" uniqKey="Turner M" first="Martin R." last="Turner">Martin R. Turner</name><affiliation><mods:affiliation>Department of Neurology</mods:affiliation></affiliation></author><author><name sortKey="Veldink, Jan H" sort="Veldink, Jan H" uniqKey="Veldink J" first="Jan H." last="Veldink">Jan H. Veldink</name><affiliation><mods:affiliation>Department of Neurology</mods:affiliation></affiliation></author><author><name sortKey="Ophoff, Roel A" sort="Ophoff, Roel A" uniqKey="Ophoff R" first="Roel A." last="Ophoff">Roel A. Ophoff</name><affiliation><mods:affiliation>Department of Medical Genetics, Rudolf Magnus Institute of Neuroscience, University Medical Center, Utrecht, the Netherlands</mods:affiliation></affiliation><affiliation><mods:affiliation>Neuropsychiatric Institute, University of California, Los Angeles, CA, USA</mods:affiliation></affiliation></author><author><name sortKey="Tripathi, Vineeta B" sort="Tripathi, Vineeta B" uniqKey="Tripathi V" first="Vineeta B." last="Tripathi">Vineeta B. Tripathi</name><affiliation><mods:affiliation>Department of Neurology</mods:affiliation></affiliation></author><author><name sortKey="Beleza, Ana" sort="Beleza, Ana" uniqKey="Beleza A" first="Ana" last="Beleza">Ana Beleza</name><affiliation><mods:affiliation>Department of Neurology</mods:affiliation></affiliation></author><author><name sortKey="Shah, Meera N" sort="Shah, Meera N" uniqKey="Shah M" first="Meera N." last="Shah">Meera N. Shah</name><affiliation><mods:affiliation>Department of Neurology</mods:affiliation></affiliation></author><author><name sortKey="Proitsi, Petroula" sort="Proitsi, Petroula" uniqKey="Proitsi P" first="Petroula" last="Proitsi">Petroula Proitsi</name><affiliation><mods:affiliation>Department of Neuroscience, MRC Centre for Neurodegeneration Research</mods:affiliation></affiliation></author><author><name sortKey="Van Hoecke, Annelies" sort="Van Hoecke, Annelies" uniqKey="Van Hoecke A" first="Annelies" last="Van Hoecke">Annelies Van Hoecke</name><affiliation><mods:affiliation>Service of Neurology (University Hospital Leuven) and Laboratory for Neurobiology, Section of Experimental Neurology, University of Leuven, Leuven B-3000, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Vesalius Research Center, Flanders Institute for Biotechnology (VIB)</mods:affiliation></affiliation></author><author><name sortKey="Carmeliet, Peter" sort="Carmeliet, Peter" uniqKey="Carmeliet P" first="Peter" last="Carmeliet">Peter Carmeliet</name><affiliation><mods:affiliation>Vesalius Research Center, Flanders Institute for Biotechnology (VIB)</mods:affiliation></affiliation></author><author><name sortKey="Horvitz, H Robert" sort="Horvitz, H Robert" uniqKey="Horvitz H" first="H. Robert" last="Horvitz">H. Robert Horvitz</name><affiliation><mods:affiliation>Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA</mods:affiliation></affiliation></author><author><name sortKey="Leigh, P Nigel" sort="Leigh, P Nigel" uniqKey="Leigh P" first="P. Nigel" last="Leigh">P. Nigel Leigh</name><affiliation><mods:affiliation>Department of Neurology</mods:affiliation></affiliation></author><author><name sortKey="Shaw, Christopher E" sort="Shaw, Christopher E" uniqKey="Shaw C" first="Christopher E." last="Shaw">Christopher E. Shaw</name><affiliation><mods:affiliation>Department of Neurology</mods:affiliation></affiliation></author><author><name sortKey="Van Den Berg, Leonard H" sort="Van Den Berg, Leonard H" uniqKey="Van Den Berg L" first="Leonard H." last="Van Den Berg">Leonard H. Van Den Berg</name><affiliation><mods:affiliation>Department of Neurology</mods:affiliation></affiliation></author><author><name sortKey="Sham, Pak C" sort="Sham, Pak C" uniqKey="Sham P" first="Pak C." last="Sham">Pak C. Sham</name><affiliation><mods:affiliation>Department of Psychiatry and Genome Centre, University of Hong Kong, Hong Kong</mods:affiliation></affiliation></author><author><name sortKey="Powell, John F" sort="Powell, John F" uniqKey="Powell J" first="John F." last="Powell">John F. Powell</name><affiliation><mods:affiliation>Department of Neuroscience, MRC Centre for Neurodegeneration Research</mods:affiliation></affiliation></author><author><name sortKey="Verstreken, Patrik" sort="Verstreken, Patrik" uniqKey="Verstreken P" first="Patrik" last="Verstreken">Patrik Verstreken</name><affiliation><mods:affiliation>Center for Human Genetics, Laboratory of Neuronal Communication, KU Leuven, Leuven B-3000, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Molecular and Developmental Genetics, VIB, Leuven B-3000, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Brown, Robert H" sort="Brown, Robert H" uniqKey="Brown R" first="Robert H." last="Brown">Robert H. Brown</name><affiliation><mods:affiliation>Cecil B Day Laboratory for Neuromuscular Research, Massachusetts General Hospital East, Charlestown, MA, USA</mods:affiliation></affiliation></author><author><name sortKey="Robberecht, Wim" sort="Robberecht, Wim" uniqKey="Robberecht W" first="Wim" last="Robberecht">Wim Robberecht</name><affiliation><mods:affiliation>Service of Neurology (University Hospital Leuven) and Laboratory for Neurobiology, Section of Experimental Neurology, University of Leuven, Leuven B-3000, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Vesalius Research Center, Flanders Institute for Biotechnology (VIB)</mods:affiliation></affiliation></author><author><name sortKey="Al Chalabi, Ammar" sort="Al Chalabi, Ammar" uniqKey="Al Chalabi A" first="Ammar" last="Al-Chalabi">Ammar Al-Chalabi</name><affiliation><mods:affiliation>Department of Neurology</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: ammar@iop.kcl.ac.uk</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Human Molecular Genetics</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2009-02-01">2009-02-01</date><biblScope unit="volume">18</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="472">472</biblScope><biblScope unit="page" to="481">481</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">A978A982B22444802EEEFD36FB8A8351D048E4B3</idno><idno type="DOI">10.1093/hmg/ddn375</idno><idno