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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en"><italic>De novo</italic> mutations in <italic>ATP1A3</italic> cause alternating hemiplegia of childhood</title><author><name sortKey="Heinzen, Erin L" sort="Heinzen, Erin L" uniqKey="Heinzen E" first="Erin L." last="Heinzen">Erin L. Heinzen</name><affiliation><nlm:aff id="A2">Department of Medicine, Duke University School of Medicine, Durham, NC 27708 USA</nlm:aff></affiliation></author><author><name sortKey="Swoboda, Kathryn J" sort="Swoboda, Kathryn J" uniqKey="Swoboda K" first="Kathryn J." last="Swoboda">Kathryn J. Swoboda</name><affiliation><nlm:aff id="A3">Department of Pediatrics, University of Utah, Salt Lake City, UT 84132 USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Department of Neurology, University of Utah, Salt Lake City, UT 84132 USA.</nlm:aff></affiliation></author><author><name sortKey="Hitomi, Yuki" sort="Hitomi, Yuki" uniqKey="Hitomi Y" first="Yuki" last="Hitomi">Yuki Hitomi</name><affiliation><nlm:aff id="A1">Center for Human Genome Variation, Duke University School of Medicine, Durham, NC 27708 USA.</nlm:aff></affiliation></author><author><name sortKey="Gurrieri, Fiorella" sort="Gurrieri, Fiorella" uniqKey="Gurrieri F" first="Fiorella" last="Gurrieri">Fiorella Gurrieri</name><affiliation><nlm:aff id="A5">Instituto di Genetica Medica, Università Cattolica del Sacro Cuore, Policlinico A. Gemelli, Rome, Italy.</nlm:aff></affiliation></author><author><name sortKey="Nicole, Sophie" sort="Nicole, Sophie" uniqKey="Nicole S" first="Sophie" last="Nicole">Sophie Nicole</name><affiliation><nlm:aff id="A6">Université Pierre et Marie Curie Paris 06, Centre de Recherche de l’Institut du Cerveau et de la Moelle Epiniere, UMR_S975, Paris, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A8">Centre National de la Recherche Scientifique, UMR 7225, Paris, France.</nlm:aff></affiliation></author><author><name sortKey="De Vries, Boukje" sort="De Vries, Boukje" uniqKey="De Vries B" first="Boukje" last="De Vries">Boukje De Vries</name><affiliation><nlm:aff id="A9">Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.</nlm:aff></affiliation></author><author><name sortKey="Tiziano, F Danilo" sort="Tiziano, F Danilo" uniqKey="Tiziano F" first="F. Danilo" last="Tiziano">F. Danilo Tiziano</name><affiliation><nlm:aff id="A5">Instituto di Genetica Medica, Università Cattolica del Sacro Cuore, Policlinico A. Gemelli, Rome, Italy.</nlm:aff></affiliation></author><author><name sortKey="Fontaine, Bertrand" sort="Fontaine, Bertrand" uniqKey="Fontaine B" first="Bertrand" last="Fontaine">Bertrand Fontaine</name><affiliation><nlm:aff id="A6">Université Pierre et Marie Curie Paris 06, Centre de Recherche de l’Institut du Cerveau et de la Moelle Epiniere, UMR_S975, Paris, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A8">Centre National de la Recherche Scientifique, UMR 7225, Paris, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A10">Assistance Publique-Hôpitaux de Paris, Département de Neurologie & centre de référence “canalopathies musculaires”, Groupe Hospitalier de la Pitié-Salpêtrière, Paris, France.</nlm:aff></affiliation></author><author><name sortKey="Walley, Nicole M" sort="Walley, Nicole M" uniqKey="Walley N" first="Nicole M." last="Walley">Nicole M. Walley</name><affiliation><nlm:aff id="A1">Center for Human Genome Variation, Duke University School of Medicine, Durham, NC 27708 USA.</nlm:aff></affiliation></author><author><name sortKey="Heavin, Sinead" sort="Heavin, Sinead" uniqKey="Heavin S" first="Sinéad" last="Heavin">Sinéad Heavin</name><affiliation><nlm:aff id="A11">Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia.</nlm:aff></affiliation></author><author><name sortKey="Panagiotakaki, Eleni" sort="Panagiotakaki, Eleni" uniqKey="Panagiotakaki E" first="Eleni" last="Panagiotakaki">Eleni Panagiotakaki</name><affiliation><nlm:aff id="A12">Epilepsy, Sleep and Pediatric Neurophysiology Dpt, Hôpital Femme Mère Enfant, University Hospitals of Lyon (HCL), Lyon, France.</nlm:aff></affiliation></author><author><name sortKey="Fiori, Stefania" sort="Fiori, Stefania" uniqKey="Fiori S" first="Stefania" last="Fiori">Stefania Fiori</name><affiliation><nlm:aff id="A5">Instituto di Genetica Medica, Università Cattolica del Sacro Cuore, Policlinico A. Gemelli, Rome, Italy.</nlm:aff></affiliation></author><author><name sortKey="Abiusi, Emanuela" sort="Abiusi, Emanuela" uniqKey="Abiusi E" first="Emanuela" last="Abiusi">Emanuela Abiusi</name><affiliation><nlm:aff id="A5">Instituto di Genetica Medica, Università Cattolica del Sacro Cuore, Policlinico A. Gemelli, Rome, Italy.</nlm:aff></affiliation></author><author><name sortKey="Di Pietro, Lorena" sort="Di Pietro, Lorena" uniqKey="Di Pietro L" first="Lorena" last="Di Pietro">Lorena Di Pietro</name><affiliation><nlm:aff id="A5">Instituto di Genetica Medica, Università Cattolica del Sacro Cuore, Policlinico A. Gemelli, Rome, Italy.</nlm:aff></affiliation></author><author><name sortKey="Sweney, Matthew T" sort="Sweney, Matthew T" uniqKey="Sweney M" first="Matthew T." last="Sweney">Matthew T. Sweney</name><affiliation><nlm:aff id="A3">Department of Pediatrics, University of Utah, Salt Lake City, UT 84132 USA.</nlm:aff></affiliation></author><author><name sortKey="Newcomb, Tara M" sort="Newcomb, Tara M" uniqKey="Newcomb T" first="Tara M." last="Newcomb">Tara M. Newcomb</name><affiliation><nlm:aff id="A3">Department of Pediatrics, University of Utah, Salt Lake City, UT 84132 USA.</nlm:aff></affiliation></author><author><name sortKey="Viollet, Louis" sort="Viollet, Louis" uniqKey="Viollet L" first="Louis" last="Viollet">Louis Viollet</name><affiliation><nlm:aff id="A4">Department of Neurology, University of Utah, Salt Lake City, UT 84132 USA.</nlm:aff></affiliation></author><author><name sortKey="Huff, Chad" sort="Huff, Chad" uniqKey="Huff C" first="Chad" last="Huff">Chad Huff</name><affiliation><nlm:aff id="A16">Department of Human Genetics, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84132 USA.</nlm:aff></affiliation></author><author><name sortKey="Jorde, Lynn B" sort="Jorde, Lynn B" uniqKey="Jorde L" first="Lynn B." last="Jorde">Lynn B. Jorde</name><affiliation><nlm:aff id="A16">Department of Human Genetics, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84132 USA.</nlm:aff></affiliation></author><author><name sortKey="Reyna, Sandra P" sort="Reyna, Sandra P" uniqKey="Reyna S" first="Sandra P." last="Reyna">Sandra P. Reyna</name><affiliation><nlm:aff id="A4">Department of Neurology, University of Utah, Salt Lake City, UT 84132 USA.</nlm:aff></affiliation></author><author><name sortKey="Murphy, Kelley J" sort="Murphy, Kelley J" uniqKey="Murphy K" first="Kelley J." last="Murphy">Kelley J. Murphy</name><affiliation><nlm:aff id="A4">Department of Neurology, University of Utah, Salt Lake City, UT 84132 USA.</nlm:aff></affiliation></author><author><name sortKey="Shianna, Kevin V" sort="Shianna, Kevin V" uniqKey="Shianna K" first="Kevin V." last="Shianna">Kevin V. Shianna</name><affiliation><nlm:aff id="A1">Center for Human Genome Variation, Duke University School of Medicine, Durham, NC 27708 USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Department of Medicine, Duke University School of Medicine, Durham, NC 27708 USA</nlm:aff></affiliation></author><author><name sortKey="Gumbs, Curtis E" sort="Gumbs, Curtis E" uniqKey="Gumbs C" first="Curtis E." last="Gumbs">Curtis E. Gumbs</name><affiliation><nlm:aff id="A1">Center for Human Genome Variation, Duke University School of Medicine, Durham, NC 27708 USA.</nlm:aff></affiliation></author><author><name sortKey="Little, Latasha" sort="Little, Latasha" uniqKey="Little L" first="Latasha" last="Little">Latasha Little</name><affiliation><nlm:aff id="A1">Center for Human Genome Variation, Duke University School of Medicine, Durham, NC 27708 USA.</nlm:aff></affiliation></author><author><name sortKey="Silver, Kenneth" sort="Silver, Kenneth" uniqKey="Silver K" first="Kenneth" last="Silver">Kenneth Silver</name><affiliation><nlm:aff id="A17">Department of Neurology, Comer Children’s Hospital, University of Chicago, Chicago, IL 60637 USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A18">Departments of Pediatrics, Comer Children’s Hospital, University of Chicago, Chicago, IL 60637 USA.</nlm:aff></affiliation></author><author><name sortKey="Ptac Ek, Louis J" sort="Ptac Ek, Louis J" uniqKey="Ptac Ek L" first="Louis J." last="Ptác Ek">Louis J. Ptác Ek</name><affiliation><nlm:aff id="A19">Department of Neurology, University of California, San Francisco, San Francisco, CA 94158 USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A20">Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158 USA.</nlm:aff></affiliation></author><author><name sortKey="Haan, Joost" sort="Haan, Joost" uniqKey="Haan J" first="Joost" last="Haan">Joost Haan</name><affiliation><nlm:aff id="A21">Department of Neurology, Rijnland Hospital, Leiderdorp, The Netherlands.</nlm:aff></affiliation><affiliation><nlm:aff id="A22">Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands.</nlm:aff></affiliation></author><author><name sortKey="Ferrari, Michel D" sort="Ferrari, Michel D" uniqKey="Ferrari M" first="Michel D." last="Ferrari">Michel D. Ferrari</name><affiliation><nlm:aff id="A22">Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands.</nlm:aff></affiliation></author><author><name sortKey="Bye, Ann M" sort="Bye, Ann M" uniqKey="Bye A" first="Ann M." last="Bye">Ann M. Bye</name><affiliation><nlm:aff id="A23">Department of Paediatric Neurology, Sydney Children’s Hospital, Randwick, New South Wales, Australia.</nlm:aff></affiliation></author><author><name sortKey="Herkes, Geoffrey K" sort="Herkes, Geoffrey K" uniqKey="Herkes G" first="Geoffrey K." last="Herkes">Geoffrey K. Herkes</name><affiliation><nlm:aff id="A24">University of Sydney, RNSH, St Leonards, Sydney, New South Wales, Australia.</nlm:aff></affiliation></author><author><name sortKey="Whitelaw, Charlotte M" sort="Whitelaw, Charlotte M" uniqKey="Whitelaw C" first="Charlotte M." last="Whitelaw">Charlotte M. Whitelaw</name><affiliation><nlm:aff id="A25">Department of Paediatrics, Royal Hobart Hospital, Hobart 7000, Tasmania, Australia.</nlm:aff></affiliation></author><author><name sortKey="Webb, David" sort="Webb, David" uniqKey="Webb D" first="David" last="Webb">David Webb</name><affiliation><nlm:aff id="A26">Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland.</nlm:aff></affiliation></author><author><name sortKey="Lynch, Bryan J" sort="Lynch, Bryan J" uniqKey="Lynch B" first="Bryan J." last="Lynch">Bryan J. Lynch</name><affiliation><nlm:aff id="A27">The Childrens University Hospital Temple St, Dublin 1, Ireland.</nlm:aff></affiliation></author><author><name sortKey="Uldall, Peter" sort="Uldall, Peter" uniqKey="Uldall P" first="Peter" last="Uldall">Peter Uldall</name><affiliation><nlm:aff id="A28">Department of Paediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.</nlm:aff></affiliation></author><author><name sortKey="King, Mary D" sort="King, Mary D" uniqKey="King M" first="Mary D." last="King">Mary D. King</name><affiliation><nlm:aff id="A27">The Childrens University Hospital Temple St, Dublin 1, Ireland.</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="A11">Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia.</nlm:aff></affiliation><affiliation><nlm:aff id="A29">Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Melbourne, Australia.</nlm:aff></affiliation><affiliation><nlm:aff id="A30">Florey Neuroscience Institutes, Melbourne, Australia.</nlm:aff></affiliation></author><author><name sortKey="Neri, Giovanni" sort="Neri, Giovanni" uniqKey="Neri G" first="Giovanni" last="Neri">Giovanni Neri</name><affiliation><nlm:aff id="A5">Instituto di Genetica Medica, Università Cattolica del Sacro Cuore, Policlinico A. Gemelli, Rome, Italy.</nlm:aff></affiliation></author><author><name sortKey="Arzimanoglou, Alexis" sort="Arzimanoglou, Alexis" uniqKey="Arzimanoglou A" first="Alexis" last="Arzimanoglou">Alexis Arzimanoglou</name><affiliation><nlm:aff id="A12">Epilepsy, Sleep and Pediatric Neurophysiology Dpt, Hôpital Femme Mère Enfant, University Hospitals of Lyon (HCL), Lyon, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A31">Centre de Recherche en Neurosciences de Lyon, Centre National de la Recherche Scientifique, UMR 5292; Institut National de la Santé Et de la Recherche Médicale, U1028, Lyon, France.</nlm:aff></affiliation></author><author><name sortKey="Van Den Maagdenberg, Arn M J M" sort="Van Den Maagdenberg, Arn M J M" uniqKey="Van Den Maagdenberg A" first="Arn M. J. M." last="Van Den Maagdenberg">Arn M. J. M. Van Den Maagdenberg</name><affiliation><nlm:aff id="A9">Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.</nlm:aff></affiliation><affiliation><nlm:aff id="A22">Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands.</nlm:aff></affiliation></author><author><name sortKey="Sisodiya, Sanjay M" sort="Sisodiya, Sanjay M" uniqKey="Sisodiya S" first="Sanjay M." last="Sisodiya">Sanjay M. Sisodiya</name><affiliation><nlm:aff id="A32">Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, Queen Square, London, WC1N 3BG UK.</nlm:aff></affiliation><affiliation><nlm:aff id="A33">These authors jointly directed this work.</nlm:aff></affiliation></author><author><name sortKey="Mikati, Mohamad A" sort="Mikati, Mohamad A" uniqKey="Mikati M" first="Mohamad A." last="Mikati">Mohamad A. Mikati</name><affiliation><nlm:aff id="A33">These authors jointly directed this work.</nlm:aff></affiliation><affiliation><nlm:aff id="A33">These authors jointly directed this work.</nlm:aff></affiliation><affiliation><nlm:aff id="A35">Department of Neurobiology, Duke University, Durham, NC 27708 USA.</nlm:aff></affiliation></author><author><name sortKey="Goldstein, David B" sort="Goldstein, David B" uniqKey="Goldstein D" first="David B." last="Goldstein">David B. Goldstein</name><affiliation><nlm:aff id="A1">Center for Human Genome Variation, Duke University School of Medicine, Durham, NC 27708 USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A33">These authors jointly directed this work.</nlm:aff></affiliation><affiliation><nlm:aff id="A36">Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27708 USA.</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22842232</idno><idno type="pmc">3442240</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442240</idno><idno type="RBID">PMC:3442240</idno><idno type="doi">10.1038/ng.2358</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">002E16</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002E16</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main"><italic>De novo</italic> mutations in <italic>ATP1A3</italic> cause alternating hemiplegia of childhood</title><author><name sortKey="Heinzen, Erin L" sort="Heinzen, Erin L" uniqKey="Heinzen E" first="Erin L." last="Heinzen">Erin L. Heinzen</name><affiliation><nlm:aff id="A2">Department of Medicine, Duke University School of Medicine, Durham, NC 27708 USA</nlm:aff></affiliation></author><author><name sortKey="Swoboda, Kathryn J" sort="Swoboda, Kathryn J" uniqKey="Swoboda K" first="Kathryn J." last="Swoboda">Kathryn J. Swoboda</name><affiliation><nlm:aff id="A3">Department of Pediatrics, University of Utah, Salt Lake City, UT 84132 USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Department of Neurology, University of Utah, Salt Lake City, UT 84132 USA.</nlm:aff></affiliation></author><author><name sortKey="Hitomi, Yuki" sort="Hitomi, Yuki" uniqKey="Hitomi Y" first="Yuki" last="Hitomi">Yuki Hitomi</name><affiliation><nlm:aff id="A1">Center for Human Genome Variation, Duke University School of Medicine, Durham, NC 27708 USA.</nlm:aff></affiliation></author><author><name sortKey="Gurrieri, Fiorella" sort="Gurrieri, Fiorella" uniqKey="Gurrieri F" first="Fiorella" last="Gurrieri">Fiorella Gurrieri</name><affiliation><nlm:aff id="A5">Instituto di Genetica Medica, Università Cattolica del Sacro Cuore, Policlinico A. Gemelli, Rome, Italy.</nlm:aff></affiliation></author><author><name sortKey="Nicole, Sophie" sort="Nicole, Sophie" uniqKey="Nicole S" first="Sophie" last="Nicole">Sophie Nicole</name><affiliation><nlm:aff id="A6">Université Pierre et Marie Curie Paris 06, Centre de Recherche de l’Institut du Cerveau et de la Moelle Epiniere, UMR_S975, Paris, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A8">Centre National de la Recherche Scientifique, UMR 7225, Paris, France.</nlm:aff></affiliation></author><author><name sortKey="De Vries, Boukje" sort="De Vries, Boukje" uniqKey="De Vries B" first="Boukje" last="De Vries">Boukje De Vries</name><affiliation><nlm:aff id="A9">Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.</nlm:aff></affiliation></author><author><name sortKey="Tiziano, F Danilo" sort="Tiziano, F Danilo" uniqKey="Tiziano F" first="F. Danilo" last="Tiziano">F. Danilo Tiziano</name><affiliation><nlm:aff id="A5">Instituto di Genetica Medica, Università Cattolica del Sacro Cuore, Policlinico A. Gemelli, Rome, Italy.</nlm:aff></affiliation></author><author><name sortKey="Fontaine, Bertrand" sort="Fontaine, Bertrand" uniqKey="Fontaine B" first="Bertrand" last="Fontaine">Bertrand Fontaine</name><affiliation><nlm:aff id="A6">Université Pierre et Marie Curie Paris 06, Centre de Recherche de l’Institut du Cerveau et de la Moelle Epiniere, UMR_S975, Paris, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A8">Centre National de la Recherche Scientifique, UMR 7225, Paris, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A10">Assistance Publique-Hôpitaux de Paris, Département de Neurologie & centre de référence “canalopathies musculaires”, Groupe Hospitalier de la Pitié-Salpêtrière, Paris, France.</nlm:aff></affiliation></author><author><name sortKey="Walley, Nicole M" sort="Walley, Nicole M" uniqKey="Walley N" first="Nicole M." last="Walley">Nicole M. Walley</name><affiliation><nlm:aff id="A1">Center for Human Genome Variation, Duke University School of Medicine, Durham, NC 27708 USA.</nlm:aff></affiliation></author><author><name sortKey="Heavin, Sinead" sort="Heavin, Sinead" uniqKey="Heavin S" first="Sinéad" last="Heavin">Sinéad Heavin</name><affiliation><nlm:aff id="A11">Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia.</nlm:aff></affiliation></author><author><name sortKey="Panagiotakaki, Eleni" sort="Panagiotakaki, Eleni" uniqKey="Panagiotakaki E" first="Eleni" last="Panagiotakaki">Eleni Panagiotakaki</name><affiliation><nlm:aff id="A12">Epilepsy, Sleep and Pediatric Neurophysiology Dpt, Hôpital Femme Mère Enfant, University Hospitals of Lyon (HCL), Lyon, France.</nlm:aff></affiliation></author><author><name sortKey="Fiori, Stefania" sort="Fiori, Stefania" uniqKey="Fiori S" first="Stefania" last="Fiori">Stefania Fiori</name><affiliation><nlm:aff id="A5">Instituto di Genetica Medica, Università Cattolica del Sacro Cuore, Policlinico A. Gemelli, Rome, Italy.</nlm:aff></affiliation></author><author><name sortKey="Abiusi, Emanuela" sort="Abiusi, Emanuela" uniqKey="Abiusi E" first="Emanuela" last="Abiusi">Emanuela Abiusi</name><affiliation><nlm:aff id="A5">Instituto di Genetica Medica, Università Cattolica del Sacro Cuore, Policlinico A. Gemelli, Rome, Italy.</nlm:aff></affiliation></author><author><name sortKey="Di Pietro, Lorena" sort="Di Pietro, Lorena" uniqKey="Di Pietro L" first="Lorena" last="Di Pietro">Lorena Di Pietro</name><affiliation><nlm:aff id="A5">Instituto di Genetica Medica, Università Cattolica del Sacro Cuore, Policlinico A. Gemelli, Rome, Italy.</nlm:aff></affiliation></author><author><name sortKey="Sweney, Matthew T" sort="Sweney, Matthew T" uniqKey="Sweney M" first="Matthew T." last="Sweney">Matthew T. Sweney</name><affiliation><nlm:aff id="A3">Department of Pediatrics, University of Utah, Salt Lake City, UT 84132 USA.</nlm:aff></affiliation></author><author><name sortKey="Newcomb, Tara M" sort="Newcomb, Tara M" uniqKey="Newcomb T" first="Tara M." last="Newcomb">Tara M. Newcomb</name><affiliation><nlm:aff id="A3">Department of Pediatrics, University of Utah, Salt Lake City, UT 84132 USA.</nlm:aff></affiliation></author><author><name sortKey="Viollet, Louis" sort="Viollet, Louis" uniqKey="Viollet L" first="Louis" last="Viollet">Louis Viollet</name><affiliation><nlm:aff id="A4">Department of Neurology, University of Utah, Salt Lake City, UT 84132 USA.</nlm:aff></affiliation></author><author><name sortKey="Huff, Chad" sort="Huff, Chad" uniqKey="Huff C" first="Chad" last="Huff">Chad Huff</name><affiliation><nlm:aff id="A16">Department of Human Genetics, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84132 USA.</nlm:aff></affiliation></author><author><name sortKey="Jorde, Lynn B" sort="Jorde, Lynn B" uniqKey="Jorde L" first="Lynn B." last="Jorde">Lynn B. Jorde</name><affiliation><nlm:aff id="A16">Department of Human Genetics, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84132 USA.</nlm:aff></affiliation></author><author><name sortKey="Reyna, Sandra P" sort="Reyna, Sandra P" uniqKey="Reyna S" first="Sandra P." last="Reyna">Sandra P. Reyna</name><affiliation><nlm:aff id="A4">Department of Neurology, University of Utah, Salt Lake City, UT 84132 USA.</nlm:aff></affiliation></author><author><name sortKey="Murphy, Kelley J" sort="Murphy, Kelley J" uniqKey="Murphy K" first="Kelley J." last="Murphy">Kelley J. Murphy</name><affiliation><nlm:aff id="A4">Department of Neurology, University of Utah, Salt Lake City, UT 84132 USA.</nlm:aff></affiliation></author><author><name sortKey="Shianna, Kevin V" sort="Shianna, Kevin V" uniqKey="Shianna K" first="Kevin V." last="Shianna">Kevin V. Shianna</name><affiliation><nlm:aff id="A1">Center for Human Genome Variation, Duke University School of Medicine, Durham, NC 27708 USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Department of Medicine, Duke University School of Medicine, Durham, NC 27708 USA</nlm:aff></affiliation></author><author><name sortKey="Gumbs, Curtis E" sort="Gumbs, Curtis E" uniqKey="Gumbs C" first="Curtis E." last="Gumbs">Curtis E. Gumbs</name><affiliation><nlm:aff id="A1">Center for Human Genome Variation, Duke University School of Medicine, Durham, NC 27708 USA.</nlm:aff></affiliation></author><author><name sortKey="Little, Latasha" sort="Little, Latasha" uniqKey="Little L" first="Latasha" last="Little">Latasha Little</name><affiliation><nlm:aff id="A1">Center for Human Genome Variation, Duke University School of Medicine, Durham, NC 27708 USA.