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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en"><italic>RAD21</italic> Mutations Cause a Human Cohesinopathy</title><author><name sortKey="Deardorff, Matthew A" sort="Deardorff, Matthew A" uniqKey="Deardorff M" first="Matthew A." last="Deardorff">Matthew A. Deardorff</name><affiliation><nlm:aff id="aff1">Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104 USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104 USA</nlm:aff></affiliation></author><author><name sortKey="Wilde, Jonathan J" sort="Wilde, Jonathan J" uniqKey="Wilde J" first="Jonathan J." last="Wilde">Jonathan J. Wilde</name><affiliation><nlm:aff id="aff1">Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104 USA</nlm:aff></affiliation></author><author><name sortKey="Albrecht, Melanie" sort="Albrecht, Melanie" uniqKey="Albrecht M" first="Melanie" last="Albrecht">Melanie Albrecht</name><affiliation><nlm:aff id="aff3">Institut für Humangenetik Lübeck, Universität zu Lübeck, 23538 Lübeck, Germany</nlm:aff></affiliation></author><author><name sortKey="Dickinson, Emma" sort="Dickinson, Emma" uniqKey="Dickinson E" first="Emma" last="Dickinson">Emma Dickinson</name><affiliation><nlm:aff id="aff4">Department of Pathology, Dunedin School of Medicine, The University of Otago, Dunedin 9054, New Zealand</nlm:aff></affiliation></author><author><name sortKey="Tennstedt, Stephanie" sort="Tennstedt, Stephanie" uniqKey="Tennstedt S" first="Stephanie" last="Tennstedt">Stephanie Tennstedt</name><affiliation><nlm:aff id="aff5">Medizinische Klinik II, Universität zu Lübeck, 23538 Lübeck, Germany</nlm:aff></affiliation></author><author><name sortKey="Braunholz, Diana" sort="Braunholz, Diana" uniqKey="Braunholz D" first="Diana" last="Braunholz">Diana Braunholz</name><affiliation><nlm:aff id="aff3">Institut für Humangenetik Lübeck, Universität zu Lübeck, 23538 Lübeck, Germany</nlm:aff></affiliation></author><author><name sortKey="Monnich, Maren" sort="Monnich, Maren" uniqKey="Monnich M" first="Maren" last="Mönnich">Maren Mönnich</name><affiliation><nlm:aff id="aff4">Department of Pathology, Dunedin School of Medicine, The University of Otago, Dunedin 9054, New Zealand</nlm:aff></affiliation></author><author><name sortKey="Yan, Yuqian" sort="Yan, Yuqian" uniqKey="Yan Y" first="Yuqian" last="Yan">Yuqian Yan</name><affiliation><nlm:aff id="aff6">Research Division, Peter MacCallum Cancer Centre, East Melbourne 3002, Australia</nlm:aff></affiliation></author><author><name sortKey="Xu, Weizhen" sort="Xu, Weizhen" uniqKey="Xu W" first="Weizhen" last="Xu">Weizhen Xu</name><affiliation><nlm:aff id="aff3">Institut für Humangenetik Lübeck, Universität zu Lübeck, 23538 Lübeck, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Zhejiang Cancer Research Institute, Hangzhou 310058, China</nlm:aff></affiliation></author><author><name sortKey="Gil Rodriguez, Maria Concepcion" sort="Gil Rodriguez, Maria Concepcion" uniqKey="Gil Rodriguez M" first="María Concepcion" last="Gil-Rodríguez">María Concepcion Gil-Rodríguez</name><affiliation><nlm:aff id="aff3">Institut für Humangenetik Lübeck, Universität zu Lübeck, 23538 Lübeck, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff8">Unit of Clinical Genetics and Functional Genomics. Medical School, University of Zaragoza, Zaragoza 50009, Spain</nlm:aff></affiliation></author><author><name sortKey="Clark, Dinah" sort="Clark, Dinah" uniqKey="Clark D" first="Dinah" last="Clark">Dinah Clark</name><affiliation><nlm:aff id="aff1">Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104 USA</nlm:aff></affiliation></author><author><name sortKey="Hakonarson, Hakon" sort="Hakonarson, Hakon" uniqKey="Hakonarson H" first="Hakon" last="Hakonarson">Hakon Hakonarson</name><affiliation><nlm:aff id="aff1">Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104 USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104 USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff9">Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA</nlm:aff></affiliation></author><author><name