type="ArticleID">ddn375</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Amyotrophic lateral sclerosis (ALS) is a spontaneous, relentlessly progressive motor neuron disease, usually resulting in death from respiratory failure within 3 years. Variation in the genes SOD1 and TARDBP accounts for a small percentage of cases, and other genes have shown association in both candidate gene and genome-wide studies, but the genetic causes remain largely unknown. We have performed two independent parallel studies, both implicating the RNA polymerase II component, ELP3, in axonal biology and neuronal degeneration. In the first, an association study of 1884 microsatellite markers, allelic variants of ELP3 were associated with ALS in three human populations comprising 1483 people (P 1.96 109). In the second, an independent mutagenesis screen in Drosophila for genes important in neuronal communication and survival identified two different loss of function mutations, both in ELP3 (R475K and R456K). Furthermore, knock down of ELP3 protein levels using antisense morpholinos in zebrafish embryos resulted in dose-dependent motor axonal abnormalities [Pearson correlation: 0.49, P 1.83 1012 (start codon morpholino) and 0.46, P 4.05 109 (splice-site morpholino), and in humans, risk-associated ELP3 genotypes correlated with reduced brain ELP3 expression (P 0.01). These findings add to the growing body of evidence implicating the RNA processing pathway in neurodegeneration and suggest a critical role for ELP3 in neuron biology and of ELP3 variants in ALS.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Claire L. Simpson</name><affiliations><json:string>Department of Neurology</json:string></affiliations></json:item><json:item><name>Robin Lemmens</name><affiliations><json:string>Service of Neurology (University Hospital Leuven) and Laboratory for Neurobiology, Section of Experimental Neurology, University of Leuven, Leuven B-3000, Belgium</json:string></affiliations></json:item><json:item><name>Katarzyna Miskiewicz</name><affiliations><json:string>Center for Human Genetics, Laboratory of Neuronal Communication, KU Leuven, Leuven B-3000, Belgium</json:string><json:string>Department of Molecular and Developmental Genetics, VIB, Leuven B-3000, Belgium</json:string></affiliations></json:item><json:item><name>Wendy J. Broom</name><affiliations><json:string>Cecil B Day Laboratory for Neuromuscular Research, Massachusetts General Hospital East, Charlestown, MA, USA</json:string></affiliations></json:item><json:item><name>Valerie K. Hansen</name><affiliations><json:string>Department of Neurology</json:string></affiliations></json:item><json:item><name>Paul W.J. van Vught</name><affiliations><json:string>Department of Neurology</json:string></affiliations></json:item><json:item><name>John E. Landers</name><affiliations><json:string>Cecil B Day Laboratory for Neuromuscular Research, Massachusetts General Hospital East, Charlestown, MA, USA</json:string></affiliations></json:item><json:item><name>Peter Sapp</name><affiliations><json:string>Cecil B Day Laboratory for Neuromuscular Research, Massachusetts General Hospital East, Charlestown, MA, USA</json:string><json:string>Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA</json:string></affiliations></json:item><json:item><name>Ludo Van Den Bosch</name><affiliations><json:string>Service of Neurology (University Hospital Leuven) and Laboratory for Neurobiology, Section of Experimental Neurology, University of Leuven, Leuven B-3000, Belgium</json:string><json:string>Vesalius Research Center, Flanders Institute for Biotechnology (VIB)</json:string></affiliations></json:item><json:item><name>Joanne Knight</name><affiliations><json:string>MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Kings College London, London SE5 8AF, UK</json:string></affiliations></json:item><json:item><name>Benjamin M. Neale</name><affiliations><json:string>MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Kings College London, London SE5 8AF, UK</json:string></affiliations></json:item><json:item><name>Martin R. Turner</name><affiliations><json:string>Department of Neurology</json:string></affiliations></json:item><json:item><name>Jan H. Veldink</name><affiliations><json:string>Department of Neurology</json:string></affiliations></json:item><json:item><name>Roel A. Ophoff</name><affiliations><json:string>Department of Medical Genetics, Rudolf Magnus Institute of Neuroscience, University Medical Center, Utrecht, the Netherlands</json:string><json:string>Neuropsychiatric Institute, University of California, Los Angeles, CA, USA</json:string></affiliations></json:item><json:item><name>Vineeta B. Tripathi</name><affiliations><json:string>Department of Neurology</json:string></affiliations></json:item><json:item><name>Ana Beleza</name><affiliations><json:string>Department of Neurology</json:string></affiliations></json:item><json:item><name>Meera N. Shah</name><affiliations><json:string>Department of Neurology</json:string></affiliations></json:item><json:item><name>Petroula Proitsi</name><affiliations><json:string>Department of Neuroscience, MRC Centre for Neurodegeneration Research</json:string></affiliations></json:item><json:item><name>Annelies Van Hoecke</name><affiliations><json:string>Service of Neurology (University Hospital Leuven) and Laboratory for Neurobiology, Section of Experimental Neurology, University of Leuven, Leuven B-3000, Belgium</json:string><json:string>Vesalius Research Center, Flanders Institute for Biotechnology (VIB)</json:string></affiliations></json:item><json:item><name>Peter Carmeliet</name><affiliations><json:string>Vesalius Research Center, Flanders Institute for Biotechnology (VIB)</json:string></affiliations></json:item><json:item><name>H. Robert Horvitz</name><affiliations><json:string>Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA</json:string></affiliations></json:item><json:item><name>P. Nigel Leigh</name><affiliations><json:string>Department of Neurology</json:string></affiliations></json:item><json:item><name>Christopher E. Shaw</name><affiliations><json:string>Department of