</nlm:aff></affiliation></author><author><name sortKey="Silver, Kenneth" sort="Silver, Kenneth" uniqKey="Silver K" first="Kenneth" last="Silver">Kenneth Silver</name><affiliation><nlm:aff id="A17">Department of Neurology, Comer Children’s Hospital, University of Chicago, Chicago, IL 60637 USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A18">Departments of Pediatrics, Comer Children’s Hospital, University of Chicago, Chicago, IL 60637 USA.</nlm:aff></affiliation></author><author><name sortKey="Ptac Ek, Louis J" sort="Ptac Ek, Louis J" uniqKey="Ptac Ek L" first="Louis J." last="Ptác Ek">Louis J. Ptác Ek</name><affiliation><nlm:aff id="A19">Department of Neurology, University of California, San Francisco, San Francisco, CA 94158 USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A20">Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158 USA.</nlm:aff></affiliation></author><author><name sortKey="Haan, Joost" sort="Haan, Joost" uniqKey="Haan J" first="Joost" last="Haan">Joost Haan</name><affiliation><nlm:aff id="A21">Department of Neurology, Rijnland Hospital, Leiderdorp, The Netherlands.</nlm:aff></affiliation><affiliation><nlm:aff id="A22">Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands.</nlm:aff></affiliation></author><author><name sortKey="Ferrari, Michel D" sort="Ferrari, Michel D" uniqKey="Ferrari M" first="Michel D." last="Ferrari">Michel D. Ferrari</name><affiliation><nlm:aff id="A22">Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands.</nlm:aff></affiliation></author><author><name sortKey="Bye, Ann M" sort="Bye, Ann M" uniqKey="Bye A" first="Ann M." last="Bye">Ann M. Bye</name><affiliation><nlm:aff id="A23">Department of Paediatric Neurology, Sydney Children’s Hospital, Randwick, New South Wales, Australia.</nlm:aff></affiliation></author><author><name sortKey="Herkes, Geoffrey K" sort="Herkes, Geoffrey K" uniqKey="Herkes G" first="Geoffrey K." last="Herkes">Geoffrey K. Herkes</name><affiliation><nlm:aff id="A24">University of Sydney, RNSH, St Leonards, Sydney, New South Wales, Australia.</nlm:aff></affiliation></author><author><name sortKey="Whitelaw, Charlotte M" sort="Whitelaw, Charlotte M" uniqKey="Whitelaw C" first="Charlotte M." last="Whitelaw">Charlotte M. Whitelaw</name><affiliation><nlm:aff id="A25">Department of Paediatrics, Royal Hobart Hospital, Hobart 7000, Tasmania, Australia.</nlm:aff></affiliation></author><author><name sortKey="Webb, David" sort="Webb, David" uniqKey="Webb D" first="David" last="Webb">David Webb</name><affiliation><nlm:aff id="A26">Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland.</nlm:aff></affiliation></author><author><name sortKey="Lynch, Bryan J" sort="Lynch, Bryan J" uniqKey="Lynch B" first="Bryan J." last="Lynch">Bryan J. Lynch</name><affiliation><nlm:aff id="A27">The Childrens University Hospital Temple St, Dublin 1, Ireland.</nlm:aff></affiliation></author><author><name sortKey="Uldall, Peter" sort="Uldall, Peter" uniqKey="Uldall P" first="Peter" last="Uldall">Peter Uldall</name><affiliation><nlm:aff id="A28">Department of Paediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.</nlm:aff></affiliation></author><author><name sortKey="King, Mary D" sort="King, Mary D" uniqKey="King M" first="Mary D." last="King">Mary D. King</name><affiliation><nlm:aff id="A27">The Childrens University Hospital Temple St, Dublin 1, Ireland.</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="A11">Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia.</nlm:aff></affiliation><affiliation><nlm:aff id="A29">Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Melbourne, Australia.</nlm:aff></affiliation><affiliation><nlm:aff id="A30">Florey Neuroscience Institutes, Melbourne, Australia.</nlm:aff></affiliation></author><author><name sortKey="Neri, Giovanni" sort="Neri, Giovanni" uniqKey="Neri G" first="Giovanni" last="Neri">Giovanni Neri</name><affiliation><nlm:aff id="A5">Instituto di Genetica Medica, Università Cattolica del Sacro Cuore, Policlinico A. Gemelli, Rome, Italy.</nlm:aff></affiliation></author><author><name sortKey="Arzimanoglou, Alexis" sort="Arzimanoglou, Alexis" uniqKey="Arzimanoglou A" first="Alexis" last="Arzimanoglou">Alexis Arzimanoglou</name><affiliation><nlm:aff id="A12">Epilepsy, Sleep and Pediatric Neurophysiology Dpt, Hôpital Femme Mère Enfant, University Hospitals of Lyon (HCL), Lyon, France.</nlm:aff></affiliation><affiliation><nlm:aff id="A31">Centre de Recherche en Neurosciences de Lyon, Centre National de la Recherche Scientifique, UMR 5292; Institut National de la Santé Et de la Recherche Médicale, U1028, Lyon, France.</nlm:aff></affiliation></author><author><name sortKey="Van Den Maagdenberg, Arn M J M" sort="Van Den Maagdenberg, Arn M J M" uniqKey="Van Den Maagdenberg A" first="Arn M. J. M." last="Van Den Maagdenberg">Arn M. J. M. Van Den Maagdenberg</name><affiliation><nlm:aff id="A9">Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.</nlm:aff></affiliation><affiliation><nlm:aff id="A22">Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands.</nlm:aff></affiliation></author><author><name sortKey="Sisodiya, Sanjay M" sort="Sisodiya, Sanjay M" uniqKey="Sisodiya S" first="Sanjay M." last="Sisodiya">Sanjay M. Sisodiya</name><affiliation><nlm:aff id="A32">Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, Queen Square, London, WC1N 3BG UK.</nlm:aff></affiliation><affiliation><nlm:aff id="A33">These authors jointly directed this work.</nlm:aff></affiliation></author><author><name sortKey="Mikati, Mohamad A" sort="Mikati, Mohamad A" uniqKey="Mikati M" first="Mohamad A." last="Mikati">Mohamad A. Mikati</name><affiliation><nlm:aff id="A33">These authors jointly directed this work.</nlm:aff></affiliation><affiliation><nlm:aff id="A33">These authors jointly directed this work.</nlm:aff></affiliation><affiliation><nlm:aff id="A35">Department of Neurobiology, Duke University, Durham, NC 27708 USA.</nlm:aff></affiliation></author><author><name sortKey="Goldstein, David B" sort="Goldstein, David B" uniqKey="Goldstein D" first="David B." last="Goldstein">David B. Goldstein</name><affiliation><nlm:aff id="A1">Center for Human Genome Variation, Duke University School of Medicine, Durham, NC 27708 USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A33">These authors jointly directed this work.</nlm:aff></affiliation><affiliation><nlm:aff id="A36">Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27708 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="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P2">Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurologic manifestations. AHC is usually a sporadic disorder with unknown etiology. Using exome sequencing of seven patients with AHC, and their unaffected parents, we identified <italic>de novo</italic> nonsynonymous mutations in <italic>ATP1A3</italic> in all seven AHC patients. Subsequent sequence analysis of <italic>ATP1A3</italic> in 98 additional patients revealed that 78% of AHC cases have a likely causal <italic>ATP1A3</italic> mutation, including one inherited mutation in a familial case of AHC. Remarkably, six <italic>ATP1A3</italic> mutations explain the majority of patients, including one observed in 36 patients. Unlike <italic>ATP1A3</italic> mutations that cause rapid-onset-dystonia-parkinsonism, AHC-causing mutations revealed consistent reductions in ATPase activity without effects on protein expression. This work identifies <italic>de novo ATP1A3</italic> mutations as the primary cause of AHC, and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in this gene.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Verret, S" uniqKey="Verret S">S Verret</name></author><author><name sortKey="Steele, Jc" uniqKey="Steele J">JC Steele</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bourgeois, M" uniqKey="Bourgeois M">M Bourgeois</name></author><author><name sortKey="Aicardi, J" uniqKey="Aicardi J">J Aicardi</name></author><author><name sortKey="Goutieres, F" uniqKey="Goutieres F">F Goutieres</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mikati, Ma" uniqKey="Mikati M">MA Mikati</name></author><author><name sortKey="Kramer, U" uniqKey="Kramer U">U Kramer</name></author><author><name sortKey="Zupanc, Ml" 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<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">22842232</article-id><article-id pub-id-type="pmc">3442240</article-id><article-id pub-id-type="doi">10.1038/ng.2358</article-id><article-id pub-id-type="manuscript">UKMS49079</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title><italic>De novo</italic> mutations in <italic>ATP1A3</italic> cause alternating hemiplegia of childhood</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Heinzen</surname><given-names>Erin L.</given-names></name><xref ref-type="author-notes" rid="FN1">1</xref><xref ref-type="aff" rid="A2">3</xref></contrib><contrib contrib-type="author"><name><surname>Swoboda</surname><given-names>Kathryn J.</given-names></name><xref ref-type="author-notes" rid="FN1">1</xref><xref ref-type="aff" rid="A3">4</xref><xref ref-type="aff" rid="A4">5</xref></contrib><contrib contrib-type="author"><name><surname>Hitomi</surname><given-names>Yuki</given-names></name><xref ref-type="author-notes" rid="FN1">1</xref><xref ref-type="aff" rid="A1">2</xref></contrib><contrib contrib-type="author"><name><surname>Gurrieri</surname><given-names>Fiorella</given-names></name><xref ref-type="aff" rid="A5">6</xref></contrib><contrib contrib-type="author"><name><surname>Nicole</surname><given-names>Sophie</given-names></name><xref ref-type="aff" rid="A6">7</xref><xref ref-type="aff" rid="A8">9</xref></contrib><contrib contrib-type="author"><name><surname>de Vries</surname><given-names>Boukje</given-names></name><xref ref-type="aff" rid="A9">10</xref></contrib><contrib contrib-type="author"><name><surname>Tiziano</surname><given-names>F. Danilo</given-names></name><xref ref-type="aff" rid="A5">6</xref></contrib><contrib contrib-type="author"><name><surname>Fontaine</surname><given-names>Bertrand</given-names></name><xref ref-type="aff" rid="A6">7</xref><xref ref-type="aff" rid="A8">9</xref><xref ref-type="aff" rid="A10">11</xref></contrib><contrib contrib-type="author"><name><surname>Walley</surname><given-names>Nicole M.</given-names></name><xref ref-type="aff" rid="A1">2</xref></contrib><contrib contrib-type="author"><name><surname>Heavin</surname><given-names>Sinéad</given-names></name><xref ref-type="aff" rid="A11">12</xref></contrib><contrib contrib-type="author"><name><surname>Panagiotakaki</surname><given-names>Eleni</given-names></name><xref ref-type="aff" rid="A12">13</xref></contrib><contrib contrib-type="author"><collab>European AHC Genetics Consortium</collab><xref ref-type="aff" rid="A13">14</xref></contrib><contrib contrib-type="author"><collab>I.B.AHC Consortium</collab><xref ref-type="aff" rid="A14">15</xref></contrib><contrib contrib-type="author"><collab>ENRAH for SME Consortium</collab><xref ref-type="aff" rid="A15">16</xref></contrib><contrib contrib-type="author"><name><surname>Fiori</surname><given-names>Stefania</given-names></name><xref ref-type="aff" rid="A5">6</xref></contrib><contrib contrib-type="author"><name><surname>Abiusi</surname><given-names>Emanuela</given-names></name><xref ref-type="aff" rid="A5">6</xref></contrib><contrib contrib-type="author"><name><surname>Di Pietro</surname><given-names>Lorena</given-names></name><xref ref-type="aff" rid="A5">6</xref></contrib><contrib contrib-type="author"><name><surname>Sweney</surname><given-names>Matthew T.