sortKey="Halbach, Sara" sort="Halbach, Sara" uniqKey="Halbach S" first="Sara" last="Halbach">Sara Halbach</name><affiliation><nlm:aff id="aff10">Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA</nlm:aff></affiliation></author><author><name sortKey="Michelis, Laura Daniela" sort="Michelis, Laura Daniela" uniqKey="Michelis L" first="Laura Daniela" last="Michelis">Laura Daniela Michelis</name><affiliation><nlm:aff id="aff1">Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104 USA</nlm:aff></affiliation></author><author><name sortKey="Rampuria, Abhinav" sort="Rampuria, Abhinav" uniqKey="Rampuria A" first="Abhinav" last="Rampuria">Abhinav Rampuria</name><affiliation><nlm:aff id="aff1">Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104 USA</nlm:aff></affiliation></author><author><name sortKey="Rossier, Eva" sort="Rossier, Eva" uniqKey="Rossier E" first="Eva" last="Rossier">Eva Rossier</name><affiliation><nlm:aff id="aff11">Genetikum, Stuttgart 70174, Germany</nlm:aff></affiliation></author><author><name sortKey="Spranger, Stephanie" sort="Spranger, Stephanie" uniqKey="Spranger S" first="Stephanie" last="Spranger">Stephanie Spranger</name><affiliation><nlm:aff id="aff12">Praxis für Humangenetik, Bremen 28205, Germany</nlm:aff></affiliation></author><author><name sortKey="Van Maldergem, Lionel" sort="Van Maldergem, Lionel" uniqKey="Van Maldergem L" first="Lionel" last="Van Maldergem">Lionel Van Maldergem</name><affiliation><nlm:aff id="aff13">Centre de Génétique Humaine, Université de Franche-Comté, Besançon 25030, France</nlm:aff></affiliation></author><author><name sortKey="Lynch, Sally Ann" sort="Lynch, Sally Ann" uniqKey="Lynch S" first="Sally Ann" last="Lynch">Sally Ann Lynch</name><affiliation><nlm:aff id="aff14">Our Lady's Children's Hospital, National Centre for Medical Genetics, Dublin 12, Ireland</nlm:aff></affiliation></author><author><name sortKey="Gillessen Kaesbach, Gabriele" sort="Gillessen Kaesbach, Gabriele" uniqKey="Gillessen Kaesbach G" first="Gabriele" last="Gillessen-Kaesbach">Gabriele Gillessen-Kaesbach</name><affiliation><nlm:aff id="aff3">Institut für Humangenetik Lübeck, Universität zu Lübeck, 23538 Lübeck, Germany</nlm:aff></affiliation></author><author><name sortKey="Ludecke, Hermann Josef" sort="Ludecke, Hermann Josef" uniqKey="Ludecke H" first="Hermann-Josef" last="Lüdecke">Hermann-Josef Lüdecke</name><affiliation><nlm:aff id="aff15">Institut für Humangenetik, Universität Duisburg Essen, Essen 45122, Germany</nlm:aff></affiliation></author><author><name sortKey="Ramsay, Robert G" sort="Ramsay, Robert G" uniqKey="Ramsay R" first="Robert G." last="Ramsay">Robert G. Ramsay</name><affiliation><nlm:aff id="aff6">Research Division, Peter MacCallum Cancer Centre, East Melbourne 3002, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff16">Sir Peter MacCallum Department of Oncology and Department of Pathology, Faculty of Medicine and Dental Sciences, The University of Melbourne, Elizabeth Street, Parkville, Victoria 3000, Australia</nlm:aff></affiliation></author><author><name sortKey="Mckay, Michael J" sort="Mckay, Michael J" uniqKey="Mckay M" first="Michael J." last="Mckay">Michael J. Mckay</name><affiliation><nlm:aff id="aff17">North Coast Cancer Institute, Lismore, New South Wales 2480, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff18">The University of Sydney Medical School, Sydney, New South Wales 2006, Australia</nlm:aff></affiliation></author><author><name sortKey="Krantz, Ian D" sort="Krantz, Ian D" uniqKey="Krantz I" first="Ian D." last="Krantz">Ian D. Krantz</name><affiliation><nlm:aff id="aff1">Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104 USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104 USA</nlm:aff></affiliation></author><author><name sortKey="Xu, Huiling" sort="Xu, Huiling" uniqKey="Xu H" first="Huiling" last="Xu">Huiling Xu</name><affiliation><nlm:aff id="aff6">Research Division, Peter MacCallum Cancer Centre, East Melbourne 3002, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff16">Sir Peter MacCallum Department of Oncology