Neurology</json:string></affiliations></json:item><json:item><name>Leonard H. van den Berg</name><affiliations><json:string>Department of Neurology</json:string></affiliations></json:item><json:item><name>Pak C. Sham</name><affiliations><json:string>Department of Psychiatry and Genome Centre, University of Hong Kong, Hong Kong</json:string></affiliations></json:item><json:item><name>John F. Powell</name><affiliations><json:string>Department of Neuroscience, MRC Centre for Neurodegeneration Research</json:string></affiliations></json:item><json:item><name>Patrik Verstreken</name><affiliations><json:string>Center for Human Genetics, Laboratory of Neuronal Communication, KU Leuven, Leuven B-3000, Belgium</json:string><json:string>Department of Molecular and Developmental Genetics, VIB, Leuven B-3000, Belgium</json:string></affiliations></json:item><json:item><name>Robert H. Brown Jr</name><affiliations><json:string>Cecil B Day Laboratory for Neuromuscular Research, Massachusetts General Hospital East, Charlestown, MA, USA</json:string></affiliations></json:item><json:item><name>Wim Robberecht</name><affiliations><json:string>Service of Neurology (University Hospital Leuven) and Laboratory for Neurobiology, Section of Experimental Neurology, University of Leuven, Leuven B-3000, Belgium</json:string><json:string>Vesalius Research Center, Flanders Institute for Biotechnology (VIB)</json:string></affiliations></json:item><json:item><name>Ammar Al-Chalabi</name><affiliations><json:string>Department of Neurology</json:string><json:string>E-mail: ammar@iop.kcl.ac.uk</json:string></affiliations></json:item></author><articleId><json:string>ddn375</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>Amyotrophic lateral sclerosis (ALS) is a spontaneous, relentlessly progressive motor neuron disease, usually resulting in death from respiratory failure within 3 years. Variation in the genes SOD1 and TARDBP accounts for a small percentage of cases, and other genes have shown association in both candidate gene and genome-wide studies, but the genetic causes remain largely unknown. We have performed two independent parallel studies, both implicating the RNA polymerase II component, ELP3, in axonal biology and neuronal degeneration. In the first, an association study of 1884 microsatellite markers, allelic variants of ELP3 were associated with ALS in three human populations comprising 1483 people (P 1.96 109). In the second, an independent mutagenesis screen in Drosophila for genes important in neuronal communication and survival identified two different loss of function mutations, both in ELP3 (R475K and R456K). Furthermore, knock down of ELP3 protein levels using antisense morpholinos in zebrafish embryos resulted in dose-dependent motor axonal abnormalities [Pearson correlation: 0.49, P 1.83 1012 (start codon morpholino) and 0.46, P 4.05 109 (splice-site morpholino), and in humans, risk-associated ELP3 genotypes correlated with reduced brain ELP3 expression (P 0.01). These findings add to the growing body of evidence implicating the RNA processing pathway in neurodegeneration and suggest a critical role for ELP3 in neuron biology and of ELP3 variants in ALS.</abstract><qualityIndicators><score>7.592</score><pdfVersion>1.2</pdfVersion><pdfPageSize>612 x 797.953 pts</pdfPageSize><refBibsNative>false</refBibsNative><keywordCount>0</keywordCount><abstractCharCount>1483</abstractCharCount><pdfWordCount>6539</pdfWordCount><pdfCharCount>41181</pdfCharCount><pdfPageCount>10</pdfPageCount><abstractWordCount>216</abstractWordCount></qualityIndicators><title>Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration</title><genre><json:string>research-article</json:string></genre><host><volume>18</volume><publisherId><json:string>hmg</json:string></publisherId><pages><last>481</last><first>472</first></pages><issn><json:string>0964-6906</json:string></issn><issue>3</issue><genre><json:string>journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1460-2083</json:string></eissn><title>Human Molecular Genetics</title></host><categories><wos><json:string>BIOCHEMISTRY & MOLECULAR BIOLOGY</json:string><json:string>GENETICS & HEREDITY</json:string></wos></categories><publicationDate>2009</publicationDate><copyrightDate>2009</copyrightDate><doi><json:string>10.1093/hmg/ddn375</json:string></doi><id>A978A982B22444802EEEFD36FB8A8351D048E4B3</id><score>0.24932158</score><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/A978A982B22444802EEEFD36FB8A8351D048E4B3/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/A978A982B22444802EEEFD36FB8A8351D048E4B3/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/A978A982B22444802EEEFD36FB8A8351D048E4B3/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a">Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration</title><respStmt><resp>Références bibliographiques récupérées via GROBID</resp><name resp="ISTEX-API">ISTEX-API (INIST-CNRS)</name></respStmt></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Oxford University Press</publisher><availability><p>2008 The Author(s)</p></availability><date>2008-11-07</date></publicationStmt><notesStmt><note>The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration</title><author xml:id="author-1"><persName><forename type="first">Claire L.</forename><surname>Simpson</surname></persName><note type="biography">The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</note><affiliation>The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</affiliation><affiliation>Department of Neurology</affiliation></author><author xml:id="author-2"><persName><forename type="first">Robin</forename><surname>Lemmens</surname></persName><note type="biography">The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</note><affiliation>The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</affiliation><affiliation>Service of Neurology (University Hospital Leuven) and Laboratory for Neurobiology, Section of Experimental Neurology, University of Leuven, Leuven B-3000, Belgium</affiliation></author><author xml:id="author-3"><persName><forename type="first">Katarzyna</forename><surname>Miskiewicz</surname></persName><affiliation>Center for Human Genetics, Laboratory of Neuronal Communication, KU Leuven, Leuven B-3000, Belgium</affiliation><affiliation>Department of Molecular and Developmental Genetics, VIB, Leuven B-3000, Belgium</affiliation></author><author xml:id="author-4"><persName><forename type="first">Wendy J.