</given-names></name><xref ref-type="aff" rid="A3">4</xref></contrib><contrib contrib-type="author"><name><surname>Newcomb</surname><given-names>Tara M.</given-names></name><xref ref-type="aff" rid="A3">4</xref></contrib><contrib contrib-type="author"><name><surname>Viollet</surname><given-names>Louis</given-names></name><xref ref-type="aff" rid="A4">5</xref></contrib><contrib contrib-type="author"><name><surname>Huff</surname><given-names>Chad</given-names></name><xref ref-type="aff" rid="A16">17</xref></contrib><contrib contrib-type="author"><name><surname>Jorde</surname><given-names>Lynn B.</given-names></name><xref ref-type="aff" rid="A16">17</xref></contrib><contrib contrib-type="author"><name><surname>Reyna</surname><given-names>Sandra P.</given-names></name><xref ref-type="aff" rid="A4">5</xref></contrib><contrib contrib-type="author"><name><surname>Murphy</surname><given-names>Kelley J.</given-names></name><xref ref-type="aff" rid="A4">5</xref></contrib><contrib contrib-type="author"><name><surname>Shianna</surname><given-names>Kevin V.</given-names></name><xref ref-type="aff" rid="A1">2</xref><xref ref-type="aff" rid="A2">3</xref></contrib><contrib contrib-type="author"><name><surname>Gumbs</surname><given-names>Curtis E.</given-names></name><xref ref-type="aff" rid="A1">2</xref></contrib><contrib contrib-type="author"><name><surname>Little</surname><given-names>Latasha</given-names></name><xref ref-type="aff" rid="A1">2</xref></contrib><contrib contrib-type="author"><name><surname>Silver</surname><given-names>Kenneth</given-names></name><xref ref-type="aff" rid="A17">18</xref><xref ref-type="aff" rid="A18">19</xref></contrib><contrib contrib-type="author"><name><surname>Ptác̆ek</surname><given-names>Louis J.</given-names></name><xref ref-type="aff" rid="A19">20</xref><xref ref-type="aff" rid="A20">21</xref></contrib><contrib contrib-type="author"><name><surname>Haan</surname><given-names>Joost</given-names></name><xref ref-type="aff" rid="A21">22</xref><xref ref-type="aff" rid="A22">23</xref></contrib><contrib contrib-type="author"><name><surname>Ferrari</surname><given-names>Michel D.</given-names></name><xref ref-type="aff" rid="A22">23</xref></contrib><contrib contrib-type="author"><name><surname>Bye</surname><given-names>Ann M.</given-names></name><xref ref-type="aff" rid="A23">24</xref></contrib><contrib contrib-type="author"><name><surname>Herkes</surname><given-names>Geoffrey K.</given-names></name><xref ref-type="aff" rid="A24">25</xref></contrib><contrib contrib-type="author"><name><surname>Whitelaw</surname><given-names>Charlotte M.</given-names></name><xref ref-type="aff" rid="A25">26</xref></contrib><contrib contrib-type="author"><name><surname>Webb</surname><given-names>David</given-names></name><xref ref-type="aff" rid="A26">27</xref></contrib><contrib contrib-type="author"><name><surname>Lynch</surname><given-names>Bryan J.</given-names></name><xref ref-type="aff" rid="A27">28</xref></contrib><contrib contrib-type="author"><name><surname>Uldall</surname><given-names>Peter</given-names></name><xref ref-type="aff" rid="A28">29</xref></contrib><contrib contrib-type="author"><name><surname>King</surname><given-names>Mary D.</given-names></name><xref ref-type="aff" rid="A27">28</xref></contrib><contrib contrib-type="author"><name><surname>Scheffer</surname><given-names>Ingrid E.</given-names></name><xref ref-type="aff" rid="A11">12</xref><xref ref-type="aff" rid="A29">30</xref><xref ref-type="aff" rid="A30">31</xref></contrib><contrib contrib-type="author"><name><surname>Neri</surname><given-names>Giovanni</given-names></name><xref ref-type="aff" rid="A5">6</xref></contrib><contrib contrib-type="author"><name><surname>Arzimanoglou</surname><given-names>Alexis</given-names></name><xref ref-type="aff" rid="A12">13</xref><xref ref-type="aff" rid="A31">32</xref></contrib><contrib contrib-type="author"><name><surname>van den Maagdenberg</surname><given-names>Arn M.J.M.</given-names></name><xref ref-type="aff" rid="A9">10</xref><xref ref-type="aff" rid="A22">23</xref></contrib><contrib contrib-type="author"><name><surname>Sisodiya</surname><given-names>Sanjay M.</given-names></name><xref ref-type="aff" rid="A32">33</xref><xref ref-type="aff" rid="A33">34</xref></contrib><contrib contrib-type="author"><name><surname>Mikati</surname><given-names>Mohamad A.</given-names></name><xref ref-type="aff" rid="A33">34</xref><xref ref-type="aff" rid="A33">34</xref><xref ref-type="aff" rid="A35">36</xref></contrib><contrib contrib-type="author"><name><surname>Goldstein</surname><given-names>David B.</given-names></name><xref ref-type="aff" rid="A1">2</xref><xref ref-type="aff" rid="A33">34</xref><xref ref-type="aff" rid="A36">37</xref></contrib></contrib-group><contrib-group><contrib contrib-type="author"><collab><bold>European AHC Genetics Consortium</bold></collab></contrib><contrib contrib-type="author"><name><surname>Nicole</surname><given-names>Sophie</given-names></name><xref ref-type="aff" rid="A6">7</xref><xref ref-type="aff" rid="A8">9</xref></contrib><contrib contrib-type="author"><name><surname>Gurrieri</surname><given-names>Fiorella</given-names></name><xref ref-type="aff" rid="A5">6</xref></contrib><contrib contrib-type="author"><name><surname>Neri</surname><given-names>Giovanni</given-names></name><xref ref-type="aff" rid="A5">6</xref></contrib><contrib contrib-type="author"><name><surname>de Vries</surname><given-names>Boukje</given-names></name><xref ref-type="aff" rid="A9">10</xref></contrib><contrib contrib-type="author"><name><surname>Koelewijn</surname><given-names>Stephany</given-names></name><xref ref-type="aff" rid="A9">10</xref></contrib><contrib contrib-type="author"><name><surname>Kamphorst</surname><given-names>Jessica</given-names></name><xref ref-type="aff" rid="A9">10</xref></contrib><contrib contrib-type="author"><name><surname>Geilenkirchen</surname><given-names>Marije</given-names></name><xref ref-type="aff" rid="A9">10</xref></contrib><contrib contrib-type="author"><name><surname>Pelzer</surname><given-names>Nadine</given-names></name><xref ref-type="aff" rid="A9">10</xref></contrib><contrib contrib-type="author"><name><surname>Laan</surname><given-names>Laura</given-names></name><xref ref-type="aff" rid="A9">10</xref></contrib><contrib contrib-type="author"><name><surname>Haan</surname><given-names>Joost</given-names></name><xref ref-type="aff" rid="A21">22</xref><xref ref-type="aff" rid="A22">23</xref></contrib><contrib contrib-type="author"><name><surname>Ferrari</surname><given-names>Michel</given-names></name><xref ref-type="aff" rid="A22">23</xref></contrib><contrib contrib-type="author"><name><surname>van den Maagdenberg</surname><given-names>Arn</given-names></name><xref ref-type="aff" rid="A9">10</xref><xref ref-type="aff" rid="A22">23</xref></contrib></contrib-group><contrib-group><contrib contrib-type="author"><collab><bold>I.B.AHC Consortium</bold></collab></contrib><contrib contrib-type="author"><name><surname>Zucca</surname><given-names>Claudio</given-names></name><xref ref-type="aff" rid="A37">38</xref></contrib><contrib contrib-type="author"><name><surname>Bassi</surname><given-names>Maria Teresa</given-names></name><xref ref-type="aff" rid="A38">39</xref></contrib><contrib contrib-type="author"><name><surname>Franchini</surname><given-names>Filippo</given-names></name><xref ref-type="aff" rid="A39">40</xref></contrib><contrib contrib-type="author"><name><surname>Vavassori</surname><given-names>Rosaria</given-names></name><xref ref-type="aff" rid="A39">40</xref></contrib><contrib contrib-type="author"><name><surname>Giannotta</surname><given-names>Melania</given-names></name><xref ref-type="aff" rid="A40">41</xref></contrib><contrib contrib-type="author"><name><surname>Gobbi</surname><given-names>Giuseppe</given-names></name><xref ref-type="aff" rid="A40">41</xref></contrib><contrib contrib-type="author"><name><surname>Granata</surname><given-names>Tiziana</given-names></name><xref ref-type="aff" rid="A41">42</xref></contrib><contrib contrib-type="author"><name><surname>Nardocci</surname><given-names>Nardo</given-names></name><xref ref-type="aff" rid="A41">42</xref></contrib><contrib contrib-type="author"><name><surname>De Grandis</surname><given-names>Elisa</given-names></name><xref ref-type="aff" rid="A42">43</xref></contrib><contrib contrib-type="author"><name><surname>Veneselli</surname><given-names>Edvige</given-names></name><xref ref-type="aff" rid="A42">43</xref></contrib><contrib contrib-type="author"><name><surname>Stagnaro</surname><given-names>Michela</given-names></name><xref ref-type="aff" rid="A42">43</xref></contrib><contrib contrib-type="author"><name><surname>Gurrieri</surname><given-names>Fiorella</given-names></name><xref ref-type="aff" rid="A5">6</xref></contrib><contrib contrib-type="author"><name><surname>Neri</surname><given-names>Giovanni</given-names></name><xref ref-type="aff" rid="A5">6</xref></contrib><contrib contrib-type="author"><name><surname>Vigevano</surname><given-names>Federico</given-names></name><xref ref-type="aff" rid="A43">44</xref></contrib></contrib-group><contrib-group><contrib contrib-type="author"><collab><bold>ENRAH for SME</bold></collab></contrib><contrib contrib-type="author"><name><surname>Panagiotakaki</surname><given-names>Eleni</given-names></name><xref ref-type="aff" rid="A12">13</xref></contrib><contrib contrib-type="author"><name><surname>Oechsler</surname><given-names>Claudia</given-names></name><xref ref-type="aff" rid="A12">13</xref></contrib><contrib contrib-type="author"><name><surname>Arzimanoglou</surname><given-names>Alexis</given-names></name><xref ref-type="aff" rid="A12">13</xref><xref ref-type="aff" rid="A31">32</xref></contrib><contrib contrib-type="author"><name><surname>Nicole</surname><given-names>Sophie</given-names></name><xref ref-type="aff" rid="A6">7</xref><xref ref-type="aff" rid="A8">9</xref></contrib><contrib contrib-type="author"><name><surname>Giannotta</surname><given-names>Melania</given-names></name><xref ref-type="aff" rid="A40">41</xref></contrib><contrib contrib-type="author"><name><surname>Gobbi</surname><given-names>Giuseppe</given-names></name><xref ref-type="aff" rid="A40">41</xref></contrib><contrib contrib-type="author"><name><surname>Ninan</surname><given-names>Miriam</given-names></name><xref ref-type="aff" rid="A44">45</xref></contrib><contrib contrib-type="author"><name><surname>Neville</surname><given-names>Brian</given-names></name><xref ref-type="aff" rid="A44">45</xref></contrib><contrib contrib-type="author"><name><surname>Ebinger</surname><given-names>Friedrich</given-names></name><xref ref-type="aff" rid="A45">46</xref></contrib><contrib contrib-type="author"><name><surname>Fons</surname><given-names>Carmen</given-names></name><xref ref-type="aff" rid="A46">47</xref></contrib><contrib contrib-type="author"><name><surname>Campistol</surname><given-names>Jaume</given-names></name><xref ref-type="aff" rid="A46">47</xref></contrib><contrib contrib-type="author"><name><surname>Kemlink</surname><given-names>David</given-names></name><xref ref-type="aff" rid="A47">48</xref></contrib><contrib contrib-type="author"><name><surname>Nevsimalova</surname><given-names>Sona</given-names></name><xref