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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en"><italic>GRIN2A</italic> mutations cause epilepsy-aphasia spectrum disorders</title><author><name sortKey="Carvill, Gemma L" sort="Carvill, Gemma L" uniqKey="Carvill G" first="Gemma L" last="Carvill">Gemma L. Carvill</name><affiliation><nlm:aff id="A1">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, 98195, USA</nlm:aff></affiliation></author><author><name sortKey="Regan, Brigid M" sort="Regan, Brigid M" uniqKey="Regan B" first="Brigid M" last="Regan">Brigid M. Regan</name><affiliation><nlm:aff id="A2">Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Australia</nlm:aff></affiliation></author><author><name sortKey="Yendle, Simone C" sort="Yendle, Simone C" uniqKey="Yendle S" first="Simone C" last="Yendle">Simone C. Yendle</name><affiliation><nlm:aff id="A2">Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Australia</nlm:aff></affiliation></author><author><name sortKey="O Oak, Brian J" sort="O Oak, Brian J" uniqKey="O Oak B" first="Brian J" last="O Oak">Brian J. O Oak</name><affiliation><nlm:aff id="A3">Department of Genome Sciences, University of Washington, Seattle, Washington, 98195, USA</nlm:aff></affiliation></author><author><name sortKey="Lozovaya, Natalia" sort="Lozovaya, Natalia" uniqKey="Lozovaya N" first="Natalia" last="Lozovaya">Natalia Lozovaya</name><affiliation><nlm:aff id="A4">Mediterranean Institute of Neurobiology (INMED), Marseille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A5">INSERM UMR_S901, Marseille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Aix-Marseille University, Marseille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A7">INSERM UMR_S663, Paris Descartes University, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Bruneau, Nadine" sort="Bruneau, Nadine" uniqKey="Bruneau N" first="Nadine" last="Bruneau">Nadine Bruneau</name><affiliation><nlm:aff id="A4">Mediterranean Institute of Neurobiology (INMED), Marseille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A5">INSERM UMR_S901, Marseille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Aix-Marseille University, Marseille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A8">French EPILAND network on Epilepsy, Language and Development</nlm:aff></affiliation></author><author><name sortKey="Burnashev, Nail" sort="Burnashev, Nail" uniqKey="Burnashev N" first="Nail" last="Burnashev">Nail Burnashev</name><affiliation><nlm:aff id="A4">Mediterranean Institute of Neurobiology (INMED), Marseille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A5">INSERM UMR_S901, Marseille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Aix-Marseille University, Marseille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A8">French EPILAND network on Epilepsy, Language and Development</nlm:aff></affiliation></author><author><name sortKey="Khan, Adiba" sort="Khan, Adiba" uniqKey="Khan A" first="Adiba" last="Khan">Adiba Khan</name><affiliation><nlm:aff id="A1">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, 98195, USA</nlm:aff></affiliation></author><author><name sortKey="Cook, Joseph" sort="Cook, Joseph" uniqKey="Cook J" first="Joseph" last="Cook">Joseph Cook</name><affiliation><nlm:aff id="A1">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, 98195, USA</nlm:aff></affiliation></author><author><name sortKey="Geraghty, Eileen" sort="Geraghty, Eileen" uniqKey="Geraghty E" first="Eileen" last="Geraghty">Eileen Geraghty</name><affiliation><nlm:aff id="A1">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, 98195, USA</nlm:aff></affiliation></author><author><name sortKey="Sadleir, Lynette G" sort="Sadleir, Lynette G" uniqKey="Sadleir L" first="Lynette G" last="Sadleir">Lynette G. Sadleir</name><affiliation><nlm:aff id="A9">Department of Pediatrics, School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand</nlm:aff></affiliation></author><author><name sortKey="Turner, Samantha J" sort="Turner, Samantha J" uniqKey="Turner S" first="Samantha J" last="Turner">Samantha J. Turner</name><affiliation><nlm:aff id="A2">Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A10">Department of Pediatrics, University of Melbourne, Royal Children’s Hospital, Australia</nlm:aff></affiliation></author><author><name sortKey="Tsai, Meng Han" sort="Tsai, Meng Han" uniqKey="Tsai M" first="Meng-Han" last="Tsai">Meng-Han Tsai</name><affiliation><nlm:aff id="A2">Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Australia</nlm:aff></affiliation></author><author><name sortKey="Webster, Richard" sort="Webster, Richard" uniqKey="Webster R" first="Richard" last="Webster">Richard Webster</name><affiliation><nlm:aff id="A11">T.Y. Nelson Department of Neurology and Neurosurgery, The Children’s Hospital at Westmead, Sydney, New South Wales, Australia</nlm:aff></affiliation></author><author><name sortKey="Ouvrier, Robert" sort="Ouvrier, Robert" uniqKey="Ouvrier R" first="Robert" last="Ouvrier">Robert Ouvrier</name><affiliation><nlm:aff id="A11">T.Y. Nelson Department of Neurology and Neurosurgery, The Children’s Hospital at Westmead, Sydney, New South Wales, Australia</nlm:aff></affiliation></author><author><name sortKey="Damiano, John A" sort="Damiano, John A" uniqKey="Damiano J" first="John A" last="Damiano">John A. Damiano</name><affiliation><nlm:aff id="A2">Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Australia</nlm:aff></affiliation></author><author><name sortKey="Berkovic, Samuel F" sort="Berkovic, Samuel F" uniqKey="Berkovic S" first="Samuel F" last="Berkovic">Samuel F. Berkovic</name><affiliation><nlm:aff id="A2">Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Australia</nlm:aff></affiliation></author><author><name sortKey="Shendure, Jay" sort="Shendure, Jay" uniqKey="Shendure J" first="Jay" last="Shendure">Jay Shendure</name><affiliation><nlm:aff id="A3">Department of Genome Sciences, University of Washington, Seattle, Washington, 98195, USA</nlm:aff></affiliation></author><author><name sortKey="Hildebrand, Michael S" sort="Hildebrand, Michael S" uniqKey="Hildebrand M" first="Michael S" last="Hildebrand">Michael S. Hildebrand</name><affiliation><nlm:aff id="A2">Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Australia</nlm:aff></affiliation></author><author><name sortKey="Szepetowski, Pierre" sort="Szepetowski, Pierre" uniqKey="Szepetowski P" first="Pierre" last="Szepetowski">Pierre Szepetowski</name><affiliation><nlm:aff id="A4">Mediterranean Institute of Neurobiology (INMED), Marseille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A5">INSERM UMR_S901, Marseille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Aix-Marseille University, Marseille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A8">French EPILAND network on Epilepsy, Language and Development</nlm:aff></affiliation></author><author><name sortKey="Scheffer, Ingrid E" sort="Scheffer, Ingrid E" uniqKey="Scheffer I" first="Ingrid E" last="Scheffer">Ingrid E. Scheffer</name><affiliation><nlm:aff id="A2">Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A10">Department of Pediatrics, University of Melbourne, Royal Children’s Hospital, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A12">Florey Institute, Melbourne, Australia</nlm:aff></affiliation></author><author><name sortKey="Mefford, Heather C" sort="Mefford, Heather C" uniqKey="Mefford H" first="Heather