and Department of Pathology, Faculty of Medicine and Dental Sciences, The University of Melbourne, Elizabeth Street, Parkville, Victoria 3000, Australia</nlm:aff></affiliation></author><author><name sortKey="Horsfield, Julia A" sort="Horsfield, Julia A" uniqKey="Horsfield J" first="Julia A." last="Horsfield">Julia A. Horsfield</name><affiliation><nlm:aff id="aff4">Department of Pathology, Dunedin School of Medicine, The University of Otago, Dunedin 9054, New Zealand</nlm:aff></affiliation></author><author><name sortKey="Kaiser, Frank J" sort="Kaiser, Frank J" uniqKey="Kaiser F" first="Frank J." last="Kaiser">Frank J. Kaiser</name><affiliation><nlm:aff id="aff3">Institut für Humangenetik Lübeck, Universität zu Lübeck, 23538 Lübeck, Germany</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22633399</idno><idno type="pmc">3370273</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3370273</idno><idno type="RBID">PMC:3370273</idno><idno type="doi">10.1016/j.ajhg.2012.04.019</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">001680</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001680</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main"><italic>RAD21</italic> Mutations Cause a Human Cohesinopathy</title><author><name sortKey="Deardorff, Matthew A" sort="Deardorff, Matthew A" uniqKey="Deardorff M" first="Matthew A." last="Deardorff">Matthew A. Deardorff</name><affiliation><nlm:aff id="aff1">Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104 USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104 USA</nlm:aff></affiliation></author><author><name sortKey="Wilde, Jonathan J" sort="Wilde, Jonathan J" uniqKey="Wilde J" first="Jonathan J." last="Wilde">Jonathan J. Wilde</name><affiliation><nlm:aff id="aff1">Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104 USA</nlm:aff></affiliation></author><author><name sortKey="Albrecht, Melanie" sort="Albrecht, Melanie" uniqKey="Albrecht M" first="Melanie" last="Albrecht">Melanie Albrecht</name><affiliation><nlm:aff id="aff3">Institut für Humangenetik Lübeck, Universität zu Lübeck, 23538 Lübeck, Germany</nlm:aff></affiliation></author><author><name sortKey="Dickinson, Emma" sort="Dickinson, Emma" uniqKey="Dickinson E" first="Emma" last="Dickinson">Emma Dickinson</name><affiliation><nlm:aff id="aff4">Department of Pathology, Dunedin School of Medicine, The University of Otago, Dunedin 9054, New Zealand</nlm:aff></affiliation></author><author><name sortKey="Tennstedt, Stephanie" sort="Tennstedt, Stephanie" uniqKey="Tennstedt S" first="Stephanie" last="Tennstedt">Stephanie Tennstedt</name><affiliation><nlm:aff id="aff5">Medizinische Klinik II, Universität zu Lübeck, 23538 Lübeck, Germany</nlm:aff></affiliation></author><author><name sortKey="Braunholz, Diana" sort="Braunholz, Diana" uniqKey="Braunholz D" first="Diana" last="Braunholz">Diana Braunholz</name><affiliation><nlm:aff id="aff3">Institut für Humangenetik Lübeck, Universität zu Lübeck, 23538 Lübeck, Germany</nlm:aff></affiliation></author><author><name sortKey="Monnich, Maren" sort="Monnich, Maren" uniqKey="Monnich M" first="Maren" last="Mönnich">Maren Mönnich</name><affiliation><nlm:aff id="aff4">Department of Pathology, Dunedin School of Medicine, The University of Otago, Dunedin 9054, New Zealand</nlm:aff></affiliation></author><author><name sortKey="Yan, Yuqian" sort="Yan, Yuqian" uniqKey="Yan Y" first="Yuqian" last="Yan">Yuqian Yan</name><affiliation><nlm:aff id="aff6">Research Division, Peter MacCallum Cancer Centre, East Melbourne 3002, Australia</nlm:aff></affiliation></author><author><name sortKey="Xu, Weizhen" sort="Xu, Weizhen" uniqKey="Xu W" first="Weizhen" last="Xu">Weizhen Xu</name><affiliation><nlm:aff id="aff3">Institut für Humangenetik Lübeck, Universität zu Lübeck, 23538 Lübeck, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Zhejiang Cancer Research Institute, Hangzhou 310058, China</nlm:aff></affiliation></author><author><name sortKey="Gil Rodriguez, Maria Concepcion" sort="Gil Rodriguez, Maria Concepcion" uniqKey="Gil Rodriguez M" first="María