ref-type="aff" rid="A47">48</xref></contrib><contrib contrib-type="author"><name><surname>Laan</surname><given-names>Laura</given-names></name><xref ref-type="aff" rid="A22">23</xref></contrib><contrib contrib-type="author"><name><surname>Peeters-Scholte</surname><given-names>Cacha</given-names></name><xref ref-type="aff" rid="A22">23</xref></contrib><contrib contrib-type="author"><name><surname>van den Maagdenberg</surname><given-names>Arn</given-names></name><xref ref-type="aff" rid="A9">10</xref><xref ref-type="aff" rid="A22">23</xref></contrib><contrib contrib-type="author"><name><surname>Casaer</surname><given-names>Paul</given-names></name><xref ref-type="aff" rid="A48">49</xref></contrib><contrib contrib-type="author"><name><surname>Casari</surname><given-names>Giorgio</given-names></name><xref ref-type="aff" rid="A49">50</xref></contrib><contrib contrib-type="author"><name><surname>Sange</surname><given-names>Guenter</given-names></name><xref ref-type="aff" rid="A50">51</xref></contrib><contrib contrib-type="author"><name><surname>Spiel</surname><given-names>Georg</given-names></name><xref ref-type="aff" rid="A50">51</xref></contrib><contrib contrib-type="author"><name><surname>Boneschi</surname><given-names>Filippo Martinelli</given-names></name><xref ref-type="aff" rid="A51">52</xref></contrib><contrib contrib-type="author"><name><surname>Zucca</surname><given-names>Claudio</given-names></name><xref ref-type="aff" rid="A37">38</xref></contrib><contrib contrib-type="author"><name><surname>Bassi</surname><given-names>Maria Teresa</given-names></name><xref ref-type="aff" rid="A38">39</xref></contrib><contrib contrib-type="author"><name><surname>Schyns</surname><given-names>Tsveta</given-names></name><xref ref-type="aff" rid="A52">53</xref></contrib><contrib contrib-type="author"><name><surname>Crawley</surname><given-names>Francis</given-names></name><xref ref-type="aff" rid="A53">54</xref></contrib><contrib contrib-type="author"><name><surname>Poncelin</surname><given-names>Dominique</given-names></name><xref ref-type="aff" rid="A54">55</xref></contrib><contrib contrib-type="author"><name><surname>Vavassori</surname><given-names>Rosaria</given-names></name><xref ref-type="aff" rid="A39">40</xref></contrib></contrib-group><aff id="A1"><label>2</label>Center for Human Genome Variation, Duke University School of Medicine, Durham, NC 27708 USA.</aff><aff id="A2"><label>3</label>Department of Medicine, Duke University School of Medicine, Durham, NC 27708 USA</aff><aff id="A3"><label>4</label>Department of Pediatrics, University of Utah, Salt Lake City, UT 84132 USA.</aff><aff id="A4"><label>5</label>Department of Neurology, University of Utah, Salt Lake City, UT 84132 USA.</aff><aff id="A5"><label>6</label>Instituto di Genetica Medica, Università Cattolica del Sacro Cuore, Policlinico A. Gemelli, Rome, Italy.</aff><aff id="A6"><label>7</label>Université Pierre et Marie Curie Paris 06, Centre de Recherche de l’Institut du Cerveau et de la Moelle Epiniere, UMR_S975, Paris, France.</aff><aff id="A7"><label>8</label>Institut National de la Santé Et de la Recherche Médicale, U975, Paris, France.</aff><aff id="A8"><label>9</label>Centre National de la Recherche Scientifique, UMR 7225, Paris, France.</aff><aff id="A9"><label>10</label>Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.</aff><aff id="A10"><label>11</label>Assistance Publique-Hôpitaux de Paris, Département de Neurologie & centre de référence “canalopathies musculaires”, Groupe Hospitalier de la Pitié-Salpêtrière, Paris, France.</aff><aff id="A11"><label>12</label>Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia.</aff><aff id="A12"><label>13</label>Epilepsy, Sleep and Pediatric Neurophysiology Dpt, Hôpital Femme Mère Enfant, University Hospitals of Lyon (HCL), Lyon, France.</aff><aff id="A13"><label>14</label>European Alternating Hemiplegia of Childhood Genetics Consortium.</aff><aff id="A14"><label>15</label>Biobanca e Registro Clinico per l’Emiplegia Alternante (I.B.AHC) Consortium.</aff><aff id="A15"><label>16</label>The European Network for Research on Alternating Hemiplegia (ENRAH) for Small-and-Medium sized Enterprises (SME) Consortium.</aff><aff id="A16"><label>17</label>Department of Human Genetics, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84132 USA.</aff><aff id="A17"><label>18</label>Department of Neurology, Comer Children’s Hospital, University of Chicago, Chicago, IL 60637 USA.</aff><aff id="A18"><label>19</label>Departments of Pediatrics, Comer Children’s Hospital, University of Chicago, Chicago, IL 60637 USA.</aff><aff id="A19"><label>20</label>Department of Neurology, University of California, San Francisco, San Francisco, CA 94158 USA.</aff><aff id="A20"><label>21</label>Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158 USA.</aff><aff id="A21"><label>22</label>Department of Neurology, Rijnland Hospital, Leiderdorp, The Netherlands.</aff><aff id="A22"><label>23</label>Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands.</aff><aff id="A23"><label>24</label>Department of Paediatric Neurology, Sydney Children’s Hospital, Randwick, New South Wales, Australia.</aff><aff id="A24"><label>25</label>University of Sydney, RNSH, St Leonards, Sydney, New South Wales, Australia.</aff><aff id="A25"><label>26</label>Department of Paediatrics, Royal Hobart Hospital, Hobart 7000, Tasmania, Australia.</aff><aff id="A26"><label>27</label>Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland.</aff><aff id="A27"><label>28</label>The Childrens University Hospital Temple St, Dublin 1, Ireland.</aff><aff id="A28"><label>29</label>Department of Paediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.</aff><aff id="A29"><label>30</label>Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Melbourne, Australia.</aff><aff id="A30"><label>31</label>Florey Neuroscience Institutes, Melbourne, Australia.</aff><aff id="A31"><label>32</label>Centre de Recherche en Neurosciences de Lyon, Centre National de la Recherche Scientifique, UMR 5292; Institut National de la Santé Et de la Recherche Médicale, U1028, Lyon, France.</aff><aff id="A32"><label>33</label>Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, Queen Square, London, WC1N 3BG UK.</aff><aff id="A33"><label>34</label>These authors jointly directed this work.</aff><aff id="A34"><label>35</label>Division of Pediatric Neurology, Duke University Medical Center, Durham, NC 27710 USA.</aff><aff id="A35"><label>36</label>Department of Neurobiology, Duke University, Durham, NC 27708 USA.</aff><aff id="A36"><label>37</label>Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27708 USA.</aff><aff id="A37"><label>38</label>Clinical Neurophysiology Unit, Scientific Institute E. Medea, Lecco, Italy</aff><aff id="A38"><label>39</label>Laboratory of Molecular Biology, Scientific Institute E. Medea, Lecco, Italy</aff><aff id="A39"><label>40</label>Associazione Italiana per la Sindrome di Emiplegia Alternante (A.I.S.EA) Onlus, Lecco, Italy.</aff><aff id="A40"><label>41</label>Child Neurology Unit, Maggiore Hospital, Bologna, Italy.</aff><aff id="A41"><label>42</label>Department of Child Neurology, National Neurological Institute C. Besta, Milan, Italy.</aff><aff id="A42"><label>43</label>Department of Child Neuropsychiatry, G. Gaslini Hospital, University of Genoa, Genoa, Italy.</aff><aff id="A43"><label>44</label>Division of Neurology, Bambino Gesù Children’s Hospital, Rome, Italy.</aff><aff id="A44"><label>45</label>Neurosciences Unit, University College London Institute of Child Health, London, UK.</aff><aff id="A45"><label>46</label>Department of Child Neurology, Heidelberg University Hospital, Heidelberg, Germany.</aff><aff id="A46"><label>47</label>Department of Child Neurology, Sant Joan de Deu Hospital, Barcelona, Spain.</aff><aff id="A47"><label>48</label>Department of Neurology, Charles University, 1st Faculty of Medicine and Teaching Hospital, Prague, Czech Republic.</aff><aff id="A48"><label>49</label>Department of Child Neurology, University Hospital Gasthuisberg, Leuven, Belgium.</aff><aff id="A49"><label>50</label>San Raffaele Scientific Institute, Milan, Italy.</aff><aff id="A50"><label>51</label>Department of Neurology and Psychiatry of Children and Adolescents, General Hospital, Klagenfurt, Austria.</aff><aff id="A51"><label>52</label>Institute of Experimental Neurology (INSPE), and Department of Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.</aff><aff id="A52"><label>53</label>The ENRAH Consortium, Brussels, Belgium.</aff><aff id="A53"><label>54</label>Good Clinical Practice Alliance – Europe (GCPA), Kessel-Lo, Belgium.</aff><aff id="A54"><label>55</label>Association Française de l’Hémiplégie Alternante (AFHA), St Germain les Arpajon, France.</aff><author-notes><corresp id="CR1"><bold>Corresponding authors</bold> David B. Goldstein, Ph.D. Center for Human Genome Variation Duke University 308 Research Drive, Box 91009 LSRC B Wing, Room 330 Durham, NC 27708 USA (P) 919-684-0896 (F) 919-668-6787 <email>d.goldstein@dm.duke.edu</email> Mohamad A. Mikati, M.D. Division of Pediatric Neurology Duke University 2301 Erwin Road, Box 3936 T0913J Children’s Health Center Durham, NC 27710 USA (P) 919-668-0477 (F) 919-681-8943 <email>mohamad.mikati@dm.duke.edu</email></corresp><fn fn-type="equal" id="FN1"><label>1</label><p id="P1">These authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>10</day><month>7</month><year>2012</year></pub-date><pub-date pub-type="epub"><day>29</day><month>7</month><year>2012</year></pub-date><pub-date pub-type="ppub"><month>9</month><year>2012</year></pub-date><pub-date pub-type="pmc-release"><day>01</day><month>3</month><year>2013</year></pub-date><volume>44</volume><issue>9</issue><fpage>1030</fpage><lpage>1034</lpage><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><abstract><p id="P2">Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurologic manifestations. AHC is usually a sporadic disorder with unknown etiology. Using exome sequencing of seven patients with AHC, and their unaffected parents, we identified <italic>de novo</italic> nonsynonymous mutations in <italic>ATP1A3</italic> in all seven AHC patients. Subsequent sequence analysis of <italic>ATP1A3</italic> in 98 additional patients revealed that 78% of AHC cases have a likely causal <italic>ATP1A3</italic> mutation, including one inherited mutation in a familial case of AHC. Remarkably, six <italic>ATP1A3</italic> mutations explain the majority of patients, including one observed in 36 patients. Unlike <italic>ATP1A3</italic> mutations that cause rapid-onset-dystonia-parkinsonism, AHC-causing mutations revealed consistent reductions in ATPase activity without effects on protein expression. This work identifies <italic>de novo ATP1A3</italic> mutations as the primary cause of AHC, and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in this gene.