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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">A Regulatory Path Associated with X-Linked Intellectual Disability and Epilepsy Links <italic>KDM5C</italic> to the Polyalanine Expansions in ARX</title><author><name sortKey="Poeta, Loredana" sort="Poeta, Loredana" uniqKey="Poeta L" first="Loredana" last="Poeta">Loredana Poeta</name><affiliation><nlm:aff id="aff1">Institute of Genetics and Biophysics “Adriano Buzzati Traverso,” Consiglio Nazionale delle Ricerche, Naples 80131, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">University of Basilicata, Potenza 85100, Italy</nlm:aff></affiliation></author><author><name sortKey="Fusco, Francesca" sort="Fusco, Francesca" uniqKey="Fusco F" first="Francesca" last="Fusco">Francesca Fusco</name><affiliation><nlm:aff id="aff1">Institute of Genetics and Biophysics “Adriano Buzzati Traverso,” Consiglio Nazionale delle Ricerche, Naples 80131, Italy</nlm:aff></affiliation></author><author><name sortKey="Drongitis, Denise" sort="Drongitis, Denise" uniqKey="Drongitis D" first="Denise" last="Drongitis">Denise Drongitis</name><affiliation><nlm:aff id="aff1">Institute of Genetics and Biophysics “Adriano Buzzati Traverso,” Consiglio Nazionale delle Ricerche, Naples 80131, Italy</nlm:aff></affiliation></author><author><name sortKey="Shoubridge, Cheryl" sort="Shoubridge, Cheryl" uniqKey="Shoubridge C" first="Cheryl" last="Shoubridge">Cheryl Shoubridge</name><affiliation><nlm:aff id="aff3">Department of Paediatrics, University of Adelaide, Adelaide, South Australia 5006, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Genetics and Molecular Pathology, Adelaide, South Australia 5006, Australia</nlm:aff></affiliation></author><author><name sortKey="Manganelli, Genesia" sort="Manganelli, Genesia" uniqKey="Manganelli G" first="Genesia" last="Manganelli">Genesia Manganelli</name><affiliation><nlm:aff id="aff1">Institute of Genetics and Biophysics “Adriano Buzzati Traverso,” Consiglio Nazionale delle Ricerche, Naples 80131, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Istituto Di Ricovero e Cura a Carattere Scientifico, Neuromed, Pozzilli 86077, Italy</nlm:aff></affiliation></author><author><name sortKey="Filosa, Stefania" sort="Filosa, Stefania" uniqKey="Filosa S" first="Stefania" last="Filosa">Stefania Filosa</name><affiliation><nlm:aff id="aff1">Institute of Genetics and Biophysics “Adriano Buzzati Traverso,” Consiglio Nazionale delle Ricerche, Naples 80131, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Istituto Di Ricovero e Cura a Carattere Scientifico, Neuromed, Pozzilli 86077, Italy</nlm:aff></affiliation></author><author><name sortKey="Paciolla, Mariateresa" sort="Paciolla, Mariateresa" uniqKey="Paciolla M" first="Mariateresa" last="Paciolla">Mariateresa Paciolla</name><affiliation><nlm:aff id="aff1">Institute of Genetics and Biophysics “Adriano Buzzati Traverso,” Consiglio Nazionale delle Ricerche, Naples 80131, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">University of Basilicata, Potenza 85100, Italy</nlm:aff></affiliation></author><author><name sortKey="Courtney, Monica" sort="Courtney, Monica" uniqKey="Courtney M" first="Monica" last="Courtney">Monica Courtney</name><affiliation><nlm:aff id="aff6">Université Nice Sophia Antipolis, Nice 06108, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Institut National de la Santé et de la Recherche Médicale Unité 1091, Diabetes Genetics Team, Institute of Biology Valrose, Nice 06108, France</nlm:aff></affiliation></author><author><name sortKey="Collombat, Patrick" sort="Collombat, Patrick" uniqKey="Collombat P" first="Patrick" last="Collombat">Patrick Collombat</name><affiliation><nlm:aff id="aff6">Université Nice Sophia Antipolis, Nice 06108, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Institut National de la Santé et de la Recherche Médicale Unité 1091, Diabetes Genetics Team, Institute of Biology Valrose, Nice 06108, France</nlm:aff></affiliation></author><author><name sortKey="Lioi, Maria Brigida" sort="Lioi, Maria Brigida" uniqKey="Lioi M" first="Maria Brigida" last="Lioi">Maria Brigida Lioi</name><affiliation><nlm:aff id="aff2">University of Basilicata, Potenza 85100, Italy</nlm:aff></affiliation></author><author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name><affiliation><nlm:aff id="aff3">Department of Paediatrics, University of Adelaide, Adelaide, South Australia 5006, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Genetics and