C" last="Mefford">Heather C. Mefford</name><affiliation><nlm:aff id="A1">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, 98195, USA</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">23933818</idno><idno type="pmc">3868952</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868952</idno><idno type="RBID">PMC:3868952</idno><idno type="doi">10.1038/ng.2727</idno><date when="2013">2013</date><idno type="wicri:Area/Pmc/Corpus">002E28</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002E28</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main"><italic>GRIN2A</italic> mutations cause epilepsy-aphasia spectrum disorders</title><author><name sortKey="Carvill, Gemma L" sort="Carvill, Gemma L" uniqKey="Carvill G" first="Gemma L" last="Carvill">Gemma L. Carvill</name><affiliation><nlm:aff id="A1">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, 98195, USA</nlm:aff></affiliation></author><author><name sortKey="Regan, Brigid M" sort="Regan, Brigid M" uniqKey="Regan B" first="Brigid M" last="Regan">Brigid M. Regan</name><affiliation><nlm:aff id="A2">Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Australia</nlm:aff></affiliation></author><author><name sortKey="Yendle, Simone C" sort="Yendle, Simone C" uniqKey="Yendle S" first="Simone C" last="Yendle">Simone C. Yendle</name><affiliation><nlm:aff id="A2">Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Australia</nlm:aff></affiliation></author><author><name sortKey="O Oak, Brian J" sort="O Oak, Brian J" uniqKey="O Oak B" first="Brian J" last="O Oak">Brian J. O Oak</name><affiliation><nlm:aff id="A3">Department of Genome Sciences, University of Washington, Seattle, Washington, 98195, USA</nlm:aff></affiliation></author><author><name sortKey="Lozovaya, Natalia" sort="Lozovaya, Natalia" uniqKey="Lozovaya N" first="Natalia" last="Lozovaya">Natalia Lozovaya</name><affiliation><nlm:aff id="A4">Mediterranean Institute of Neurobiology (INMED), Marseille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A5">INSERM UMR_S901, Marseille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Aix-Marseille University, Marseille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A7">INSERM UMR_S663, Paris Descartes University, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Bruneau, Nadine" sort="Bruneau, Nadine" uniqKey="Bruneau N" first="Nadine" last="Bruneau">Nadine Bruneau</name><affiliation><nlm:aff id="A4">Mediterranean Institute of Neurobiology (INMED), Marseille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A5">INSERM UMR_S901, Marseille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Aix-Marseille University, Marseille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A8">French EPILAND network on Epilepsy, Language and Development</nlm:aff></affiliation></author><author><name sortKey="Burnashev, Nail" sort="Burnashev, Nail" uniqKey="Burnashev N" first="Nail" last="Burnashev">Nail Burnashev</name><affiliation><nlm:aff id="A4">Mediterranean Institute of Neurobiology (INMED), Marseille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A5">INSERM UMR_S901, Marseille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Aix-Marseille University, Marseille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A8">French EPILAND network on Epilepsy, Language and Development</nlm:aff></affiliation></author><author><name sortKey="Khan, Adiba" sort="Khan, Adiba" uniqKey="Khan A" first="Adiba" last="Khan">Adiba Khan</name><affiliation><nlm:aff id="A1">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, 98195, USA</nlm:aff></affiliation></author><author><name sortKey="Cook, Joseph" sort="Cook, Joseph" uniqKey="Cook J" first="Joseph" last="Cook">Joseph Cook</name><affiliation><nlm:aff id="A1">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, 98195, USA</nlm:aff></affiliation></author><author><name sortKey="Geraghty, Eileen" sort="Geraghty, Eileen" uniqKey="Geraghty E" first="Eileen" last="Geraghty">Eileen Geraghty</name><affiliation><nlm:aff id="A1">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, 98195, USA</nlm:aff></affiliation></author><author><name sortKey="Sadleir, Lynette G" sort="Sadleir, Lynette G" uniqKey="Sadleir L" first="Lynette G" last="Sadleir">Lynette G. Sadleir</name><affiliation><nlm:aff id="A9">Department of Pediatrics, School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand</nlm:aff></affiliation></author><author><name sortKey="Turner, Samantha J" sort="Turner, Samantha J" uniqKey="Turner S" first="Samantha J" last="Turner">Samantha J. Turner</name><affiliation><nlm:aff id="A2">Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A10">Department of Pediatrics, University of Melbourne, Royal Children’s Hospital, Australia</nlm:aff></affiliation></author><author><name sortKey="Tsai, Meng Han" sort="Tsai, Meng Han" uniqKey="Tsai M" first="Meng-Han" last="Tsai">Meng-Han Tsai</name><affiliation><nlm:aff id="A2">Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Australia</nlm:aff></affiliation></author><author><name sortKey="Webster, Richard" sort="Webster, Richard" uniqKey="Webster R" first="Richard" last="Webster">Richard Webster</name><affiliation><nlm:aff id="A11">T.Y. Nelson Department of Neurology and Neurosurgery, The Children’s Hospital at Westmead, Sydney, New South Wales, Australia</nlm:aff></affiliation></author><author><name sortKey="Ouvrier, Robert" sort="Ouvrier, Robert" uniqKey="Ouvrier R" first="Robert" last="Ouvrier">Robert Ouvrier</name><affiliation><nlm:aff id="A11">T.Y. Nelson Department of Neurology and Neurosurgery, The Children’s Hospital at Westmead, Sydney, New South Wales, Australia</nlm:aff></affiliation></author><author><name sortKey="Damiano, John A" sort="Damiano, John A" uniqKey="Damiano J" first="John A" last="Damiano">John A. Damiano</name><affiliation><nlm:aff id="A2">Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Australia</nlm:aff></affiliation></author><author><name sortKey="Berkovic, Samuel F" sort="Berkovic, Samuel F" uniqKey="Berkovic S" first="Samuel F" last="Berkovic">Samuel F. Berkovic</name><affiliation><nlm:aff id="A2">Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Australia</nlm:aff></affiliation></author><author><name sortKey="Shendure, Jay" sort="Shendure, Jay" uniqKey="Shendure J" first="Jay" last="Shendure">Jay Shendure</name><affiliation><nlm:aff id="A3">Department of Genome Sciences, University of Washington, Seattle, Washington, 98195, USA</nlm:aff></affiliation></author><author><name sortKey="Hildebrand, Michael S" sort="Hildebrand, Michael S" uniqKey="Hildebrand M" first="Michael S" last="Hildebrand">Michael S. Hildebrand</name><affiliation><nlm:aff id="A2">Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Australia</nlm:aff></affiliation></author><author><name sortKey="Szepetowski, Pierre" sort="Szepetowski, Pierre" uniqKey="Szepetowski P" first="Pierre" last="Szepetowski">Pierre Szepetowski</name><affiliation><nlm:aff id="A4">Mediterranean Institute of Neurobiology (INMED), Marseille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A5">INSERM UMR_S901, Marseille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Aix-Marseille University, Marseille, France</nlm:aff></affiliation><affiliation><nlm:aff id="A8">French EPILAND network on Epilepsy, Language and Development</nlm:aff></affiliation></author><author><name sortKey="Scheffer, Ingrid E" sort="Scheffer, Ingrid E" uniqKey="Scheffer