</p></abstract><funding-group><award-group><funding-source country="United Kingdom">Wellcome Trust : </funding-source><award-id>084730 || WT</award-id></award-group></funding-group></article-meta></front><body><p id="P3">Alternating hemiplegia of childhood (AHC) was first characterized as a distinct syndrome in 1971 with a report describing eight patients with episodes of intermittent hemiplegia on alternating sides of the body, developmental delay, dystonia, and choreoathetosis beginning in infancy<sup><xref ref-type="bibr" rid="R1">1</xref></sup>. Since that time, specific diagnostic criteria have more clearly defined the classic paroxysmal and interictal neurologic manifestations associated with this disease<sup><xref ref-type="bibr" rid="R2">2</xref>-<xref ref-type="bibr" rid="R6">6</xref></sup>. AHC is estimated to affect approximately one in one million individuals<sup><xref ref-type="bibr" rid="R7">7</xref></sup>, with most cases occurring sporadically<sup><xref ref-type="bibr" rid="R5">5</xref>,<xref ref-type="bibr" rid="R8">8</xref>-<xref ref-type="bibr" rid="R10">10</xref></sup>. While the etiology of AHC is usually unknown, a missense mutation in <italic>ATP1A2</italic> was reported in one case of atypical familial alternating hemiplegia<sup><xref ref-type="bibr" rid="R9">9</xref>,<xref ref-type="bibr" rid="R10">10</xref></sup>; however the clinical presentation of some of the family members with the <italic>ATP1A2</italic> mutation was more consistent with familial hemiplegic migraine<sup><xref ref-type="bibr" rid="R9">9</xref></sup>, which is caused by mutations in <italic>ATP1A2</italic><sup><xref ref-type="bibr" rid="R11">11</xref>,<xref ref-type="bibr" rid="R12">12</xref></sup>. To date, no cases of sporadic AHC have been attributed to <italic>ATP1A2</italic> mutations.</p><p id="P4">In this study, we used next-generation sequencing (NGS) to exome or whole-genome sequence ten AHC probands and their unaffected parents where possible. We identified and confirmed rare (MAF <0.01%) mutations in <italic>ATP1A3</italic> in eight of the 10 probands; for all seven patients where parental DNA was available we could demonstrate that the mutations had occurred <italic>de novo</italic>. The <italic>ATP1A3</italic> mutations included five distinct nonsynonymous mutations, one of which was found in four AHC patients (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 1</xref>). <italic>ATP1A3</italic> was then further interrogated in the two unexplained AHC probands for structural variants in the whole genome sequence data, and for overlooked single nucleotide and insertion-deletion variants by Sanger sequencing of the protein coding exons; neither analysis identified candidate causal <italic>ATP1A3</italic> mutations in these individuals. Given the rarity of functional <italic>de novo</italic> mutations, the occurrence of seven <italic>de novo</italic> mutations in the same gene in seven AHC patients, provides definitive genetic evidence that mutations in <italic>ATP1A3</italic> cause sporadic AHC.</p><p id="P5">We then Sanger-sequenced the protein-coding exons of <italic>ATP1A3</italic> in an additional cohort of 95 AHC patients. In these 95 subjects, we identified rare (MAF <0.01%) <italic>ATP1A3</italic> mutations in 74 patients (<xref ref-type="table" rid="T1">Table 1</xref>), all of which were found to be <italic>de novo</italic> in the 59 sporadic AHC patients with parental DNA available. Including samples sequenced with NGS, we, in total, identified 18 different <italic>ATP1A3</italic> mutations in 82 out of 105 (78%) patients studied. The majority of these mutations fell in or near transmembrane domains of ATP1A3 (<xref ref-type="fig" rid="F1">Fig. 1</xref>). Six of the mutations were identified in multiple AHC cases, including D801N and E815K that were identified in 36 (34%) patients and 19 (18%) patients, respectively (<xref ref-type="table" rid="T1">Table 1</xref>). One of the 95 AHC patients evaluated was a case of autosomal dominant alternating hemiplegia, first described in 1992<sup><xref ref-type="bibr" rid="R8">8</xref></sup>. In this familial case of AHC, we identified a rare <italic>ATP1A3</italic> mutation (I274N) in the cytoplasmic domain that co-segregates with the AHC phenotype (<xref ref-type="fig" rid="F2">Fig. 2</xref>).</p><p id="P6">Thirteen of the 17 <italic>ATP1A3</italic> mutations seen in sporadic AHC cases were confirmed to be <italic>de novo</italic> (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 1</xref>). We also observed, however, 15 sporadic patients with rare (MAF <0.01%) <italic>ATP1A3</italic> variants where parents were not available. This raises the possibility that some of these are inherited benign polymorphisms. While this is unlikely given the rarity of functional variants in <italic>ATP1A3</italic>, we can conservatively estimate the number of patients with pathogenic <italic>ATP1A3</italic> mutations by only considering those mutations observed as <italic>de novo</italic> in at least one patient as pathogenic. Under this assumption, 11 of the 15 patients have a pathogenic <italic>ATP1A3</italic> mutation. We can therefore conclude that at least 74% of sporadic patients with typical presentation of AHC studied here harbor disease-causing mutations in <italic>ATP1A3</italic>.</p><p id="P7"><italic>ATP1A3</italic> encodes an alpha-subunit of the Na<sup>+</sup>/K<sup>+</sup>-ATPase pump that is partly responsible for establishing and maintaining electrochemical gradients of sodium and potassium ions across the plasma membrane of neurons<sup><xref ref-type="bibr" rid="R13">13</xref></sup>. Mutations in <italic>ATP1A3</italic> have been shown to cause rapid-onset-dystonia-parkinsonism (DYT12)<sup><xref ref-type="bibr" rid="R14">14</xref>-<xref ref-type="bibr" rid="R18">18</xref></sup>. None of the mutations known to cause DYT12 was found in AHC patients. Two AHC mutations (D801N and I274N), however, affect the same amino acids as the DYT12 mutations.</p><p id="P8">To better understand how <italic>ATP1A3</italic> mutations cause two clinically distinct disorders, the functional consequences of the five mutations identified in the NGS screens of AHC patients and ten mutations that cause DYT12 were studied <italic>in vitro</italic>. All fifteen mutations were introduced in expression constructs and assessed for <italic>ATP1A3</italic> expression and function. None of the mutations was found to affect <italic>ATP1A3</italic> mRNA expression (<xref ref-type="supplementary-material" rid="SD1">Supplementary Fig. 1</xref>). However, seven out of ten mutations that cause DYT12 reduced ATP1A3 protein expression to undetectable levels, while none of the AHC-causing mutations reduced protein expression compared to wild-type (<xref ref-type="fig" rid="F3">Fig. 3</xref> and <xref ref-type="supplementary-material" rid="SD1">Supplementary Fig. 2</xref>). Despite different effects on protein expression both the mutations that cause AHC and those that cause DYT12 reduced ATPase activity <italic>in vitro</italic> by 54-90% (<xref ref-type="fig" rid="F3">Fig. 3</xref>). We note that the previous study of ATP1A3 protein expression in DYT12 reported that D801Y attenuates protein expression and I274T does not affect protein expression<sup><xref ref-type="bibr" rid="R14">14</xref></sup>, whereas we observe opposite effects in our study. This discrepancy may be attributed to different sensitivities of the assay in specific cell lines. Despite this inconsistency, both studies show that DYT12 mutations typically reduce ATP1A3 protein expression, whereas in our study no AHC mutation reduces protein levels. These data suggest that <italic>ATP1A3</italic> mutations causing DYT12 do so through hypomorphic effects on the Na<sup>+</sup>/K<sup>+</sup>-ATPase pump, while AHC-causing mutations modulate the activity of the pump. The reason for this inference is that if hypomorphic mutations could cause AHC we would expect some of the mutations to reduce protein level, and that the mutations would be distributed through the protein rather than concentrated in transmembrane domains. Further supporting the hypothesis, evaluation of the crystal structure of the Na<sup>+</sup>/K<sup>+</sup>-ATPase<sup><xref ref-type="bibr" rid="R19">19</xref></sup> predicts that a change from aspartic acid at position 801 to asparagine (i.e. D801N) in AHC will prevent the binding of potassium ions. One possible exception to this pattern is the <italic>de novo</italic> splice-site mutation in an AHC patient that may result in protein elimination by a frame-shift, although it could result in a protein with altered activity.</p><p id="P9">As noted previously, six of the AHC mutations result in the same amino acid substitution in multiple patients. A recurrent mutation in <italic>FGFR3</italic> was previously reported to cause the majority of cases of achondroplasia<sup><xref ref-type="bibr" rid="R20">20</xref></sup>, suggesting the presence of hypermutable sequence in that gene. In AHC, the recurrence of <italic>de novo</italic> mutations may be due to hypermutable sequences in <italic>ATP1A3,</italic> the ascertainment effect of only a specific subset of mutations causing AHC, or both. Some contribution of hypermutability is indicated by a simple analysis. We observe 13 sites that carry <italic>de novo</italic> mutations in <italic>ATP1A3</italic>. Under the null hypothesis that the mutation rate is equal amongst these sites, the chance that any single site would have 36 or more mutations (as observed for D801N) out of the total 77 observations (patients studied with a “pathogenic” mutation) is low (<italic>P</italic> < 0.0001). Furthermore, three of six of these sites recurrently mutated in AHC are G>A substitutions occurring at hypermutable methylated CpG-dinucleotide sequences<sup><xref ref-type="bibr" rid="R21">21</xref></sup> (D801N, E815K, G947R). It also appears, however, that only a specific subset of <italic>ATP1A3</italic> mutations produce AHC since nearly all identified AHC mutations fall in or near transmembrane domains of the protein, while the DYT12 mutations are more evenly distributed (<xref ref-type="fig" rid="F1">Fig. 1</xref>). Collectively, this suggests that the observed patterns of AHC-causing mutations across <italic>ATP1A3</italic> results from both hypermutable sequence and that only a small set of specific mutations can cause AHC. This is consistent with the functional analyses suggesting that AHC mutations may have specific effects on protein function as opposed to simply reducing activity. While not evaluated in this study, functional evaluation of the inherited <italic>ATP1A3</italic> mutation (I124N) may reveal distinct effects on the activity of the Na<sup>+</sup>/K<sup>+</sup>-ATPase that may help explain the atypical familial AHC phenotype.</p><p id="P10">We also evaluated whether patients with and without <italic>ATP1A3</italic> mutations have different clinical presentations. <italic>Myshkin</italic> mice that are heterozygous for missense <italic>Atp1a3</italic> mutation (I801N) that inactivates Na<sup>+</sup>/K<sup>+</sup>-ATPase are predisposed to seizure activity that is rescued by replacement with functional <italic>Atp1a3</italic><sup><xref ref-type="bibr" rid="R22">22</xref></sup>. We therefore first evaluated whether patients with <italic>ATP1A3</italic> mutations were more likely to have seizures than those without, and found a minor but significant effect (54% versus 29% respectively, <italic>P</italic> = 0.01, binomial probability calculation). For one patient cohort studied here (n = 30) with consistent phenotyping<sup><xref ref-type="bibr" rid="R5">5</xref></sup> we also compared age at first paroxystic event, age at first hemiplegic attack, and a series of disability indices, but found no statistically significant differences. More detailed investigations are needed to characterize the phenotypic spectrum associated with <italic>ATP1A3</italic> mutations, and to compare phenotypes among patients with different <italic>ATP1A3</italic> mutations.