Concepcion" last="Gil-Rodríguez">María Concepcion Gil-Rodríguez</name><affiliation><nlm:aff id="aff3">Institut für Humangenetik Lübeck, Universität zu Lübeck, 23538 Lübeck, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff8">Unit of Clinical Genetics and Functional Genomics. Medical School, University of Zaragoza, Zaragoza 50009, Spain</nlm:aff></affiliation></author><author><name sortKey="Clark, Dinah" sort="Clark, Dinah" uniqKey="Clark D" first="Dinah" last="Clark">Dinah Clark</name><affiliation><nlm:aff id="aff1">Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104 USA</nlm:aff></affiliation></author><author><name sortKey="Hakonarson, Hakon" sort="Hakonarson, Hakon" uniqKey="Hakonarson H" first="Hakon" last="Hakonarson">Hakon Hakonarson</name><affiliation><nlm:aff id="aff1">Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104 USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104 USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff9">Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA</nlm:aff></affiliation></author><author><name sortKey="Halbach, Sara" sort="Halbach, Sara" uniqKey="Halbach S" first="Sara" last="Halbach">Sara Halbach</name><affiliation><nlm:aff id="aff10">Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA</nlm:aff></affiliation></author><author><name sortKey="Michelis, Laura Daniela" sort="Michelis, Laura Daniela" uniqKey="Michelis L" first="Laura Daniela" last="Michelis">Laura Daniela Michelis</name><affiliation><nlm:aff id="aff1">Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104 USA</nlm:aff></affiliation></author><author><name sortKey="Rampuria, Abhinav" sort="Rampuria, Abhinav" uniqKey="Rampuria A" first="Abhinav" last="Rampuria">Abhinav Rampuria</name><affiliation><nlm:aff id="aff1">Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104 USA</nlm:aff></affiliation></author><author><name sortKey="Rossier, Eva" sort="Rossier, Eva" uniqKey="Rossier E" first="Eva" last="Rossier">Eva Rossier</name><affiliation><nlm:aff id="aff11">Genetikum, Stuttgart 70174, Germany</nlm:aff></affiliation></author><author><name sortKey="Spranger, Stephanie" sort="Spranger, Stephanie" uniqKey="Spranger S" first="Stephanie" last="Spranger">Stephanie Spranger</name><affiliation><nlm:aff id="aff12">Praxis für Humangenetik, Bremen 28205, Germany</nlm:aff></affiliation></author><author><name sortKey="Van Maldergem, Lionel" sort="Van Maldergem, Lionel" uniqKey="Van Maldergem L" first="Lionel" last="Van Maldergem">Lionel Van Maldergem</name><affiliation><nlm:aff id="aff13">Centre de Génétique Humaine, Université de Franche-Comté, Besançon 25030, France</nlm:aff></affiliation></author><author><name sortKey="Lynch, Sally Ann" sort="Lynch, Sally Ann" uniqKey="Lynch S" first="Sally Ann" last="Lynch">Sally Ann Lynch</name><affiliation><nlm:aff id="aff14">Our Lady's Children's Hospital, National Centre for Medical Genetics, Dublin 12, Ireland</nlm:aff></affiliation></author><author><name sortKey="Gillessen Kaesbach, Gabriele" sort="Gillessen Kaesbach, Gabriele" uniqKey="Gillessen Kaesbach G" first="Gabriele" last="Gillessen-Kaesbach">Gabriele Gillessen-Kaesbach</name><affiliation><nlm:aff id="aff3">Institut für Humangenetik Lübeck, Universität zu Lübeck, 23538 Lübeck, Germany</nlm:aff></affiliation></author><author><name sortKey="Ludecke, Hermann Josef" sort="Ludecke, Hermann Josef" uniqKey="Ludecke H" first="Hermann-Josef" last="Lüdecke">Hermann-Josef Lüdecke</name><affiliation><nlm:aff id="aff15">Institut für Humangenetik, Universität Duisburg Essen, Essen 45122, Germany</nlm:aff></affiliation></author><author><name sortKey="Ramsay, Robert G" sort="Ramsay, Robert G" uniqKey="Ramsay R" first="Robert G." last="Ramsay">Robert G. Ramsay</name><affiliation><nlm:aff id="aff6">Research Division, Peter MacCallum Cancer Centre, East Melbourne 3002, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff16">Sir Peter MacCallum Department of Oncology and Department of Pathology, Faculty of Medicine and Dental Sciences, The University of Melbourne, Elizabeth Street, Parkville, Victoria 