I" first="Ingrid E" last="Scheffer">Ingrid E. Scheffer</name><affiliation><nlm:aff id="A2">Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A10">Department of Pediatrics, University of Melbourne, Royal Children’s Hospital, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A12">Florey Institute, Melbourne, Australia</nlm:aff></affiliation></author><author><name sortKey="Mefford, Heather C" sort="Mefford, Heather C" uniqKey="Mefford H" first="Heather C" last="Mefford">Heather C. Mefford</name><affiliation><nlm:aff id="A1">Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, 98195, USA</nlm:aff></affiliation></author></analytic><series><title level="j">Nature genetics</title><idno type="ISSN">1061-4036</idno><idno type="eISSN">1546-1718</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Berg, At" uniqKey="Berg A">AT Berg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tassinari, Ca" uniqKey="Tassinari C">CA Tassinari</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tsai, M" uniqKey="Tsai M">M Tsai</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Deonna, Tw" uniqKey="Deonna T">TW Deonna</name></author><author><name sortKey="Roulet, E" uniqKey="Roulet E">E Roulet</name></author><author><name sortKey="Fontan, D" uniqKey="Fontan D">D Fontan</name></author><author><name sortKey="Marcoz, Jp" uniqKey="Marcoz J">JP Marcoz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Scheffer, Ie" uniqKey="Scheffer I">IE Scheffer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kugler, Sl" uniqKey="Kugler S">SL Kugler</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Michelucci, R" uniqKey="Michelucci R">R Michelucci</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Roll, P" uniqKey="Roll P">P Roll</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vears, Df" uniqKey="Vears D">DF Vears</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lesca, G" uniqKey="Lesca G">G Lesca</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Reutlinger, C" uniqKey="Reutlinger C">C Reutlinger</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Endele, S" uniqKey="Endele S">S Endele</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="De Ligt, J" uniqKey="De Ligt J">J de Ligt</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Carvill, Gl" uniqKey="Carvill G">GL Carvill</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="O Oak, Bj" uniqKey="O Oak B">BJ O’Roak</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Talukder, I" uniqKey="Talukder I">I Talukder</name></author><author><name sortKey="Borker, P" uniqKey="Borker P">P Borker</name></author><author><name sortKey="Wollmuth, Lp" uniqKey="Wollmuth L">LP Wollmuth</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Traynelis, Sf" uniqKey="Traynelis S">SF Traynelis</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="O Oak, Bj" uniqKey="O Oak B">BJ O’Roak</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">9216904</journal-id><journal-id journal-id-type="pubmed-jr-id">2419</journal-id><journal-id journal-id-type="nlm-ta">Nat Genet</journal-id><journal-id journal-id-type="iso-abbrev">Nat. Genet.</journal-id><journal-title-group><journal-title>Nature genetics</journal-title></journal-title-group><issn pub-type="ppub">1061-4036</issn><issn pub-type="epub">1546-1718</issn></journal-meta><article-meta><article-id pub-id-type="pmid">23933818</article-id><article-id pub-id-type="pmc">3868952</article-id><article-id pub-id-type="doi">10.1038/ng.2727</article-id><article-id pub-id-type="manuscript">NIHMS507718</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title><italic>GRIN2A</italic> mutations cause epilepsy-aphasia spectrum disorders</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Carvill</surname><given-names>Gemma L</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Regan</surname><given-names>Brigid M</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Yendle</surname><given-names>Simone C</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>O’Roak</surname><given-names>Brian J</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Lozovaya</surname><given-names>Natalia</given-names></name><xref ref-type="aff" rid="A4">4</xref><xref ref-type="aff" rid="A5">5</xref><xref ref-type="aff" rid="A6">6</xref><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Bruneau</surname><given-names>Nadine</given-names></name><xref ref-type="aff" rid="A4">4</xref><xref ref-type="aff" rid="A5">5</xref><xref ref-type="aff" rid="A6">6</xref><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><name><surname>Burnashev</surname><given-names>Nail</given-names></name><xref ref-type="aff" rid="A4">4</xref><xref ref-type="aff" rid="A5">5</xref><xref ref-type="aff" rid="A6">6</xref><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><name><surname>Khan</surname><given-names>Adiba</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Cook</surname><given-names>Joseph</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Geraghty</surname><given-names>Eileen</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Sadleir</surname><given-names>Lynette G</given-names></name><xref ref-type="aff" rid="A9">9</xref></contrib><contrib contrib-type="author"><name><surname>Turner</surname><given-names>Samantha J</given-names></name><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A10">10</xref></contrib><contrib contrib-type="author"><name><surname>Tsai</surname><given-names>Meng-Han</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Webster</surname><given-names>Richard</given-names></name><xref ref-type="aff" rid="A11">11</xref></contrib><contrib contrib-type="author"><name><surname>Ouvrier</surname><given-names>Robert</given-names></name><xref ref-type="aff" rid="A11">11</xref></contrib><contrib contrib-type="author"><name><surname>Damiano</surname><given-names>John A</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Berkovic</surname><given-names>Samuel F</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Shendure</surname><given-names>Jay</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Hildebrand</surname><given-names>Michael S</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Szepetowski</surname><given-names>Pierre</given-names></name><xref ref-type="aff" rid="A4">4</xref><xref ref-type="aff" rid="A5">5</xref><xref ref-type="aff" rid="A6">6</xref><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><name><surname>Scheffer</surname><given-names>Ingrid E</given-names></name><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A10">10</xref><xref ref-type="aff" rid="A12">12</xref><xref rid="FN2" ref-type="author-notes">*</xref></contrib><contrib contrib-type="author"><name><surname>Mefford</surname><given-names>Heather C</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref rid="FN2" ref-type="author-notes">*</xref></contrib></contrib-group><aff id="A1"><label>1</label>Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, 98195, USA</aff><aff id="A2"><label>2</label>Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Australia</aff><aff id="A3"><label>3</label>Department of Genome Sciences, University of Washington, Seattle, Washington, 98195, USA</aff><aff id="A4"><label>4</label>Mediterranean Institute of Neurobiology (INMED), Marseille, France</aff><aff id="A5"><label>5</label>INSERM UMR_S901, Marseille, France</aff><aff id="A6"><label>6</label>Aix-Marseille