Molecular Pathology, Adelaide, South Australia 5006, Australia</nlm:aff></affiliation></author><author><name sortKey="Ursini, Matilde Valeria" sort="Ursini, Matilde Valeria" uniqKey="Ursini M" first="Matilde Valeria" last="Ursini">Matilde Valeria Ursini</name><affiliation><nlm:aff id="aff1">Institute of Genetics and Biophysics “Adriano Buzzati Traverso,” Consiglio Nazionale delle Ricerche, Naples 80131, Italy</nlm:aff></affiliation></author><author><name sortKey="Miano, Maria Giuseppina" sort="Miano, Maria Giuseppina" uniqKey="Miano M" first="Maria Giuseppina" last="Miano">Maria Giuseppina Miano</name><affiliation><nlm:aff id="aff1">Institute of Genetics and Biophysics “Adriano Buzzati Traverso,” Consiglio Nazionale delle Ricerche, Naples 80131, Italy</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">23246292</idno><idno type="pmc">3542471</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3542471</idno><idno type="RBID">PMC:3542471</idno><idno type="doi">10.1016/j.ajhg.2012.11.008</idno><date when="2013">2013</date><idno type="wicri:Area/Pmc/Corpus">001201</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001201</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A Regulatory Path Associated with X-Linked Intellectual Disability and Epilepsy Links <italic>KDM5C</italic> to the Polyalanine Expansions in ARX</title><author><name sortKey="Poeta, Loredana" sort="Poeta, Loredana" uniqKey="Poeta L" first="Loredana" last="Poeta">Loredana Poeta</name><affiliation><nlm:aff id="aff1">Institute of Genetics and Biophysics “Adriano Buzzati Traverso,” Consiglio Nazionale delle Ricerche, Naples 80131, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">University of Basilicata, Potenza 85100, Italy</nlm:aff></affiliation></author><author><name sortKey="Fusco, Francesca" sort="Fusco, Francesca" uniqKey="Fusco F" first="Francesca" last="Fusco">Francesca Fusco</name><affiliation><nlm:aff id="aff1">Institute of Genetics and Biophysics “Adriano Buzzati Traverso,” Consiglio Nazionale delle Ricerche, Naples 80131, Italy</nlm:aff></affiliation></author><author><name sortKey="Drongitis, Denise" sort="Drongitis, Denise" uniqKey="Drongitis D" first="Denise" last="Drongitis">Denise Drongitis</name><affiliation><nlm:aff id="aff1">Institute of Genetics and Biophysics “Adriano Buzzati Traverso,” Consiglio Nazionale delle Ricerche, Naples 80131, Italy</nlm:aff></affiliation></author><author><name sortKey="Shoubridge, Cheryl" sort="Shoubridge, Cheryl" uniqKey="Shoubridge C" first="Cheryl" last="Shoubridge">Cheryl Shoubridge</name><affiliation><nlm:aff id="aff3">Department of Paediatrics, University of Adelaide, Adelaide, South Australia 5006, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Genetics and Molecular Pathology, Adelaide, South Australia 5006, Australia</nlm:aff></affiliation></author><author><name sortKey="Manganelli, Genesia" sort="Manganelli, Genesia" uniqKey="Manganelli G" first="Genesia" last="Manganelli">Genesia Manganelli</name><affiliation><nlm:aff id="aff1">Institute of Genetics and Biophysics “Adriano Buzzati Traverso,” Consiglio Nazionale delle Ricerche, Naples 80131, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Istituto Di Ricovero e Cura a Carattere Scientifico, Neuromed, Pozzilli 86077, Italy</nlm:aff></affiliation></author><author><name sortKey="Filosa, Stefania" sort="Filosa, Stefania" uniqKey="Filosa S" first="Stefania" last="Filosa">Stefania Filosa</name><affiliation><nlm:aff id="aff1">Institute of Genetics and Biophysics “Adriano Buzzati Traverso,” Consiglio Nazionale delle Ricerche, Naples 80131, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Istituto Di Ricovero e Cura a Carattere Scientifico, Neuromed, Pozzilli 86077, Italy</nlm:aff></affiliation></author><author><name sortKey="Paciolla, Mariateresa" sort="Paciolla, Mariateresa" uniqKey="Paciolla M" first="Mariateresa" last="Paciolla">Mariateresa Paciolla</name><affiliation><nlm:aff id="aff1">Institute of Genetics and Biophysics “Adriano Buzzati Traverso,” Consiglio Nazionale delle Ricerche, Naples 80131, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">University of Basilicata, Potenza 85100, Italy</nlm:aff></affiliation></author><author><name sortKey="Courtney, Monica" sort="Courtney, Monica" uniqKey="Courtney M" first="Monica" last="Courtney">Monica Courtney</name><affiliation><nlm:aff id="aff6">Université Nice Sophia Antipolis, Nice 06108, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Institut National de la Santé et de la