3000, Australia</nlm:aff></affiliation></author><author><name sortKey="Mckay, Michael J" sort="Mckay, Michael J" uniqKey="Mckay M" first="Michael J." last="Mckay">Michael J. Mckay</name><affiliation><nlm:aff id="aff17">North Coast Cancer Institute, Lismore, New South Wales 2480, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff18">The University of Sydney Medical School, Sydney, New South Wales 2006, Australia</nlm:aff></affiliation></author><author><name sortKey="Krantz, Ian D" sort="Krantz, Ian D" uniqKey="Krantz I" first="Ian D." last="Krantz">Ian D. Krantz</name><affiliation><nlm:aff id="aff1">Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104 USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104 USA</nlm:aff></affiliation></author><author><name sortKey="Xu, Huiling" sort="Xu, Huiling" uniqKey="Xu H" first="Huiling" last="Xu">Huiling Xu</name><affiliation><nlm:aff id="aff6">Research Division, Peter MacCallum Cancer Centre, East Melbourne 3002, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff16">Sir Peter MacCallum Department of Oncology and Department of Pathology, Faculty of Medicine and Dental Sciences, The University of Melbourne, Elizabeth Street, Parkville, Victoria 3000, Australia</nlm:aff></affiliation></author><author><name sortKey="Horsfield, Julia A" sort="Horsfield, Julia A" uniqKey="Horsfield J" first="Julia A." last="Horsfield">Julia A. Horsfield</name><affiliation><nlm:aff id="aff4">Department of Pathology, Dunedin School of Medicine, The University of Otago, Dunedin 9054, New Zealand</nlm:aff></affiliation></author><author><name sortKey="Kaiser, Frank J" sort="Kaiser, Frank J" uniqKey="Kaiser F" first="Frank J." last="Kaiser">Frank J. Kaiser</name><affiliation><nlm:aff id="aff3">Institut für Humangenetik Lübeck, Universität zu Lübeck, 23538 Lübeck, Germany</nlm:aff></affiliation></author></analytic><series><title level="j">American Journal of Human Genetics</title><idno type="ISSN">0002-9297</idno><idno type="eISSN">1537-6605</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The evolutionarily conserved cohesin complex was originally described for its role in regulating sister-chromatid cohesion during mitosis and meiosis. Cohesin and its regulatory proteins have been implicated in several human developmental disorders, including Cornelia de Lange (CdLS) and Roberts syndromes. Here we show that human mutations in the integral cohesin structural protein RAD21 result in a congenital phenotype consistent with a “cohesinopathy.” Children with <italic>RAD21</italic> mutations display growth retardation, minor skeletal anomalies, and facial features that overlap findings in individuals with CdLS. Notably, unlike children with mutations in <italic>NIPBL, SMC1A</italic>, or <italic>SMC3</italic>, these individuals have much milder cognitive impairment than those with classical CdLS. Mechanistically, these mutations act at the RAD21 interface with the other cohesin proteins STAG2 and SMC1A, impair cellular DNA damage response, and disrupt transcription in a zebrafish model. Our data suggest that, compared to loss-of-function mutations, dominant missense mutations result in more severe functional defects and cause worse structural and cognitive clinical findings. These results underscore the essential role of RAD21 in eukaryotes and emphasize the need for further understanding of the role of cohesin in human development.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Am J Hum Genet</journal-id><journal-id journal-id-type="iso-abbrev">Am. J. Hum. Genet</journal-id><journal-title-group><journal-title>American Journal of Human Genetics</journal-title></journal-title-group><issn pub-type="ppub">0002-9297</issn><issn pub-type="epub">1537-6605</issn><publisher><publisher-name>Elsevier</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">22633399</article-id><article-id pub-id-type="pmc">3370273</article-id><article-id pub-id-type="publisher-id">AJHG1152</article-id><article-id pub-id-type="doi">10.1016/j.ajhg.2012.04.019</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title><italic>RAD21</italic> Mutations Cause a Human Cohesinopathy</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Deardorff</surname><given-names>Matthew A.