University, Marseille, France</aff><aff id="A7"><label>7</label>INSERM UMR_S663, Paris Descartes University, Paris, France</aff><aff id="A8"><label>8</label>French EPILAND network on Epilepsy, Language and Development</aff><aff id="A9"><label>9</label>Department of Pediatrics, School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand</aff><aff id="A10"><label>10</label>Department of Pediatrics, University of Melbourne, Royal Children’s Hospital, Australia</aff><aff id="A11"><label>11</label>T.Y. Nelson Department of Neurology and Neurosurgery, The Children’s Hospital at Westmead, Sydney, New South Wales, Australia</aff><aff id="A12"><label>12</label>Florey Institute, Melbourne, Australia</aff><author-notes><corresp id="FN1">Correspondence to: Dr. Heather Mefford: <email>hmefford@u.washington.edu</email> and Prof Ingrid Scheffer: <email>scheffer@unimelb.edu.au</email></corresp><fn id="FN2" fn-type="equal"><label>*</label><p>These authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>21</day><month>8</month><year>2013</year></pub-date><pub-date pub-type="epub"><day>11</day><month>8</month><year>2013</year></pub-date><pub-date pub-type="ppub"><month>9</month><year>2013</year></pub-date><pub-date pub-type="pmc-release"><day>01</day><month>3</month><year>2014</year></pub-date><volume>45</volume><issue>9</issue><fpage>1073</fpage><lpage>1076</lpage><pmc-comment>elocation-id from pubmed: 10.1038/ng.2727</pmc-comment>
<permissions><license><license-p>Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
<uri xlink:type="simple" xlink:href="http://www.nature.com/authors/editorial_policies/license.html#terms">http://www.nature.com/authors/editorial_policies/license.html#terms</uri></license-p></license></permissions></article-meta></front><body><sec id="S1"><title>Letter to the editor</title><p id="P1">The epilepsy-aphasia syndromes (EAS) are a group of rare, severe epileptic encephalopathies of unknown etiology with a characteristic EEG pattern and developmental regression, particularly affecting language. Rare pathogenic deletions that include <italic>GRIN2A</italic> have been implicated in neurodevelopmental disorders. We sought to delineate the pathogenic role of <italic>GRIN2A</italic> in 519 epileptic encephalopathy probands with diverse epilepsy syndromes. We identified four probands with <italic>GRIN2A</italic> variants that segregated with the disorder in their families. Strikingly, all four families presented with EAS, accounting for 9% of epilepsy-aphasia cases. We did not detect pathogenic variants in other epileptic encephalopathies (n=475), nor in 81 probands with benign childhood epilepsy with centro-temporal spikes. We report the first monogenic cause for EAS. <italic>GRIN2A</italic> mutations are restricted to this group of patients, with important ramifications for diagnostic testing and treatment, and novel insights into the pathogenesis of this debilitating group of conditions.</p><p id="P2">The epileptic encephalopathies are a severe group of disorders characterized by seizures and abundant epileptiform activity that contribute to cognitive and behavioral impairment<sup><xref rid="R1" ref-type="bibr">1</xref></sup>. The epileptic encephalopathies comprise a range of electroclinical syndromes with characteristic ages of onset, clinical and EEG manifestations. Two syndromes with overlapping manifestations have the remarkable EEG signature of continuous spike-wave during slow wave sleep (CSWS) in which the non-REM sleep EEG shows virtually continuous (≥85%) high voltage bilateral slow spike wave activity that largely remits on awakening. In Landau-Kleffner syndrome (LKS), children who were previously normal or isolated language delay present with an acquired epileptic aphasia; focal motor seizures occur in 70% of cases and are usually easily controlled. In contrast, in the syndrome of epileptic encephalopathy with continuous spike-wave during slow wave sleep (ECSWS), prior development is delayed in half the children and refractory epilepsy with multiple seizure types is usual. Regression is more global with language, behavior and motor impairment<sup><xref rid="R2" ref-type="bibr">2</xref></sup>. MRI brain studies are often normal or may show a malformation of cortical development such as perisylvian polymicrogyria.</p><p id="P3">In clinical practice, there are patients who do not meet the criteria on EEG or clinical grounds for LKS and ECSWS, usually because their EEG abnormalities do not occupy 85% of slow sleep, yet they have significant language or learning difficulties which may fluctuate in severity. There is debate whether <85% of bilateral epileptiform activity in non-REM sleep is diagnosable as CSWS or whether it should be regarded as an intermediate epilepsy-aphasia disorder (IEAD)<sup><xref rid="R3" ref-type="bibr">3</xref></sup>. These disorders can be conceptualized as falling along a spectrum with LKS, ECSWS at the severe end, IEAD in the middle and benign childhood epilepsy with centro-temporal spikes (BECTS) at the mild end of the spectrum<sup><xref rid="R3" ref-type="bibr">3</xref></sup>. BECTS is the most common focal epilepsy syndrome in childhood and occurs in normal children who present with focal motor rolandic seizures. The EEG shows unilateral or bilateral centro-temporal spikes that are activated by sleep but do not show the almost continuous bilaterally synchronous pattern of CSWS, and the children do not show cognitive decline. The presence of subtle oral dyspraxia has been noted in some patients with BECTS<sup><xref rid="R4" ref-type="bibr">4</xref></sup>.</p><p id="P4">Until recently there has been scant evidence for a genetic etiology for the disorders of the epilepsy-aphasia spectrum. To date, only four families have been reported with monogenic inheritance of rolandic epilepsy and speech or language difficulties. We reported an autosomal dominant family in 1995 with the syndrome of autosomal dominant rolandic epilepsy with speech dyspraxia (ADRESD)<sup><xref rid="R5" ref-type="bibr">5</xref></sup>. An additional three-generational family with a strikingly similar phenotype was reported more recently<sup><xref rid="R6" ref-type="bibr">6</xref></sup>. Finally a family with dysphasia and epilepsy with generalized and focal manifestations was reported<sup><xref rid="R7" ref-type="bibr">7</xref></sup>. A causal gene has not been implicated in these families. Conversely, a fourth family, presenting with X-linked rolandic epilepsy, oral and speech dyspraxia and intellectual disability (ID) was identified with a gain-of-glycosylation <italic>SRPX2</italic> mutation<sup><xref rid="R8" ref-type="bibr">8</xref></sup>. Besides a <italic>SRPX2</italic> mutation in an unrelated proband with perisylvian polymicrogyria and rolandic seizures and female relatives with mild ID, no additional <italic>SRPX2</italic> variants in epilepsy-aphasia phenotypes have been described.</p><p id="P5">Clinical genetic studies of probands with BECTS or EAS provide little support for genes of major effect. Investigation of relatives up to three degrees of relatedness to probands with BECTS or the epilepsy-aphasia spectrum suggest that complex inheritance is most likely with febrile seizures being the most common phenotype in relatives of probands<sup><xref rid="R3" ref-type="bibr">3</xref>, <xref rid="R9" ref-type="bibr">9</xref></sup>.