Recherche Médicale Unité 1091, Diabetes Genetics Team, Institute of Biology Valrose, Nice 06108, France</nlm:aff></affiliation></author><author><name sortKey="Collombat, Patrick" sort="Collombat, Patrick" uniqKey="Collombat P" first="Patrick" last="Collombat">Patrick Collombat</name><affiliation><nlm:aff id="aff6">Université Nice Sophia Antipolis, Nice 06108, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Institut National de la Santé et de la Recherche Médicale Unité 1091, Diabetes Genetics Team, Institute of Biology Valrose, Nice 06108, France</nlm:aff></affiliation></author><author><name sortKey="Lioi, Maria Brigida" sort="Lioi, Maria Brigida" uniqKey="Lioi M" first="Maria Brigida" last="Lioi">Maria Brigida Lioi</name><affiliation><nlm:aff id="aff2">University of Basilicata, Potenza 85100, Italy</nlm:aff></affiliation></author><author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name><affiliation><nlm:aff id="aff3">Department of Paediatrics, University of Adelaide, Adelaide, South Australia 5006, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Genetics and Molecular Pathology, Adelaide, South Australia 5006, Australia</nlm:aff></affiliation></author><author><name sortKey="Ursini, Matilde Valeria" sort="Ursini, Matilde Valeria" uniqKey="Ursini M" first="Matilde Valeria" last="Ursini">Matilde Valeria Ursini</name><affiliation><nlm:aff id="aff1">Institute of Genetics and Biophysics “Adriano Buzzati Traverso,” Consiglio Nazionale delle Ricerche, Naples 80131, Italy</nlm:aff></affiliation></author><author><name sortKey="Miano, Maria Giuseppina" sort="Miano, Maria Giuseppina" uniqKey="Miano M" first="Maria Giuseppina" last="Miano">Maria Giuseppina Miano</name><affiliation><nlm:aff id="aff1">Institute of Genetics and Biophysics “Adriano Buzzati Traverso,” Consiglio Nazionale delle Ricerche, Naples 80131, Italy</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="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Intellectual disability (ID) and epilepsy often occur together and have a dramatic impact on the development and quality of life of the affected children. Polyalanine (polyA)-expansion-encoding mutations of aristaless-related homeobox (<italic>ARX</italic>) cause a spectrum of X-linked ID (XLID) diseases and chronic epilepsy, including infantile spasms. We show that lysine-specific demethylase 5C (<italic>KDM5C</italic>), a gene known to be mutated in XLID-affected children and involved in chromatin remodeling, is directly regulated by ARX through the binding in a conserved noncoding element. We have studied altered ARX carrying various polyA elongations in individuals with XLID and/or epilepsy. The changes in polyA repeats cause hypomorphic ARX alterations, which exhibit a decreased <italic>trans</italic>-activity and reduced, but not abolished, binding to the <italic>KDM5C</italic> regulatory region. The altered functioning of the mutants tested is likely to correlate with the severity of XLID and/or epilepsy. By quantitative RT-PCR, we observed a dramatic <italic>Kdm5c</italic> mRNA downregulation in murine <italic>Arx</italic>-knockout embryonic and neural stem cells. Such <italic>Kdm5c</italic> mRNA diminution led to a severe decrease in the KDM5C content during in vitro neuronal differentiation, which inversely correlated with an increase in H3K4me3 signal. We established that ARX polyA alterations damage the regulation of <italic>KDM5C</italic> expression, and we propose a potential ARX-dependent path acting via chromatin remodeling.</p></div></front></TEI><pmc article-type="brief-report"><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">23246292</article-id><article-id pub-id-type="pmc">3542471</article-id><article-id pub-id-type="publisher-id">S0002-9297(12)00591-5</article-id><article-id pub-id-type="doi">10.1016/j.ajhg.2012.11.008</article-id><article-categories><subj-group subj-group-type="heading"><subject>Report</subject></subj-group></article-categories><title-group><article-title>A Regulatory Path Associated with X-Linked Intellectual Disability and Epilepsy Links <italic>KDM5C</italic> to the Polyalanine Expansions in