</given-names></name><email>deardorff@email.chop.edu</email><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib><contrib contrib-type="author"><name><surname>Wilde</surname><given-names>Jonathan J.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Albrecht</surname><given-names>Melanie</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Dickinson</surname><given-names>Emma</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Tennstedt</surname><given-names>Stephanie</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Braunholz</surname><given-names>Diana</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Mönnich</surname><given-names>Maren</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Yan</surname><given-names>Yuqian</given-names></name><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Xu</surname><given-names>Weizhen</given-names></name><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Gil-Rodríguez</surname><given-names>María Concepcion</given-names></name><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Clark</surname><given-names>Dinah</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Hakonarson</surname><given-names>Hakon</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref><xref rid="aff9" ref-type="aff">9</xref></contrib><contrib contrib-type="author"><name><surname>Halbach</surname><given-names>Sara</given-names></name><xref rid="aff10" ref-type="aff">10</xref></contrib><contrib contrib-type="author"><name><surname>Michelis</surname><given-names>Laura Daniela</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Rampuria</surname><given-names>Abhinav</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Rossier</surname><given-names>Eva</given-names></name><xref rid="aff11" ref-type="aff">11</xref></contrib><contrib contrib-type="author"><name><surname>Spranger</surname><given-names>Stephanie</given-names></name><xref rid="aff12" ref-type="aff">12</xref></contrib><contrib contrib-type="author"><name><surname>Van Maldergem</surname><given-names>Lionel</given-names></name><xref rid="aff13" ref-type="aff">13</xref></contrib><contrib contrib-type="author"><name><surname>Lynch</surname><given-names>Sally Ann</given-names></name><xref rid="aff14" ref-type="aff">14</xref></contrib><contrib contrib-type="author"><name><surname>Gillessen-Kaesbach</surname><given-names>Gabriele</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Lüdecke</surname><given-names>Hermann-Josef</given-names></name><xref rid="aff15" ref-type="aff">15</xref></contrib><contrib contrib-type="author"><name><surname>Ramsay</surname><given-names>Robert G.</given-names></name><xref rid="aff6" ref-type="aff">6</xref><xref rid="aff16" ref-type="aff">16</xref></contrib><contrib contrib-type="author"><name><surname>McKay</surname><given-names>Michael J.</given-names></name><xref rid="aff17" ref-type="aff">17</xref><xref rid="aff18" ref-type="aff">18</xref></contrib><contrib contrib-type="author"><name><surname>Krantz</surname><given-names>Ian D.</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Xu</surname><given-names>Huiling</given-names></name><xref rid="aff6" ref-type="aff">6</xref><xref rid="aff16" ref-type="aff">16</xref></contrib><contrib contrib-type="author"><name><surname>Horsfield</surname><given-names>Julia A.</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Kaiser</surname><given-names>Frank J.