</p><p id="P6">While there has been strong contention that the epilepsy-aphasia syndromes have an immune basis, partly due to their resolution with high dose steroids, a genetic etiology is supported by the rare familial forms described. Furthermore, recent evidence for a genetic etiology has come from copy number variant (CNV) studies. An excess of rare CNVs was noted in a cohort of LKS and CSWS probands<sup><xref rid="R10" ref-type="bibr">10</xref></sup>, including a single LKS proband with a 16p13 deletion containing one gene, <italic>GRIN2A</italic> (NM_000833.3)<sup><xref rid="R10" ref-type="bibr">10</xref></sup>. Furthermore, three children with complex dysmorphic phenotypes were reported with 16p13 deletions that included <italic>GRIN2A</italic><sup><xref rid="R11" ref-type="bibr">11</xref></sup>. <italic>GRIN2A</italic> encodes the NR2A subunit of the N-methyl-D-aspartate (NMDA) receptor, a neurotransmitter-gated ion channel that mediates excitatory transmission in the mammalian brain, making it an attractive candidate for epileptogenesis. <italic>GRIN2A</italic> mutation screening in 127 probands with epilepsy or an abnormal EEG and/or ID detected two pathogenic mutations: a nonsense mutation segregating with epilepsy or an abnormal EEG in three family members and a <italic>de novo</italic> missense mutation in a patient with severe early-onset epileptic encephalopathies <sup><xref rid="R12" ref-type="bibr">12</xref></sup>. Furthermore, a missense mutation was recently reported in a single proband in a large exome sequencing cohort with ID<sup><xref rid="R13" ref-type="bibr">13</xref></sup>. While these observations strongly support a role for <italic>GRIN2A</italic> in epilepsy and ID, no clear genotype-phenotype correlations have emerged. Therefore, we sought to delineate the phenotypic spectrum of <italic>GRIN2A</italic> mutations by screening a large cohort of patients with epileptic encephalopathy.</p><p id="P7">We performed high-throughput sequence analysis of <italic>GRIN2A</italic> in 519 probands with a range of epileptic encephalopathies (<xref rid="T1" ref-type="table">Table 1</xref>). As part of a larger study <sup><xref rid="R14" ref-type="bibr">14</xref></sup> we performed targeted gene capture of 18 genes associated with epilepsy, including <italic>GRIN2A</italic>. Briefly, we re-sequenced all exons and flanking 5 base pairs using molecular inversion probes (MIPs), highly multiplex PCR and next generation sequencing as described previously with minor exceptions (online methods)<sup><xref rid="R15" ref-type="bibr">15</xref></sup>. Using this approach we achieved, on average, 98% coverage (>25X) across <italic>GRIN2A</italic> for all probands.</p><p id="P8">We identified four probands with <italic>GRIN2A</italic> mutations, each of which was confirmed by Sanger sequencing. Segregation analysis in additional family members showed that each variant segregated in an autosomal dominant manner (<xref rid="T2" ref-type="table">Table 2</xref>, <xref rid="F1" ref-type="fig">Figure 1</xref>). These <italic>GRIN2A</italic> variants are not present in 6500 control exomes (see Resources). Two families (A, C) carried the same c.1005-1C>T variant, affecting the highly conserved donor splice site. Genotyping of microsatellite makers and a rare SNV flanking this <italic>GRIN2A</italic> mutation revealed an identical haplotype in these families, suggesting a common founder mutation (<xref rid="SD1" ref-type="supplementary-material">Supplementary Figure 1</xref>). The c1005-1C>T variant was predicted <italic>in silico</italic> to cause skipping of exon four during pre-mRNA splicing, resulting in the removal of 593 exonic nucleotides from the mature transcript and thus a frameshift mutation, Phe139Ilefs*15 (predicted) (see <xref rid="SD1" ref-type="supplementary-material">Supplementary Table1</xref>). We tested for the presence of a rare exonic SNV (rs61753382), encompassed by the common haplotype in affected individuals, in the RNA transcripts of three affected individuals from both families. We detected monoallelic expression of the wild-type variant, suggesting nonsense mediated decay of the mutant transcript (<xref rid="SD1" ref-type="supplementary-material">Supplementary Figure 2</xref>).</p><p id="P9">We detected a p. Met1Thr variant in family B. The alteration of this translation start codon is likely to have detrimental effects on <italic>GRIN2A</italic> protein synthesis, resulting in either complete absence of product due to failure of translation initiation at the start codon, or a truncated protein stemming from translation initiation at an alternate start codon. We were unable to test this as proband RNA was unavailable.</p><p id="P10">Finally we describe a p.Thr531Met variant that affects a highly conserved residue (as predicted by high GERP and Grantham scores), that is predicted to be probably damaging by Polyphen2 and SIFT (<xref rid="T2" ref-type="table">Table 2</xref>). This variant is located in the extracellular ligand-binding domain of NR2A. Specific sites within this domain are known to influence gating and kinetic properties of NMDA receptors<sup><xref rid="R16" ref-type="bibr">16</xref>, <xref rid="R17" ref-type="bibr">17</xref></sup>. We assessed the effect of the p.Thr531Met mutation on NR2A function by co-expression with NR1 in COS-7 cells to form a mutant heteromeric NMDA receptor. A resultant shift in NMDA receptor kinetics was observed by single channel recordings with a four-fold increase in mean open time of the mutant channels (36.7±2.5 ms ; n=2299 channel events), as compared to the wild-type channels (9.1±0.2 ms; n=6715 channel events) (P<0.0001, Mann Whitney test, two-tailed) (<xref rid="F2" ref-type="fig">Figure 2</xref>). This novel variant displayed similar clinical and functional consequences to missense mutations in the same domain in a parallel study by Lesca and colleagues (this issue).</p><p id="P11">The c1005-1C>T and Met1Thr variants likely cause disease as a result of haploinsufficiency of the NR2 subunit of the NMDA receptor, possibly by aberrant NMDA receptor composition or distribution in the brain. Furthermore, we show that the p. Thr531Met variant has a profound effect on NMDA receptor kinetics. Given the pathogenic effect of these mutations and their segregation with the disorder, we conclude that the <italic>GRIN2A</italic> mutations ascribe causality in these families.</p><p id="P12">Remarkably, all four <italic>GRIN2A</italic> positive families presented with EAS, yielding a 9% (4/44) mutation rate in patients with this group of EE. No additional pathogenic variants were detected in the remaining epileptic encephalopathy phenotypes (<xref rid="T1" ref-type="table">Table 1</xref>). In the 40 remaining EAS patients, we performed array-CGH using a custom microarray with probes spanning <italic>GRIN2A</italic> at an average density of one probe every ~350bp. No copy number alterations were detected.</p><p id="P13">Given that BECTS lies at the mild end of the EAS, we next screened 81 probands with BECTS for <italic>GRIN2A</italic> variants using Sanger sequencing. No additional pathogenic variants were identified.