</forename><surname>Broom</surname></persName><affiliation>Cecil B Day Laboratory for Neuromuscular Research, Massachusetts General Hospital East, Charlestown, MA, USA</affiliation></author><author xml:id="author-5"><persName><forename type="first">Valerie K.</forename><surname>Hansen</surname></persName><affiliation>Department of Neurology</affiliation></author><author xml:id="author-6"><persName><forename type="first">Paul W.J.</forename><surname>van Vught</surname></persName><affiliation>Department of Neurology</affiliation></author><author xml:id="author-7"><persName><forename type="first">John E.</forename><surname>Landers</surname></persName><affiliation>Cecil B Day Laboratory for Neuromuscular Research, Massachusetts General Hospital East, Charlestown, MA, USA</affiliation></author><author xml:id="author-8"><persName><forename type="first">Peter</forename><surname>Sapp</surname></persName><affiliation>Cecil B Day Laboratory for Neuromuscular Research, Massachusetts General Hospital East, Charlestown, MA, USA</affiliation><affiliation>Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA</affiliation></author><author xml:id="author-9"><persName><forename type="first">Ludo</forename><surname>Van Den Bosch</surname></persName><affiliation>Service of Neurology (University Hospital Leuven) and Laboratory for Neurobiology, Section of Experimental Neurology, University of Leuven, Leuven B-3000, Belgium</affiliation><affiliation>Vesalius Research Center, Flanders Institute for Biotechnology (VIB)</affiliation></author><author xml:id="author-10"><persName><forename type="first">Joanne</forename><surname>Knight</surname></persName><affiliation>MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Kings College London, London SE5 8AF, UK</affiliation></author><author xml:id="author-11"><persName><forename type="first">Benjamin M.</forename><surname>Neale</surname></persName><affiliation>MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Kings College London, London SE5 8AF, UK</affiliation></author><author xml:id="author-12"><persName><forename type="first">Martin R.</forename><surname>Turner</surname></persName><affiliation>Department of Neurology</affiliation></author><author xml:id="author-13"><persName><forename type="first">Jan H.</forename><surname>Veldink</surname></persName><affiliation>Department of Neurology</affiliation></author><author xml:id="author-14"><persName><forename type="first">Roel A.</forename><surname>Ophoff</surname></persName><affiliation>Department of Medical Genetics, Rudolf Magnus Institute of Neuroscience, University Medical Center, Utrecht, the Netherlands</affiliation><affiliation>Neuropsychiatric Institute, University of California, Los Angeles, CA, USA</affiliation></author><author xml:id="author-15"><persName><forename type="first">Vineeta B.</forename><surname>Tripathi</surname></persName><affiliation>Department of Neurology</affiliation></author><author xml:id="author-16"><persName><forename type="first">Ana</forename><surname>Beleza</surname></persName><affiliation>Department of Neurology</affiliation></author><author xml:id="author-17"><persName><forename type="first">Meera N.</forename><surname>Shah</surname></persName><affiliation>Department of Neurology</affiliation></author><author xml:id="author-18"><persName><forename type="first">Petroula</forename><surname>Proitsi</surname></persName><affiliation>Department of Neuroscience, MRC Centre for Neurodegeneration Research</affiliation></author><author xml:id="author-19"><persName><forename type="first">Annelies</forename><surname>Van Hoecke</surname></persName><affiliation>Service of Neurology (University Hospital Leuven) and Laboratory for Neurobiology, Section of Experimental Neurology, University of Leuven, Leuven B-3000, Belgium</affiliation><affiliation>Vesalius Research Center, Flanders Institute for Biotechnology (VIB)</affiliation></author><author xml:id="author-20"><persName><forename type="first">Peter</forename><surname>Carmeliet</surname></persName><affiliation>Vesalius Research Center, Flanders Institute for Biotechnology (VIB)</affiliation></author><author xml:id="author-21"><persName><forename type="first">H. Robert</forename><surname>Horvitz</surname></persName><affiliation>Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA</affiliation></author><author xml:id="author-22"><persName><forename type="first">P. Nigel</forename><surname>Leigh</surname></persName><affiliation>Department of Neurology</affiliation></author><author xml:id="author-23"><persName><forename type="first">Christopher E.</forename><surname>Shaw</surname></persName><affiliation>Department of Neurology</affiliation></author><author xml:id="author-24"><persName><forename type="first">Leonard H.</forename><surname>van den Berg</surname></persName><affiliation>Department of Neurology</affiliation></author><author xml:id="author-25"><persName><forename type="first">Pak C.</forename><surname>Sham</surname></persName><affiliation>Department of Psychiatry and Genome Centre, University of Hong Kong, Hong Kong</affiliation></author><author xml:id="author-26"><persName><forename type="first">John F.</forename><surname>Powell</surname></persName><affiliation>Department of Neuroscience, MRC Centre for Neurodegeneration Research</affiliation></author><author xml:id="author-27"><persName><forename type="first">Patrik</forename><surname>Verstreken</surname></persName><affiliation>Center for Human Genetics, Laboratory of Neuronal Communication, KU Leuven, Leuven B-3000, Belgium</affiliation><affiliation>Department of Molecular and Developmental Genetics, VIB, Leuven B-3000, Belgium</affiliation></author><author xml:id="author-28"><persName><forename type="first">Robert H.