ARX</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Poeta</surname><given-names>Loredana</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>Fusco</surname><given-names>Francesca</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Drongitis</surname><given-names>Denise</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Shoubridge</surname><given-names>Cheryl</given-names></name><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Manganelli</surname><given-names>Genesia</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Filosa</surname><given-names>Stefania</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Paciolla</surname><given-names>Mariateresa</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>Courtney</surname><given-names>Monica</given-names></name><xref rid="aff6" ref-type="aff">6</xref><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Collombat</surname><given-names>Patrick</given-names></name><xref rid="aff6" ref-type="aff">6</xref><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Lioi</surname><given-names>Maria Brigida</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Gecz</surname><given-names>Jozef</given-names></name><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Ursini</surname><given-names>Matilde Valeria</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Miano</surname><given-names>Maria Giuseppina</given-names></name><email>miano@igb.cnr.it</email><xref rid="aff1" ref-type="aff">1</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib></contrib-group><aff id="aff1"><label>1</label>Institute of Genetics and Biophysics “Adriano Buzzati Traverso,” Consiglio Nazionale delle Ricerche, Naples 80131, Italy</aff><aff id="aff2"><label>2</label>University of Basilicata, Potenza 85100, Italy</aff><aff id="aff3"><label>3</label>Department of Paediatrics, University of Adelaide, Adelaide, South Australia 5006, Australia</aff><aff id="aff4"><label>4</label>Department of Genetics and Molecular Pathology, Adelaide, South Australia 5006, Australia</aff><aff id="aff5"><label>5</label>Istituto Di Ricovero e Cura a Carattere Scientifico, Neuromed, Pozzilli 86077, Italy</aff><aff id="aff6"><label>6</label>Université Nice Sophia Antipolis, Nice 06108, France</aff><aff id="aff7"><label>7</label>Institut National de la Santé et de la Recherche Médicale Unité 1091, Diabetes Genetics Team, Institute of Biology Valrose, Nice 06108, France</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>miano@igb.cnr.it</email></corresp></author-notes><pub-date pub-type="ppub"><day>10</day><month>1</month><year>2013</year></pub-date><volume>92</volume><issue>1</issue><fpage>114</fpage><lpage>125</lpage><history><date date-type="received"><day>10</day><month>5</month><year>2012</year></date><date date-type="rev-recd"><day>7</day><month>6</month><year>2012</year></date><date date-type="accepted"><day>13</day><month>11</month><year>2012</year></date></history><permissions><copyright-statement>© 2013 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved.</copyright-statement><copyright-year>2013</copyright-year><copyright-holder>The American Society of Human Genetics</copyright-holder></permissions><abstract><p>Intellectual disability (ID) and epilepsy often occur together and have a dramatic impact on the development and quality of life of the affected children. Polyalanine (polyA)-expansion-encoding mutations of aristaless-related homeobox (<italic>ARX</italic>) cause a spectrum of X-linked ID (XLID) diseases and chronic epilepsy, including infantile spasms. We show that lysine-specific demethylase 5C (<italic>KDM5C</italic>), a gene known to be mutated in XLID-affected children and involved in chromatin remodeling, is directly regulated by ARX through the binding in a conserved noncoding element. We have studied altered ARX carrying various polyA elongations in individuals with XLID and/or epilepsy. The changes in polyA repeats cause hypomorphic ARX alterations, which exhibit a decreased <italic>trans</italic>-activity and reduced, but not abolished, binding to the <italic>KDM5C</italic> regulatory region. The altered functioning of the mutants tested is likely to correlate with the severity of XLID and/or epilepsy. By quantitative RT-PCR, we observed a dramatic <italic>Kdm5c</italic> mRNA downregulation in murine <italic>Arx</italic>-knockout embryonic and neural stem cells. Such <italic>Kdm5c</italic> mRNA diminution led to a severe decrease in the KDM5C content during in vitro neuronal differentiation, which inversely correlated with an increase in H3K4me3 signal. We established that ARX polyA alterations damage the regulation of <italic>KDM5C</italic> expression, and we propose a potential ARX-dependent path acting via chromatin remodeling.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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