</p><p id="P14">There were 16 subjects with <italic>GRIN2A</italic> mutations. Segregation was perfect in the 7 affected members of the original family with autosomal dominant rolandic epilepsy with speech dyspraxia (Family A, <xref rid="F1" ref-type="fig">Fig. 1</xref>)<sup><xref rid="R5" ref-type="bibr">5</xref></sup>. The same mutation was found in a father-son pair with ECSWS (Family C). Interestingly the <italic>GRIN2A</italic> mutations were associated with a range of EAS phenotypes including LKS, ECSWS and IEAD (Table 3). All individuals with LKS and ECSWS showed CSWS on EEG studies. Individuals with IEAD had not had a sleep EEG performed to detect CSWS. Affected family members had a complex phenotype including epilepsy (14/16), speech and language difficulties (16/16). While intellectual disability occurred in 6/16 mutation carriers, a further two were of borderline intellect (<xref rid="SD1" ref-type="supplementary-material">Supplementary Table 2</xref>).</p><p id="P15">Previous cases implicating <italic>GRIN2A</italic> have not identified a consistent epilepsy phenotype but have shared features with our cases. Four cases with 16p13 microdeletions including <italic>GRIN2A</italic> have been reported; one had LKS<sup><xref rid="R10" ref-type="bibr">10</xref></sup>. The remaining three were more complex with dysmorphic features and moderate to severe ID; two were non-verbal and only one walked independently <sup><xref rid="R3" ref-type="bibr">3</xref></sup>. All had seizures; one had atypical benign partial epilepsy, which is part of the EAS. One had rolandic seizures without regression and EEG studies were not available. In two patients, eyelid myoclonias were noted which is somewhat atypical for EAS. Two had an EEG pattern suggestive of CSWS. In another study, a three generation family with a translocation disrupting <italic>GRIN2A</italic> was associated with childhood and adolescent onset convulsions in the setting of learning difficulties or ID. There was no suggestion of CSWS on their EEG studies and no epilepsy syndrome was determined.</p><p id="P16">We conclude that <italic>GRIN2A</italic> mutations are highly predictive of EAS that include LKS, ECSWS and IEAD. Furthermore, in a separate study Lesca and colleagues report <italic>GRIN2A</italic> mutations in 20% of LKS, ECSWS and atypical rolandic epilepsy with speech impairment confirming the importance of <italic>GRIN2A</italic> to the EAS (this issue). Of note, we did not detect any <italic>GRIN2A</italic> variants in 475 probands with other epileptic encephalopathy phenotypes, or in 81 probands with BECTS. Furthermore, in a large series (n= 1703) of autism probands no <italic>GRIN2A</italic> mutations were identified<sup><xref rid="R18" ref-type="bibr">18</xref></sup>. These results demonstrate that the genetic etiology of EAS may well be distinct, an observation that balks the current trend towards an overlapping etiology for neurodevelopmental disorders. We hypothesize that altered NMDA receptor activity due to <italic>GRIN2A</italic> haploinsufficiency or missense mutations results in aberrant ion flux and disruption of the downstream signaling cascade. The role of NMDA receptor aberration and its potential role in the corticothalamic network disrupted in slow sleep will be an important area of future research. This study is the first to detect a monogenic cause for epilepsy-aphasia syndromes with a mutational rate of 9%. These results strongly suggest that <italic>GRIN2A</italic> diagnostic testing is warranted in patients with epilepsy-aphasia and will enhance prognostic and genetic counseling for families.</p></sec><sec id="S2" specific-use="web-only"><title>Online methods</title><sec id="S3"><title>Data analysis and variant calling</title><p id="P17">Raw read processing and alignment was performed as previously<sup><xref rid="R14" ref-type="bibr">14</xref></sup>. However variant (single nucleotide and indel) calling and filtering was performed using the Genome Analysis Tool Kit (GATK) (see URLs version). Variants that did not adhere to the following criteria were excluded from further analysis: allele balance >0.70, QUAL<30, QD<5, coverage<25X, clustered variants (window size-10) and variants in homopolymer runs (5 bp). Variants were annotated with Seattle seq (see URLS and version) and the ESP6500 dataset (see URLs) used to assess variant frequency in control population. PCR and Sanger sequencing were conducted according to standard methods as described previously.</p></sec><sec id="S4"><title>Array CGH</title><p id="P18">We performed array CGH using a custom designed 8plex microarray [Agilent], designed to detect copy number alterations in known epilepsy genes. <italic>GRIN2A</italic> was covered at a density of one probe every ~350bp. All experiments were performed as per the manufacturer’s instructions and data analysis conducted using Genomic Workbench [Agilent].</p></sec><sec id="S5"><title>Genotyping</title><p id="P19">We performed genotyping in all available affected and unaffected members of Family A and B, who carried the c.1005-1C>T variant. We selected three microsatellite markers, D16S404, D16S3126 and D16S407, spanning a 0.56Mb interval across <italic>GRIN2A</italic>. Fluorescently labeled PCR products were analyzed on an ABI3100 genetic analyzer, and allele size ranges determined with the GS500LIZ size standard [Applied Biosystems] using the PeakScanner V2.0 software [Applied Biosystems]. Furthermore, we genotyped all family members for the rare exonic GRIN2A variant (rs61753382) using Sanger DNA sequencing.</p></sec><sec id="S6"><title>RNA transcript analysis</title><p id="P20">RNA was isolated from whole blood of affected family members and controls using the PAXgene blood RNA kit [PreAnalytiX]. cDNA synthesis was performed using 1ug of DNA using the iScript Reverse Transcription Supermix kit [Bio-Rad]. Nested PCR and Sanger sequencing was performed for <italic>GRIN2A</italic> RNA transcripts analysis in three affected family members from both c1005-1C>T carrier families. We assessed the presence of the rs6173382 variant, the minor allele was linked to the c.1005-1C>T mutation (see <xref rid="SD1" ref-type="supplementary-material">Supplementary Table 3</xref> for primer pairs).</p></sec><sec id="S7"><title>Constructs and transfections</title><p id="P21">NR1 and NR2A constructs were commercially purchased [Genecopeia]. Site-directed mutagenesis [Agilent Technologies] was used to generate the mutant NR2A (p.Thr531Met) construct, using the following 5′-gtgccctttgtggaaatgggaatcagtgtcatgg and corresponding reverse complement primers. All wild-type and mutant constructs were verified by Sanger sequencing. Monkey kidney fibroblast like COS-7 cells were seeded in six-well plates (10<sup>5</sup> cells/well) one day before transfection. Magnetofection of NR1 and NR2A constructs (1:3 ratio) was performed using the Magnetofectamine transfection kit [OzBiosciences, France]. The presence of the NR1 and NR2A (wt and mutant) subunits at the plasma membrane was verified by immunocytochemistry experiments (data not shown).