</forename><surname>Brown</surname></persName><roleName type="degree">Jr</roleName><affiliation>Cecil B Day Laboratory for Neuromuscular Research, Massachusetts General Hospital East, Charlestown, MA, USA</affiliation></author><author xml:id="author-29"><persName><forename type="first">Wim</forename><surname>Robberecht</surname></persName><affiliation>Service of Neurology (University Hospital Leuven) and Laboratory for Neurobiology, Section of Experimental Neurology, University of Leuven, Leuven B-3000, Belgium</affiliation><affiliation>Vesalius Research Center, Flanders Institute for Biotechnology (VIB)</affiliation></author><author xml:id="author-30"><persName><forename type="first">Ammar</forename><surname>Al-Chalabi</surname></persName><email>ammar@iop.kcl.ac.uk</email><affiliation>Department of Neurology</affiliation></author></analytic><monogr><title level="j">Human Molecular Genetics</title><idno type="pISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2009-02-01"></date><biblScope unit="volume">18</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="472">472</biblScope><biblScope unit="page" to="481">481</biblScope></imprint></monogr><idno type="istex">A978A982B22444802EEEFD36FB8A8351D048E4B3</idno><idno type="DOI">10.1093/hmg/ddn375</idno><idno type="ArticleID">ddn375</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2008-11-07</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>Amyotrophic lateral sclerosis (ALS) is a spontaneous, relentlessly progressive motor neuron disease, usually resulting in death from respiratory failure within 3 years. Variation in the genes SOD1 and TARDBP accounts for a small percentage of cases, and other genes have shown association in both candidate gene and genome-wide studies, but the genetic causes remain largely unknown. We have performed two independent parallel studies, both implicating the RNA polymerase II component, ELP3, in axonal biology and neuronal degeneration. In the first, an association study of 1884 microsatellite markers, allelic variants of ELP3 were associated with ALS in three human populations comprising 1483 people (P 1.96 109). In the second, an independent mutagenesis screen in Drosophila for genes important in neuronal communication and survival identified two different loss of function mutations, both in ELP3 (R475K and R456K). Furthermore, knock down of ELP3 protein levels using antisense morpholinos in zebrafish embryos resulted in dose-dependent motor axonal abnormalities [Pearson correlation: 0.49, P 1.83 1012 (start codon morpholino) and 0.46, P 4.05 109 (splice-site morpholino), and in humans, risk-associated ELP3 genotypes correlated with reduced brain ELP3 expression (P 0.01). These findings add to the growing body of evidence implicating the RNA processing pathway in neurodegeneration and suggest a critical role for ELP3 in neuron biology and of ELP3 variants in ALS.</p></abstract></profileDesc><revisionDesc><change when="2008-11-07">Created</change><change when="2009-02-01">Published</change><change xml:id="refBibs-istex" who="#ISTEX-API" when="2016-10-14">References added</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/A978A982B22444802EEEFD36FB8A8351D048E4B3/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="publisher-id">hmg</journal-id><journal-id journal-id-type="hwp">hmg</journal-id><journal-title>Human Molecular Genetics</journal-title><issn pub-type="ppub">0964-6906</issn><issn pub-type="epub">1460-2083</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1093/hmg/ddn375</article-id><article-id pub-id-type="publisher-id">ddn375</article-id><article-categories><subj-group subj-group-type="heading"><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title>Variants of the <italic>elongator protein 3</italic> (<italic>ELP3</italic>) gene are associated with motor neuron degeneration</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Simpson</surname><given-names>Claire L.</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="author-notes" rid="FN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Lemmens</surname><given-names>Robin</given-names></name><xref ref-type="aff" rid="af4">4</xref><xref ref-type="author-notes" rid="FN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Miskiewicz</surname><given-names>Katarzyna</given-names></name><xref ref-type="aff" rid="af6">6</xref><xref ref-type="aff" rid="af7">7</xref></contrib><contrib contrib-type="author"><name><surname>Broom</surname><given-names>Wendy J.</given-names></name><xref ref-type="aff" rid="af8">8</xref></contrib><contrib contrib-type="author"><name><surname>Hansen</surname><given-names>Valerie K.</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>van Vught</surname><given-names>Paul W.J.</given-names></name><xref ref-type="aff" rid="af9">9</xref></contrib><contrib contrib-type="author"><name><surname>Landers</surname><given-names>John E.</given-names></name><xref ref-type="aff" rid="af8">8</xref></contrib><contrib contrib-type="author"><name><surname>Sapp</surname><given-names>Peter</given-names></name><xref ref-type="aff" rid="af8">8</xref><xref ref-type="aff" rid="af11">11</xref></contrib><contrib contrib-type="author"><name><surname>Van Den Bosch</surname><given-names>Ludo</given-names></name><xref ref-type="aff" rid="af4">4</xref><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Knight</surname><given-names>Joanne</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Neale</surname><given-names>Benjamin M.</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Turner</surname><given-names>Martin R.</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Veldink</surname><given-names>Jan H.</given-names></name><xref ref-type="aff" rid="af9">9</xref></contrib><contrib contrib-type="author"><name><surname>Ophoff</surname><given-names>Roel A.</given-names></name><xref ref-type="aff" rid="af10">10</xref><xref ref-type="aff" rid="af12">12</xref></contrib><contrib contrib-type="author"><name><surname>Tripathi</surname><given-names>Vineeta B.</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Beleza</surname><given-names>Ana</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Shah</surname><given-names>Meera N.