</p><p id="P11">In conclusion, mutations in <italic>ATP1A3</italic> likely account for at least 74% of patients with a diagnosis of typical sporadic AHC. Since the present study only assessed patients with typical AHC further work will be needed to assess whether <italic>ATP1A3</italic> mutations cause distinct but related conditions. In addition to identifying the cause of the majority of AHC patients, our results now implicate another clinically-distinct disease linked to <italic>ATP1A3</italic>, and open the door to detailed functional characterization of mutations that cause the different diseases. Having the ability to test the functional consequences of two groups of mutations that lead to clinically-distinct phenotypes offers unique insight into the pathophysiologic processes unique to each disease and will likely facilitate drug discovery for these and related conditions.</p><sec sec-type="methods" id="S1"><title>Online Methods</title><sec id="S2"><title>Study population</title><p id="P12">All sequenced patients met the diagnostic criteria for typical AHC<sup><xref ref-type="bibr" rid="R4">4</xref></sup>. Exome and genome sequenced patients were recruited to take part in this study through the Genetics of Epilepsy study at Duke University Medical Center, the Genetics of Epilepsy study at University College London, and at the University of Utah. Blood samples for DNA extraction were collected from each affected child and from unaffected parents when possible. Patients comprising the follow-up cohort were obtained from Duke University Medical Center (n = 2), the I.B.AHC Biobank and Clinical Registry for Alternating Hemiplegia (n = 34), the European AHC Genetics Consortium (n = 16), the University of Melbourne (n = 7), the University of Utah (n = 1), the French DNA and Cell Biobank for AHC (n = 30), Our Lady’s Children’s Hospital (Dublin, Ireland, n = 4), and The Children’s University Hospital (Dublin, Ireland, n = 1). All patients were recruited and consented based on the standards set forth by the ethics boards at the patient collection sites. Detailed phenotypic and demographic information of AHC patients with <italic>ATP1A3</italic> mutations are provided in <xref ref-type="supplementary-material" rid="SD1">Supplementary Table 1</xref>.</p></sec><sec id="S3"><title>Next-generation sequencing</title><p id="P13">Samples were either exome sequenced using Agilent’s All Exon (50 MB) capture, or whole-genome sequenced. All exome and whole genome sequencing was performed on either Illumina GAIIx or HiSeq 2000 machines in the Genomic Analysis Facility within the Center for Human Genome Variation (Duke University). Sequence data from 484 controls non-enriched for neuropsychiatric diseases that were sequenced as part of other in-house studies (e.g. genetics of cognition, birth weight, and HIV resistance) were used to ascertain candidate variant genotype frequencies. Sequencing was performed using standard protocols. The targeted exonic regions of all exome sequenced AHC samples and their parents were sequenced to an average coverage of 90-fold (minimum 65-fold), with at least 95 percent of the captured region having >5-fold coverage. Whole genome sequenced patient samples were sequenced to an average coverage of greater than 25-fold.</p><p id="P14">Paired-end reads were aligned to the Human Reference Genome (NCBI Build 36) using BWA software<sup><xref ref-type="bibr" rid="R26">26</xref></sup>. Variant calling to detect single nucleotide variants and indels was performed using SAMtools software<sup><xref ref-type="bibr" rid="R27">27</xref></sup>. Structural variation was called from whole-genome sequenced samples using software developed in the Center for Human Genome Variation, ERDS<sup><xref ref-type="bibr" rid="R28">28</xref></sup> and SV-Finder. SequenceVariantAnalyzer (SVA)<sup><xref ref-type="bibr" rid="R29">29</xref></sup> was used to annotate variants identified from the sequence data (Ensembl 50_36l). This software provides each variant with a genomic context (nonsynonymous coding vs. splice site, gene name, transcript, associated GO term, etc)<sup><xref ref-type="bibr" rid="R29">29</xref></sup>. Identity-by-descent calculations were used to confirm paternity and maternity.</p><p id="P15">Pictures of aligned NGS fragments covering the <italic>de novo ATP1A3</italic> variants in the seven sequenced AHC trios (parents and affected child) are provided in <xref ref-type="supplementary-material" rid="SD1">Supplementary Fig. 3</xref>.</p></sec><sec id="S4"><title>Prioritization of candidate disease-causing mutations</title><p id="P16">Genotypes of variants identified in each of the seven patients were evaluated for presence in their unaffected parents and also in a set of 484 population controls. Any genotype identified in either the unaffected parent or a population control was assumed to be non-causal. Genotypes present in the patients and absent in the unaffected parents, 484 sequenced controls, and 5400 individuals sequenced as part of the NHLBI Exome Sequencing Project (ESP) Exome Variant Server (v.0.0.8, release ESP5400) were considered as possibly causal.</p><p id="P17">Candidate disease-causing mutations were confirmed to be both present and <italic>de novo</italic> using Sanger sequencing.</p></sec><sec id="S5"><title>Sanger sequencing of the protein-coding exons of <italic>ATP1A3</italic></title><p id="P18">Some or all of the protein-coding exons of <italic>ATP1A3</italic> were Sanger sequenced in a follow-up cohort of 95 AHC patients using standard methods. When parental DNA samples were not available, heterozygous mutations absent in any publically available database were presumed to be causal (confirmed <italic>de novo</italic> status is noted in <xref ref-type="supplementary-material" rid="SD1">Supplementary Table 1</xref>). Sequencing primers are available upon request. We compared the sample sources between clinical sites to ensure no overlap. For 59 of the 70 AHC patients with recurrent <italic>ATP1A3</italic> mutations, we genotyped ten common polymorphisms to confirm that samples harboring the same <italic>ATP1A3</italic> mutation and each were unique.</p></sec><sec id="S6"><title>Functional characterization of disease-causing mutations</title><p id="P19">Pathogenic mutations in <italic>ATP1A3</italic> identified in this study and a series of mutations previously implicated in DYT12<sup><xref ref-type="bibr" rid="R14">14</xref>-<xref ref-type="bibr" rid="R18">18</xref></sup> were evaluated for effects on protein expression and overall ATPase activity <italic>in vitro</italic>.</p><sec id="S7"><title>Plasmids</title><p id="P20">Human <italic>APT1A3</italic> cDNA samples were amplified in four fragments from first-strand cDNA derived from total RNA extracted from human neuroblastoma A172. Each part of <italic>ATP1A3</italic> cDNA was then subcloned into the pCR-Blunt II-TOPO vector (Invitrogen-Life Technologies, Carlsbad, CA, USA). Fifteen different mutant alleles were produced by PCR-directed mutagenesis and the sequences were confirmed. The wild-type or mutant cDNA parts were then subcloned into pCR-Blunt II to generate full length cDNAs. Each full length <italic>ATP1A3</italic> cDNA (wild-type and 15 mutants) was then subcloned into the expression vector, pcDNA3.1 (+). The sequences of the constructs were confirmed by sequence analysis. Primer sequences used for the generation of the plasmids are available upon request.</p></sec><sec id="S8"><title>Quantitative RT-PCR</title><p id="P21">Empty pcDNA3.1(+) vector, pcDNA3.1(+)-ATP1A3-wildtype vector, and each allele of pcDNA3.1(+)-ATP1A3 vectors were transfected into human epithelial carcinoma cell line HeLa by lipofection using Lipofectamine 2000 (Invitrogen-Life Technologies). Total RNA was extracted from transfectant, and cDNAs were synthesized. <italic>ATP1A3</italic> and <italic>GAPDH</italic> mRNA expression was estimated using RT–PCR (primer sequences available upon request).</p></sec><sec id="S9"><title>Western Blotting</title><p id="P22">Empty pcDNA3.1 (+) vector, pcDNA3.1(+)-ATP1A3-wildtype vector, and each of the pcDNA3.1(+)-ATP1A3-mutant allele vectors were transfected into human epithelial carcinoma cell line (HeLa) and monkey kidney cell line (COS-7) by lipofection. After 48h of transfection, the cell lysates were subjected to SDS–PAGE gel and transferred to a polyvinylidene difluoride membrane (Millipore, Billerica, MA). The membranes were then incubated with anti-human-ATP1A3 monoclonal antibody (Santa Cruz Biotechnology, Santa Cruz, CA), or anti-beta-actin (Cell Signaling Technology, Beverly, MA). Proteins were visualized with the ECL plus western blotting detection system (GE Healthcare, Piscataway, NJ). The effects of the mutations were quantified using Image J software.</p></sec><sec id="S10"><title>ATPase assay</title><p id="P23">COS-7 cells expressing wild-type or mutant alleles of <italic>ATP1A3</italic> were lysed gently by Mammalian Protein Extraction Buffer (GE Healthcare) and protease inhibitor cocktail (Sigma-Aldrich). Only mutant alleles with detectable ATP1A3 protein levels in the Western blot assay were assessed in the ATPase assay. COS-7 cells were chosen for the ATPase analysis because HeLa cells do not express <italic>ATP1A2</italic>, an essential subunit of the Na+/K+-ATPase. The lysates were then incubated with 250 μM of ATP, 40mM of NaCl, 25mM of KCl, 3mM of MgCl<sub>2</sub> and 1mM EGTA in 37 degree for 1h. Synthesized ADP by ATPase reaction was detected by ADP-Glo™ Kinase Assay (Promega). ATPase activity was estimated by subtracting the luminescence signal with the addition of 100 μM of Ouabain from the luminescence reading without Ouabain.</p></sec></sec></sec><sec sec-type="supplementary-material" id="SM"><title>Supplementary Material</title><supplementary-material content-type="local-data" id="SD1"><label>1</label><media xlink:href="NIHMS49079-supplement-1.pdf" orientation="portrait" xlink:type="simple" id="d35e1671" position="anchor" mimetype="application" mime-subtype="pdf"></media></supplementary-material></sec></body><back><ack id="S11"><title>Acknowledgements</title><p>We are deeply indebted to all the AHC families for their participation in this study.</p><p>We would like to thank the Alternating Hemiplegia of Childhood Foundation for their efforts in coordinating the collection of US samples, the financial support of Kathryn Swoboda, MD, Sandra Reyna, MD, & Tara Newcomb, MS in the form of grants, and the facilitation of US research collaboration. We also would like to thank the French Family Foundation (Dominique Poncelin) and the Italian AHC Family Foundation (Rosaria Vavassori) for facilitating the international collaboration.