</p></sec><sec id="S8"><title>Single channel recordings and analysis</title><p id="P22">Single channel recordings were made from transfected COS-7 cells (ATCC, CRL-1651) in cell-attached patches at holding potential +100 mV using an EPC-10 amplifier (HEKA Elektronik, Germany). Cells were negative for Mycoplasma contamination using the MycoTrace Mycoplasma PCR detection kit (PAA, France). No authentication was made. Cells in the recording chamber were perfused with oxygenated ACSF containing (in mM): 126 NaCl, 3.5 KCl, 1 MgCl<sub>2</sub>, 2 CaCl<sub>2</sub>, 10 D(+)-glucose, 1.20 NaH<sub>2</sub>PO<sub>4</sub>, 26 NaHCO<sub>3</sub> (oxygenated with 5% CO<sub>2</sub>/95% O<sub>2</sub>). Recording patch pipettes were pulled from borosilicate glass capillaries (World Precision Instruments Inc., Sarasota, USA) and had resistances of 4 to 7 MΩ when filled with the solution of the following composition (in mM): 140 NaCl, 2.8 KCl, 2 CaCl<sub>2</sub>, 10 Glucose, 20 HEPES/NaOH, (pH 7.5, 320–330 mOsm). The channels were activated by 50 μM glycine and 1 mM glutamate in the pipette solution. Recordings were performed at room temperature (22–24°C). For analysis, the recordings were filtered at 2 kHz (−3 dB) and digitized at 20 kHz. Lifetime analysis was performed using a Clampfit 10.2 (Molecular Devices, Eugene, OR) and Origin 8.5 (Origin-Lab, Northampton, MA) software. For data analysis by Clampfit, a digital 8-pole Bessel low-pass filter was set at 1 kHz. Average values were expressed as means ± SEM. Statistical significance of the differences was evaluated by nonparametric Mann Whitney test, two-tailed.</p></sec></sec><sec sec-type="supplementary-material" id="S9"><title>Supplementary Material</title><supplementary-material content-type="local-data" id="SD1"><label>1</label><media xlink:href="NIHMS507718-supplement-1.pdf" mimetype="application" mime-subtype="pdf" orientation="portrait" xlink:type="simple" id="d37e707" position="anchor"></media></supplementary-material></sec></body><back><ack id="S10"><p>We thank the patients and their families for participating in our research. H.C.M. is supported by a grant from the NIH (NINDS 1R01NS069605) and is a recipient of a Burroughs Wellcome Fund Career Award for Medical Scientists. This work was supported by the National Health and Medical Research Council of Australia (Program Grant 628952 to S.F.B., I.E.S., Practitioner Fellowship 1006110 to I.E.S, CJ Martin Fellowship (546493) to M.S.H) and the Health Research Council of New Zealand project grant to L.G.S. PS is supported by ANR (Agence Nationale de la Recherche) grant ‘EPILAND’ with EuroBiomed label, and PS, NBurnashev, NBruneau by INSERM (Institut National de la Santé et de la Recherche Médicale).</p></ack><fn-group><fn id="FN3" fn-type="con"><p><bold>Author Contributions</bold></p><p>GLC, HCM and IES designed the study and wrote the manuscript. HCM and IES supervised the study. GLC constructed libraries, developed the variant calling pipeline (assisted by JC), analyzed the sequence data, conducted RNA transcript analysis (assisted by EG) and performed haplotyping. JC and GLC performed array CGH. AK performed mutation segregation analysis. BJO and JS developed the MIPs methodology and analysis pipeline. BMR, SCY, LGS, SJT, MT, RW performed phenotypic analysis. RO, JAD, MSH conducted mutation screening in BECTS cohort. BMR, SFB and IES critically reviewed the manuscript. NL, NBruneau, NBurnashev, PS generated mutant transcripts and performed single-channel recordings and analysis.</p></fn><fn id="FN4"><p><bold>URLs</bold></p><p>Exome Variant Server, NHLBI GO Exome Sequencing Project (ESP), Seattle, WA (URL: <ext-link ext-link-type="uri" xlink:href="http://evs.gs.washington.edu/EVS/">http://evs.gs.washington.edu/EVS/</ext-link>) [10/2012 accessed]</p><p>Polyphen2 (<ext-link ext-link-type="uri" xlink:href="http://genetics.bwh.harvard.edu/pph2/">http://genetics.bwh.harvard.edu/pph2/</ext-link>)</p><p>SIFT (<ext-link ext-link-type="uri" xlink:href="http://sift.bii.a-star.edu.sg/">http://sift.bii.a-star.edu.sg/</ext-link>)</p><p>Genome Analysis Toolkit GATK (version 1.6) (<ext-link ext-link-type="uri" xlink:href="http://www.broadinstitute.org/gatk/">http://www.broadinstitute.org/gatk/</ext-link>)</p><p>Seattle seq (version 134) (<ext-link ext-link-type="uri" xlink:href="http://snp.gs.washington.edu/SeattleSeqAnnotation134/">http://snp.gs.washington.edu/SeattleSeqAnnotation134/</ext-link>)</p></fn></fn-group><ref-list><ref id="R1"><label>1</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Berg</surname><given-names>AT</given-names></name><etal></etal></person-group><article-title>Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009</article-title><source>Epilepsia</source><volume>51</volume><fpage>676</fpage><lpage>85</lpage><year>2010</year><pub-id pub-id-type="pmid">20196795</pub-id></element-citation></ref><ref id="R2"><label>2</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tassinari</surname><given-names>CA</given-names></name><etal></etal></person-group><article-title>Encephalopathy with electrical status epilepticus during slow sleep or ESES syndrome including the acquired aphasia</article-title><source>Clin Neurophysiol</source><volume>111 </volume><issue>Suppl 2</issue><fpage>S94</fpage><lpage>S102</lpage><year>2000</year><pub-id pub-id-type="pmid">10996561</pub-id></element-citation></ref><ref id="R3"><label>3</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tsai</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Clinical genetic study of the epilepsy-aphasia spectrum</article-title><source>Epilepsia</source><volume>54</volume><fpage>280</fpage><lpage>287</lpage><year>2012</year><pub-id pub-id-type="pmid">23294109</pub-id></element-citation></ref><ref id="R4"><label>4</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Deonna</surname><given-names>TW</given-names></name><name><surname>Roulet</surname><given-names>E</given-names></name><name><surname>Fontan</surname><given-names>D</given-names></name><name><surname>Marcoz</surname><given-names>JP</given-names></name></person-group><article-title>Speech and oromotor deficits of epileptic origin in benign partial epilepsy of childhood with rolandic spikes (BPERS). 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Rev</source><volume>62</volume><fpage>405</fpage><lpage>496</lpage><year>2010</year><pub-id pub-id-type="pmid">20716669</pub-id></element-citation></ref><ref id="R18"><label>18</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>O’Roak</surname><given-names>BJ</given-names></name><etal></etal></person-group><article-title>Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations</article-title><source>Nature</source><volume>485</volume><fpage>246</fpage><lpage>250</lpage><year>2012</year><pub-id pub-id-type="pmid">22495309</pub-id></element-citation></ref></ref-list></back><floats-group><fig id="F1" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Phenotypes and segregation of <italic>GRIN2A</italic> mutations in four families with epilepsy-aphasia syndromes</p></caption><graphic xlink:href="nihms507718f1"></graphic></fig><fig id="F2" orientation="portrait" position="float"><label>Figure 2</label><caption><p>NR2A-p.Thr531Met mutation increases mean open time of NMDA receptors. Left panels: representative steady-state unitary currents through (a) NR1/NR2A-wt and (b) NR1/NR2A-p.Thr531Met channels, recorded in cell-attached patches from transiently transfected COS-7 cells (n=5 to 7 cells). Holding potential +100 mV. Channels are activated by 50 μM glycine and 1 mM glutamate. o: open state; c: closed state; ms: milliseconds; pA: picoAmpere. Note that single channel amplitudes were not significantly affected by the mutation. Right panels: open duration histograms for the same single channel patches. The histograms were well fitted with single exponentials.