</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Proitsi</surname><given-names>Petroula</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Van Hoecke</surname><given-names>Annelies</given-names></name><xref ref-type="aff" rid="af4">4</xref><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Carmeliet</surname><given-names>Peter</given-names></name><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Horvitz</surname><given-names>H. Robert</given-names></name><xref ref-type="aff" rid="af11">11</xref></contrib><contrib contrib-type="author"><name><surname>Leigh</surname><given-names>P. Nigel</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Shaw</surname><given-names>Christopher E.</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>van den Berg</surname><given-names>Leonard H.</given-names></name><xref ref-type="aff" rid="af9">9</xref></contrib><contrib contrib-type="author"><name><surname>Sham</surname><given-names>Pak C.</given-names></name><xref ref-type="aff" rid="af13">13</xref></contrib><contrib contrib-type="author"><name><surname>Powell</surname><given-names>John F.</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Verstreken</surname><given-names>Patrik</given-names></name><xref ref-type="aff" rid="af6">6</xref><xref ref-type="aff" rid="af7">7</xref></contrib><contrib contrib-type="author"><name><surname>Brown</surname><given-names>Robert H.</given-names><suffix>Jr</suffix></name><xref ref-type="aff" rid="af8">8</xref></contrib><contrib contrib-type="author"><name><surname>Robberecht</surname><given-names>Wim</given-names></name><xref ref-type="aff" rid="af4">4</xref><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Al-Chalabi</surname><given-names>Ammar</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib></contrib-group><aff id="af1"><label>1</label><addr-line>Department of Neurology</addr-line></aff><aff id="af2"><label>2</label><addr-line>Department of Neuroscience, MRC Centre for Neurodegeneration Research</addr-line></aff><aff id="af3"><label>3</label><addr-line>MRC Social, Genetic and Developmental Psychiatry Centre</addr-line>, <institution>Institute of Psychiatry</institution>, <institution>King’s College London</institution>, <addr-line>London SE5 8AF</addr-line>, <country>UK</country></aff><aff id="af4"><label>4</label><addr-line>Service of Neurology (University Hospital Leuven) and Laboratory for Neurobiology, Section of Experimental Neurology</addr-line>, <institution>University of Leuven</institution>, <addr-line>Leuven B-3000</addr-line>, <country>Belgium</country></aff><aff id="af5"><label>5</label><addr-line>Vesalius Research Center</addr-line>, <institution>Flanders Institute for Biotechnology (VIB)</institution></aff><aff id="af6"><label>6</label><addr-line>Center for Human Genetics, Laboratory of Neuronal Communication</addr-line>, <institution>KU Leuven</institution>, <addr-line>Leuven B-3000</addr-line>, <country>Belgium</country></aff><aff id="af7"><label>7</label><addr-line>Department of Molecular and Developmental Genetics, VIB, Leuven B-3000</addr-line>, <country>Belgium</country></aff><aff id="af8"><label>8</label><addr-line>Cecil B Day Laboratory for Neuromuscular Research</addr-line>, <institution>Massachusetts General Hospital East</institution>, <addr-line>Charlestown, MA</addr-line>, <country>USA</country></aff><aff id="af9"><label>9</label><addr-line>Department of Neurology</addr-line></aff><aff id="af10"><label>10</label><addr-line>Department of Medical Genetics, Rudolf Magnus Institute of Neuroscience</addr-line>, <institution>University Medical Center</institution>, <addr-line>Utrecht</addr-line>, <country>the Netherlands</country></aff><aff id="af11"><label>11</label><addr-line>Howard Hughes Medical Institute, Department of Biology</addr-line>, <institution>Massachusetts Institute of Technology</institution>, <addr-line>Cambridge, MA</addr-line>, <country>USA</country></aff><aff id="af12"><label>12</label><addr-line>Neuropsychiatric Institute</addr-line>, <institution>University of California</institution>, <addr-line>Los Angeles, CA</addr-line>, <country>USA</country></aff><aff id="af13"><label>13</label><addr-line>Department of Psychiatry and Genome Centre</addr-line>, <institution>University of Hong Kong</institution>, <country>Hong Kong</country></aff><author-notes><corresp id="cor1"><label>*</label>To whom correspondence should be addressed at: <addr-line>MRC Centre for Neurodegeneration Research, King’s College London</addr-line>, <institution>Institute of Psychiatry P 043</institution>, <addr-line>London SE5 8AF</addr-line>, <country>UK</country>. Tel: <phone>+44 2078485172</phone>; Fax: <fax>+44 2078485190</fax>; Email: <email>ammar@iop.kcl.ac.uk</email></corresp><fn id="FN1"><label>†</label><p>The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</p></fn></author-notes><pub-date pub-type="ppub"><day>1</day><month>2</month><year>2009</year></pub-date><pub-date pub-type="epub"><day>7</day><month>11</month><year>2008</year></pub-date><volume>18</volume><issue>3</issue><fpage>472</fpage><lpage>481</lpage><history><date date-type="received"><day>7</day><month>9</month><year>2008</year></date><date date-type="rev-recd"><day>14</day><month>10</month><year>2008</year></date><date date-type="accepted"><day>4</day><month>11</month><year>2008</year></date></history><copyright-statement>© 2008 The Author(s)</copyright-statement><copyright-year>2009</copyright-year><license license-type="creative-commons" xlink:href="http://creativecommons.org/licenses/by-nc/2.0/uk/"><p>This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.