</given-names></name><email>frank.kaiser@uk-sh.de</email><xref rid="aff3" ref-type="aff">3</xref><xref rid="cor2" ref-type="corresp">∗∗</xref></contrib></contrib-group><aff id="aff1"><label>1</label>Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104 USA</aff><aff id="aff2"><label>2</label>The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104 USA</aff><aff id="aff3"><label>3</label>Institut für Humangenetik Lübeck, Universität zu Lübeck, 23538 Lübeck, Germany</aff><aff id="aff4"><label>4</label>Department of Pathology, Dunedin School of Medicine, The University of Otago, Dunedin 9054, New Zealand</aff><aff id="aff5"><label>5</label>Medizinische Klinik II, Universität zu Lübeck, 23538 Lübeck, Germany</aff><aff id="aff6"><label>6</label>Research Division, Peter MacCallum Cancer Centre, East Melbourne 3002, Australia</aff><aff id="aff7"><label>7</label>Zhejiang Cancer Research Institute, Hangzhou 310058, China</aff><aff id="aff8"><label>8</label>Unit of Clinical Genetics and Functional Genomics. Medical School, University of Zaragoza, Zaragoza 50009, Spain</aff><aff id="aff9"><label>9</label>Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA</aff><aff id="aff10"><label>10</label>Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA</aff><aff id="aff11"><label>11</label>Genetikum, Stuttgart 70174, Germany</aff><aff id="aff12"><label>12</label>Praxis für Humangenetik, Bremen 28205, Germany</aff><aff id="aff13"><label>13</label>Centre de Génétique Humaine, Université de Franche-Comté, Besançon 25030, France</aff><aff id="aff14"><label>14</label>Our Lady's Children's Hospital, National Centre for Medical Genetics, Dublin 12, Ireland</aff><aff id="aff15"><label>15</label>Institut für Humangenetik, Universität Duisburg Essen, Essen 45122, Germany</aff><aff id="aff16"><label>16</label>Sir Peter MacCallum Department of Oncology and Department of Pathology, Faculty of Medicine and Dental Sciences, The University of Melbourne, Elizabeth Street, Parkville, Victoria 3000, Australia</aff><aff id="aff17"><label>17</label>North Coast Cancer Institute, Lismore, New South Wales 2480, Australia</aff><aff id="aff18"><label>18</label>The University of Sydney Medical School, Sydney, New South Wales 2006, Australia</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>deardorff@email.chop.edu</email></corresp><corresp id="cor2"><label>∗∗</label>Corresponding author <email>frank.kaiser@uk-sh.de</email></corresp></author-notes><pub-date pub-type="ppub"><day>08</day><month>6</month><year>2012</year></pub-date><volume>90</volume><issue>6</issue><fpage>1014</fpage><lpage>1027</lpage><history><date date-type="received"><day>23</day><month>1</month><year>2012</year></date><date date-type="rev-recd"><day>3</day><month>4</month><year>2012</year></date><date date-type="accepted"><day>23</day><month>4</month><year>2012</year></date></history><permissions><copyright-statement>© 2012 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved.</copyright-statement><copyright-year>2012</copyright-year><copyright-holder>The American Society of Human Genetics</copyright-holder></permissions><abstract><p>The evolutionarily conserved cohesin complex was originally described for its role in regulating sister-chromatid cohesion during mitosis and meiosis. Cohesin and its regulatory proteins have been implicated in several human developmental disorders, including Cornelia de Lange (CdLS) and Roberts syndromes. Here we show that human mutations in the integral cohesin structural protein RAD21 result in a congenital phenotype consistent with a “cohesinopathy.” Children with <italic>RAD21</italic> mutations display growth retardation, minor skeletal anomalies, and facial features that overlap findings in individuals with CdLS. Notably, unlike children with mutations in <italic>NIPBL, SMC1A</italic>, or <italic>SMC3</italic>, these individuals have much milder cognitive impairment than those with classical CdLS. Mechanistically, these mutations act at the RAD21 interface with the other cohesin proteins STAG2 and SMC1A, impair cellular DNA damage response, and disrupt transcription in a zebrafish model. Our data suggest that, compared to loss-of-function mutations, dominant missense mutations result in more severe functional defects and cause worse structural and cognitive clinical findings. These results underscore the essential role of RAD21 in eukaryotes and emphasize the need for further understanding of the role of cohesin in human development.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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