</p></caption><graphic xlink:href="nihms507718f2"></graphic></fig><table-wrap id="T1" position="float" orientation="portrait"><label>Table 1</label><caption><p>Epileptic encephalopathy cohort screened for <italic>GRIN2A</italic> mutations</p></caption><table frame="box" rules="all"><thead><tr><th valign="top" align="left" rowspan="1" colspan="1"></th><th valign="top" align="center" rowspan="1" colspan="1">N</th><th valign="top" align="center" rowspan="1" colspan="1"><italic>GRIN2A</italic> mutations</th></tr></thead><tbody><tr><td align="left" valign="top" rowspan="1" colspan="1">Epilepsy-aphasia</td><td align="center" valign="top" rowspan="1" colspan="1">44</td><td align="center" valign="top" rowspan="1" colspan="1">4</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Focal epilepsy, Symptomatic focal epilepsy</td><td align="center" valign="top" rowspan="1" colspan="1">50</td><td align="center" valign="top" rowspan="1" colspan="1">0</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Epileptic Encephalopathies (other)</td><td align="center" valign="top" rowspan="1" colspan="1">87</td><td align="center" valign="top" rowspan="1" colspan="1">0</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Infantile Spasms</td><td align="center" valign="top" rowspan="1" colspan="1">84</td><td align="center" valign="top" rowspan="1" colspan="1">0</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Epilepsy with myoclonic-atonic seizures</td><td align="center" valign="top" rowspan="1" colspan="1">85</td><td align="center" valign="top" rowspan="1" colspan="1">0</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Symptomatic Generalized Epilepsies</td><td align="center" valign="top" rowspan="1" colspan="1">85</td><td align="center" valign="top" rowspan="1" colspan="1">0</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Febrile Infection-Related Epilepsy Syndrome</td><td align="center" valign="top" rowspan="1" colspan="1">12</td><td align="center" valign="top" rowspan="1" colspan="1">0</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Dravet syndrome</td><td align="center" valign="top" rowspan="1" colspan="1">17</td><td align="center" valign="top" rowspan="1" colspan="1">0</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Lennox Gastaut syndrome</td><td align="center" valign="top" rowspan="1" colspan="1">34</td><td align="center" valign="top" rowspan="1" colspan="1">0</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Ohtahara syndrome</td><td align="center" valign="top" rowspan="1" colspan="1">8</td><td align="center" valign="top" rowspan="1" colspan="1">0</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Epilepsy of Infancy with Migrating Focal Seizures</td><td align="center" valign="top" rowspan="1" colspan="1">7</td><td align="center" valign="top" rowspan="1" colspan="1">0</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Progressive Myoclonic Epilepsies</td><td align="center" valign="top" rowspan="1" colspan="1">6</td><td align="center" valign="top" rowspan="1" colspan="1">0</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1"><bold>TOTAL</bold></td><td align="center" valign="top" rowspan="1" colspan="1"><bold>519</bold></td><td align="center" valign="top" rowspan="1" colspan="1"><bold>4</bold></td></tr></tbody></table></table-wrap><table-wrap id="T2" position="float" orientation="landscape"><label>Table 2</label><caption><p>Pathogenic <italic>GRIN2A</italic> mutations in four epilepsy-aphasia families.</p></caption><table frame="hsides" rules="groups"><thead><tr><th valign="top" align="left" rowspan="1" colspan="1">Family</th><th valign="top" align="left" rowspan="1" colspan="1">Chr</th><th valign="top" align="left" rowspan="1" colspan="1">Pos</th><th valign="top" align="left" rowspan="1" colspan="1">cDNA change</th><th valign="top" align="left" rowspan="1" colspan="1">GERP</th><th valign="top" align="left" rowspan="1" colspan="1">Grantham score</th><th valign="top" align="left" rowspan="1" colspan="1">Polyphen score</th><th valign="top" align="left" rowspan="1" colspan="1">SIFT</th><th valign="top" align="left" rowspan="1" colspan="1">Protein change</th><th valign="top" align="left" rowspan="1" colspan="1">Phenotype</th></tr></thead><tbody><tr><td align="left" valign="top" rowspan="1" colspan="1">A</td><td align="left" valign="top" rowspan="1" colspan="1">16</td><td align="left" valign="top" rowspan="1" colspan="1">10031815</td><td align="left" valign="top" rowspan="1" colspan="1">c.1005-1C>T</td><td align="left" valign="top" rowspan="1" colspan="1">5.2</td><td align="left" valign="top" rowspan="1" colspan="1">NA</td><td align="left" valign="top" rowspan="1" colspan="1">NA</td><td align="left" valign="top" rowspan="1" colspan="1">NA</td><td align="left" valign="top" rowspan="1" colspan="1">Phe139Ilefs *15 (predicted)</td><td align="left" valign="top" rowspan="1" colspan="1">Autosomal Dominant Rolandic Epilepsy with Speech Dyspraxia</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">B</td><td align="left" valign="top" rowspan="1" colspan="1">16</td><td align="left" valign="top" rowspan="1" colspan="1">10274267</td><td align="left" valign="top" rowspan="1" colspan="1">c.2A>G</td><td align="left" valign="top" rowspan="1" colspan="1">4.5</td><td align="left" valign="top" rowspan="1" colspan="1">81</td><td align="left" valign="top" rowspan="1" colspan="1">0.213 (benign)</td><td align="left" valign="top" rowspan="1" colspan="1">0 (damaging)</td><td align="left" valign="top" rowspan="1" colspan="1">Met1Thr</td><td align="left" valign="top" rowspan="1" colspan="1">Landau-Kleffner Syndrome</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">C</td><td align="left" valign="top" rowspan="1" colspan="1">16</td><td align="left" valign="top" rowspan="1" colspan="1">10031815</td><td align="left" valign="top" rowspan="1" colspan="1">c.1005-1C>T</td><td align="left" valign="top" rowspan="1" colspan="1">5.2</td><td align="left" valign="top" rowspan="1" colspan="1">NA</td><td align="left" valign="top" rowspan="1" colspan="1">NA</td><td align="left" valign="top" rowspan="1" colspan="1">NA</td><td align="left" valign="top" rowspan="1" colspan="1">Phe139Ilefs *15 (predicted)</td><td align="left" valign="top" rowspan="1" colspan="1">ECSWS</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">D</td><td align="left" valign="top" rowspan="1" colspan="1">16</td><td align="left" valign="top" rowspan="1" colspan="1">9934563</td><td align="left" valign="top" rowspan="1" colspan="1">c.1592G>A</td><td align="left" valign="top" rowspan="1" colspan="1">5.1</td><td align="left" valign="top" rowspan="1" colspan="1">81</td><td align="left" valign="top" rowspan="1" colspan="1">1.000 (probably damaging)</td><td align="left" valign="top" rowspan="1" colspan="1">0 (damaging)</td><td align="left" valign="top" rowspan="1" colspan="1">Thr531Met</td><td align="left" valign="top" rowspan="1" colspan="1">ECSWS, Intermediate Epilepsy-Aphasia Disorder</td></tr></tbody></table><table-wrap-foot><fn id="TFN1"><p>Chromosomal coordinates as per hg19 genome build, cDNA position as per NM_000833.3 and protein change as per NP_000824.1. unk, unknown; GERP, genomic evolutionary rate profiling; SIFT, Sorting Intolerant From Tolerant; ECSWS = Epileptic Encephalopathy with Continuous Spike-Wave in slow wave Sleep</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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