</p></license><abstract><p>Amyotrophic lateral sclerosis (ALS) is a spontaneous, relentlessly progressive motor neuron disease, usually resulting in death from respiratory failure within 3 years. Variation in the genes <italic>SOD1</italic> and <italic>TARDBP</italic> accounts for a small percentage of cases, and other genes have shown association in both candidate gene and genome-wide studies, but the genetic causes remain largely unknown. We have performed two independent parallel studies, both implicating the RNA polymerase II component, <italic>ELP3</italic>, in axonal biology and neuronal degeneration. In the first, an association study of 1884 microsatellite markers, allelic variants of <italic>ELP3</italic> were associated with ALS in three human populations comprising 1483 people (<italic>P</italic> = 1.96 × 10<sup>−9</sup>). In the second, an independent mutagenesis screen in <italic>Drosophila</italic> for genes important in neuronal communication and survival identified two different loss of function mutations, both in <italic>ELP3</italic> (R475K and R456K). Furthermore, knock down of ELP3 protein levels using antisense morpholinos in zebrafish embryos resulted in dose-dependent motor axonal abnormalities [Pearson correlation: −0.49, <italic>P</italic> = 1.83 × 10<sup>−12</sup> (start codon morpholino) and −0.46, <italic>P</italic> = 4.05 × 10<sup>−9</sup> (splice-site morpholino), and in humans, risk-associated <italic>ELP3</italic> genotypes correlated with reduced brain ELP3 expression (<italic>P</italic> = 0.01). These findings add to the growing body of evidence implicating the RNA processing pathway in neurodegeneration and suggest a critical role for ELP3 in neuron biology and of <italic>ELP3</italic> variants in ALS.</p></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration</title></titleInfo><name type="personal"><namePart type="given">Claire L.</namePart><namePart type="family">Simpson</namePart><affiliation>Department of Neurology</affiliation><description>The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Robin</namePart><namePart type="family">Lemmens</namePart><affiliation>Service of Neurology (University Hospital Leuven) and Laboratory for Neurobiology, Section of Experimental Neurology, University of Leuven, Leuven B-3000, Belgium</affiliation><description>The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Katarzyna</namePart><namePart type="family">Miskiewicz</namePart><affiliation>Center for Human Genetics, Laboratory of Neuronal Communication, KU Leuven, Leuven B-3000, Belgium</affiliation><affiliation>Department of Molecular and Developmental Genetics, VIB, Leuven B-3000, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Wendy J.</namePart><namePart type="family">Broom</namePart><affiliation>Cecil B Day Laboratory for Neuromuscular Research, Massachusetts General Hospital East, Charlestown, MA, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Valerie K.</namePart><namePart type="family">Hansen</namePart><affiliation>Department of Neurology</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Paul W.J.</namePart><namePart type="family">van Vught</namePart><affiliation>Department of Neurology</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">John E.</namePart><namePart type="family">Landers</namePart><affiliation>Cecil B Day Laboratory for Neuromuscular Research, Massachusetts General Hospital East, Charlestown, MA, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Peter</namePart><namePart type="family">Sapp</namePart><affiliation>Cecil B Day Laboratory for Neuromuscular Research, Massachusetts General Hospital East, Charlestown, MA, USA</affiliation><affiliation>Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ludo</namePart><namePart type="family">Van Den Bosch</namePart><affiliation>Service of Neurology (University Hospital Leuven) and Laboratory for Neurobiology, Section of Experimental Neurology, University of Leuven, Leuven B-3000, Belgium</affiliation><affiliation>Vesalius Research Center, Flanders Institute for Biotechnology (VIB)</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Joanne</namePart><namePart type="family">Knight</namePart><affiliation>MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Kings College London, London SE5 8AF, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Benjamin M.</namePart><namePart type="family">Neale</namePart><affiliation>MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Kings College London, London SE5 8AF, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Martin R.</namePart><namePart type="family">Turner</namePart><affiliation>Department of Neurology</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jan H.</namePart><namePart type="family">Veldink</namePart><affiliation>Department of Neurology</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Roel A.</namePart><namePart type="family">Ophoff</namePart><affiliation>Department of Medical Genetics, Rudolf Magnus Institute of Neuroscience, University Medical Center, Utrecht, the Netherlands</affiliation><affiliation>Neuropsychiatric Institute, University of California, Los Angeles, CA, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Vineeta B.</namePart><namePart type="family">Tripathi</namePart><affiliation>Department of Neurology</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ana</namePart><namePart type="family">Beleza</namePart><affiliation>Department of Neurology</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Meera N.</namePart><namePart type="family">Shah</namePart><affiliation>Department of Neurology</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Petroula</namePart><namePart type="family">Proitsi</namePart><affiliation>Department of Neuroscience, MRC Centre for Neurodegeneration Research</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Annelies</namePart><namePart type="family">Van Hoecke</namePart><affiliation>Service of Neurology (University Hospital Leuven) and Laboratory for Neurobiology, Section of Experimental Neurology, University of Leuven, Leuven B-3000, Belgium</affiliation><affiliation>Vesalius Research Center, Flanders Institute for Biotechnology (VIB)</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Peter</namePart><namePart type="family">Carmeliet</namePart><affiliation>Vesalius Research Center, Flanders Institute for Biotechnology (VIB)</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">H. Robert</namePart><namePart type="family">Horvitz</namePart><affiliation>Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">P. Nigel</namePart><namePart type="family">Leigh</namePart><affiliation>Department of Neurology</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christopher E.</namePart><namePart type="family">Shaw</namePart><affiliation>Department of Neurology</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Leonard H.</namePart><namePart type="family">van den Berg</namePart><affiliation>Department of Neurology</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Pak C.</namePart><namePart type="family">Sham</namePart><affiliation>Department of Psychiatry and Genome Centre, University of Hong Kong, Hong Kong</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">John F.</namePart><namePart type="family">Powell</namePart><affiliation>Department of Neuroscience, MRC Centre for Neurodegeneration Research</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Patrik</namePart><namePart type="family">Verstreken</namePart><affiliation>Center for Human Genetics, Laboratory of Neuronal Communication, KU Leuven, Leuven B-3000, Belgium</affiliation><affiliation>Department of Molecular and Developmental Genetics, VIB, Leuven B-3000, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Robert H.</namePart><namePart type="family">Brown</namePart><namePart type="termsOfAddress">Jr</namePart><affiliation>Cecil B Day Laboratory for Neuromuscular Research, Massachusetts General Hospital East, Charlestown, MA, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Wim</namePart><namePart type="family">Robberecht</namePart><affiliation>Service of Neurology (University Hospital Leuven) and Laboratory for Neurobiology, Section of Experimental Neurology, University of Leuven, Leuven B-3000, Belgium</affiliation><affiliation>Vesalius Research Center, Flanders Institute for Biotechnology (VIB)</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ammar</namePart><namePart type="family">Al-Chalabi</namePart><affiliation>Department of Neurology</affiliation><affiliation>E-mail: ammar@iop.kcl.ac.uk</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2009-02-01</dateIssued><dateCreated encoding="w3cdtf">2008-11-07</dateCreated><copyrightDate encoding="w3cdtf">2009</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>Amyotrophic lateral sclerosis (ALS) is a spontaneous, relentlessly progressive motor neuron disease, usually resulting in death from respiratory failure within 3 years. Variation in the genes SOD1 and TARDBP accounts for a small percentage of cases, and other genes have shown association in both candidate gene and genome-wide studies, but the genetic causes remain largely unknown. We have performed two independent parallel studies, both implicating the RNA polymerase II component, ELP3, in axonal biology and neuronal degeneration. In the first, an association study of 1884 microsatellite markers, allelic variants of ELP3 were associated with ALS in three human populations comprising 1483 people (P 1.96 109). In the second, an independent mutagenesis screen in Drosophila for genes important in neuronal communication and survival identified two different loss of function mutations, both in ELP3 (R475K and R456K). Furthermore, knock down of ELP3 protein levels using antisense morpholinos in zebrafish embryos resulted in dose-dependent motor axonal abnormalities [Pearson correlation: 0.49, P 1.83 1012 (start codon morpholino) and 0.46, P 4.05 109 (splice-site morpholino), and in humans, risk-associated ELP3 genotypes correlated with reduced brain ELP3 expression (P 0.01). These findings add to the growing body of evidence implicating the RNA processing pathway in neurodegeneration and suggest a critical role for ELP3 in neuron biology and of ELP3 variants in ALS.</abstract><note type="footnotes">The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</note><relatedItem type="host"><titleInfo><title>Human Molecular Genetics</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">0964-6906</identifier><identifier type="eISSN">1460-2083</identifier><identifier type="PublisherID">hmg</identifier><identifier type="PublisherID-hwp">hmg</identifier><part><date>2009</date><detail type="volume"><caption>vol.</caption><number>18</number></detail><detail type="issue"><caption>no.</caption><number>3</number></detail><extent unit="pages"><start>472</start><end>481</end></extent></part></relatedItem><identifier type="istex">A978A982B22444802EEEFD36FB8A8351D048E4B3</identifier><identifier type="DOI">10.1093/hmg/ddn375</identifier><identifier type="ArticleID">ddn375</identifier><accessCondition type="use and reproduction" contentType="copyright">2008 The Author(s)</accessCondition><recordInfo><recordContentSource>OUP</recordContentSource></recordInfo></mods></metadata><covers><json:item><original>true</original><mimetype>image/tiff</mimetype><extension>tiff</extension><uri>https://api.istex.fr/document/A978A982B22444802EEEFD36FB8A8351D048E4B3/covers/tiff</uri></json:item><json:item><original>true</original><mimetype>text/html</mimetype><extension>html</extension><uri>https://api.istex.fr/document/A978A982B22444802EEEFD36FB8A8351D048E4B3/covers/html</uri></json:item></covers><annexes><json:item><original>true</original><mimetype>image/jpeg</mimetype><extension>jpeg</extension><uri>https://api.istex.fr/document/A978A982B22444802EEEFD36FB8A8351D048E4B3/annexes/jpeg</uri></json:item><json:item><original>true</original><mimetype>image/gif</mimetype><extension>gif</extension><uri>https://api.istex.fr/document/A978A982B22444802EEEFD36FB8A8351D048E4B3/annexes/gif</uri></json:item></annexes><enrichments><istex:catWosTEI uri="https://api.istex.fr/document/A978A982B22444802EEEFD36FB8A8351D048E4B3/enrichments/catWos"><teiHeader><profileDesc><textClass><classCode scheme="WOS">BIOCHEMISTRY & MOLECULAR BIOLOGY</classCode><classCode scheme="WOS">GENETICS & HEREDITY</classCode></textClass></profileDesc></teiHeader></istex:catWosTEI><json:item><type>refBibs</type><uri>https://api.istex.fr/document/A978A982B22444802EEEFD36FB8A8351D048E4B3/enrichments/refBibs</uri></json:item></enrichments><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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