</p><p>We thank A.I.S.EA Onlus, the Italian Patient Association for Alternating Hemiplegia, for coordinating and funding the project I.B.AHC Biobank and Clinical Registry for Alternating Hemiplegia. Specifically, we thank Maria Teresa Bassi and Erika Tenderini for preparing all of the AHC samples for analysis. Many thanks also to the Scientific Institute E. Medea, Lecco, Italy, that hosts the I.B.AHC Biobank, according to the I.B.AHC protocol.</p><p>We also thank the ENRAH for SMEs Consortium, the ENRAH validation committee and all collaborating physicians for the data collection<sup><xref ref-type="bibr" rid="R5">5</xref></sup>. We are also grateful to the DNA and cell bank of Genethon for the processing of French blood samples.</p><p>We would like to acknowledge the following individuals who contributed next-generation sequenced control samples to this study: D. Attix, E. Behr, R.Brown, J. Burke, D. Daskalakis, V. Dixon, Farfel, R.Gbadegesin, A. Holden, E. Holtzman, J. Hoover-Fong, C. Hulette, S. Kerns, D. Lancet, W. Lowe, P. Lugar, D. Marchuk, J. McEvoy, J. Milner, H. Oster, R. Ottman, S. Palmer, E. Pras, V. Shashi, N. Sobriera, D. Valle, K. Welsh-Bohmer, and M. Winn, as well as the MURDOCK study community registry. Funding for the collection of control samples was funded in whole or part with federal funds by the Center for HIV/AIDS Vaccine Immunology (“CHAVI”) under a grant from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Grant Number UO1AIO67854, Bryan ADRC NIA P30 AG028377, NINDS RC2NS070344, NINDS 1RC2NS070342-01, and the Division of Intramural Research, NIAID, NIH.</p><p>This study was funded in part by the ENRAH for SMEs Consortium grant (LSSM-CT-2005-516513 ENRAH for SMEs) of the European Commission Research Programme FP6, Inserm, CNRS, UPMC Univ Paris 06, Association Française contre les myopathies (SN), Association Française de l’Hémiplégie Alternante (SN, AMvdM, BdV), A.I.S.EA Onlus (FG, GN), the Center for Human Genome Variation, the Wellcome Trust (084730, SMS), UL1RR025764 to the University of Utah, Center for Clinical and Translational Sciences (KJS), NIH grant 1T32HL105321-01 (CH), The University of Luxembourg–Institute for Systems Biology Program (CH), and the Center for Medical Systems Biology established in the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research (project nr. 050-060-409 from AMvdM/MDF). SN is a recipient of a Contrat d’Interface from Assistance Publique-Hôpitaux de Paris.</p></ack><fn-group><fn id="FN2"><p id="P24"><bold>Competing Financial Interests</bold> DBG, ELH, KVS, MAM, and Duke University are named on a patent application filed by Duke University based on this work.</p></fn><fn id="FN3"><p id="P25"><bold>Author Contributions</bold> MAM, SMS, and DBG jointly supervised this research. ELH, YH, SMS, MAM, DBG conceived and designed the study. Genetic data were generated and analyzed by ELH, KJS, YH, FG, SN, BdV, FDT, CH, LBJ, KVS, CG, LL, GN, AA, and AMJMvdM. Patient DNA samples and phenotypic information of the AHC patients were collected, compiled, and analyzed by KJS, FG, SN, NMW, BdV, FDT, BF, SH, EP, MTS, TMN, LV, SPR, KJM, KS, LJP, JH, MDF, AMB, GKH, CMW, DW, BJL, PU, MDK, IES, GN, AA, SMS, MAM, the European AHC Genetics Consortium, IBAHC Consortium, and the ENRAH for SME Consortium. ELH, AMJMvdM, SMS, MAM, and DBG wrote the paper. All authors reviewed the compiled manuscript.</p></fn><fn id="FN4"><p id="P26"><bold>URLs</bold> Ensembl database, <ext-link ext-link-type="uri" xlink:href="http://www.ensembl.org">www.ensembl.org</ext-link></p><p id="P28">Human Gene Mutation Database (HGMD), <ext-link ext-link-type="uri" xlink:href="http://www.hgmd.org">www.hgmd.org</ext-link></p><p id="P29">I.B.AHC Biobank and Clinical Registry for Alternating Hemiplegia, <ext-link ext-link-type="uri" xlink:href="http://en.ibahc.org">http://en.ibahc.org</ext-link></p><p id="P30">Image J software, <ext-link ext-link-type="uri" xlink:href="http://rsbweb.nih.gov/ij/">http://rsbweb.nih.gov/ij/</ext-link></p><p id="P31">NHLBI Exome Sequencing Project (ESP) Exome Variant Server, <ext-link ext-link-type="uri" xlink:href="http://snp.gs.washington.edu/EVS">http://snp.gs.washington.edu/EVS</ext-link></p><p id="P32">SequenceVariantAnalyzer (SVA), <ext-link ext-link-type="uri" xlink:href="http://www.svaproject.org">http://www.svaproject.org</ext-link></p></fn></fn-group><ref-list><title>References</title><ref id="R1"><label>1</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Verret</surname><given-names>S</given-names></name><name><surname>Steele</surname><given-names>JC</given-names></name></person-group><article-title>Alternating hemiplegia in childhood: a report of eight patients with complicated migraine beginning in infancy</article-title><source>Pediatrics</source><year>1971</year><volume>47</volume><fpage>675</fpage><lpage>680</lpage><pub-id pub-id-type="pmid">5089756</pub-id></element-citation></ref><ref id="R2"><label>2</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bourgeois</surname><given-names>M</given-names></name><name><surname>Aicardi</surname><given-names>J</given-names></name><name><surname>Goutieres</surname><given-names>F</given-names></name></person-group><article-title>Alternating hemiplegia of childhood</article-title><source>J. 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J. Hum. Genet</source><comment>(in press)</comment></element-citation></ref><ref id="R29"><label>29</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ge</surname><given-names>D</given-names></name><etal></etal></person-group><article-title>SVA: software for annotating and visualizing sequenced human genomes</article-title><source>Bioinformatics</source><year>2011</year><volume>27</volume><fpage>1998</fpage><lpage>2000</lpage><pub-id pub-id-type="pmid">21624899</pub-id></element-citation></ref></ref-list></back><floats-group><boxed-text position="float" id="BX1" orientation="portrait"><caption><title>Web box</title></caption><p>David Goldstein and Mohamad Mikati report identification of de novo mutations in ATP1A3 in alternating hemiplegia of childhood, which is a rare neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurologic manifestations.</p></boxed-text><fig id="F1" orientation="portrait" position="float"><label>Figure 1</label><caption><title>Diagram of the ATP1A3 protein showing positions of AHC-causing and DYT12-causing mutation</title><p>AHC-causing mutations seen in a single case, in multiple cases and in a familial case are represented by black, red and blue dots, respectively. The white dots represent DYT12 mutations compiled from the HGMD database<sup><xref ref-type="bibr" rid="R23">23</xref></sup>. <italic>ATP1A3</italic> mutation coordinates are defined based on UniProt ID P13637<sup><xref ref-type="bibr" rid="R24">24</xref></sup> and Consensus CDS ID CCDS12594.1<sup><xref ref-type="bibr" rid="R25">25</xref></sup>.</p></caption><graphic xlink:href="ukmss-49079-f0001"></graphic></fig><fig id="F2" orientation="portrait" position="float"><label>Figure 2</label><caption><title>Pedigree of family with autosomal dominant AHC</title><p>Black shading indicates affectation status. An <italic>ATP1A3</italic> mutation (c.821T>A;I274N) was identified in patients II-3, III-4, and III-6 where DNA was available (indicated by a plus sign). DNA was unavailable in the father and grandmother of patients III-4 and III-6. Details of the family were reported previously<sup><xref ref-type="bibr" rid="R1">1</xref></sup>. Phenotypic details of the affected patients are provided in <xref ref-type="supplementary-material" rid="SD1">Supplementary Note</xref>.</p></caption><graphic xlink:href="ukmss-49079-f0002"></graphic></fig><fig id="F3" orientation="portrait" position="float"><label>Figure 3</label><caption><title>Effects of disease-causing mutations on protein expression and enzyme activity in COS-7 cells</title><p>Panel a. shows the effects of AHC-causing mutations (left) to DYT12 (right) on ATP1A3 protein abundance compared to WT. Panel b. compares the ATPase activity of disease-causing mutations (AHC and DYT12, mean ± s.d.) to that of WT.</p><p>*P < 0.05, **P < 0.01, ***P < 0.001, Student’s t-test (uncorrected for multiple testing), compared to WT</p></caption><graphic xlink:href="ukmss-49079-f0003"></graphic></fig><table-wrap id="T1" position="float" orientation="portrait"><label>Table 1</label><caption><p><italic>ATP1A3</italic> mutations identified in AHC patients.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" rowspan="1" colspan="1">ATP1A3<break></break>mutation<xref ref-type="table-fn" rid="TFN1">a</xref></th><th align="center" valign="middle" rowspan="1" colspan="1">Nucleotide<break></break>change<xref ref-type="table-fn" rid="TFN1">a</xref></th><th align="center" valign="middle" rowspan="1" colspan="1">Number of AHC<break></break>probands with the<break></break>mutation</th></tr></thead><tbody><tr><td align="center" valign="middle" rowspan="1" colspan="1">S137Y</td><td align="center" valign="middle" rowspan="1" colspan="1">c.410C>A</td><td align="center" valign="middle" rowspan="1" colspan="1">2</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">S137F</td><td align="center" valign="middle" rowspan="1" colspan="1">c.410C>T</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Q140L</td><td align="center" valign="middle" rowspan="1" colspan="1">c.419A>T</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">D220N</td><td align="center" valign="middle" rowspan="1" colspan="1">c.658G>A</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">I274N</td><td align="center" valign="middle" rowspan="1" colspan="1">c.821T>A</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">C333F</td><td align="center" valign="middle" rowspan="1" colspan="1">c.998G>T</td><td align="center" valign="middle" rowspan="1" colspan="1">2</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">G755S</td><td align="center" valign="middle" rowspan="1" colspan="1">c.2263G>A</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">N773S</td><td align="center" valign="middle" rowspan="1" colspan="1">c.2318A>G</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">D801N</td><td align="center" valign="middle" rowspan="1" colspan="1">c.2401G>A</td><td align="center" valign="middle" rowspan="1" colspan="1">36</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">M806R</td><td align="center" valign="middle" rowspan="1" colspan="1">c.2417T>G</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">I810S</td><td align="center" valign="middle" rowspan="1" colspan="1">c.2429T>G</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">S811P</td><td align="center" valign="middle" rowspan="1" colspan="1">c.2431T>C</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">E815K</td><td align="center" valign="middle" rowspan="1" colspan="1">c.2443G>A</td><td align="center" valign="middle" rowspan="1" colspan="1">19</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">splice site</td><td align="center" valign="middle" rowspan="1" colspan="1">c.2542-1:G>A</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">V919del</td><td align="center" valign="middle" rowspan="1" colspan="1">c.2755_2757delGTC</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">G947R</td><td align="center" valign="middle" rowspan="1" colspan="1">c.2839G>A</td><td align="center" valign="middle" rowspan="1" colspan="1">7</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">A955D</td><td align="center" valign="middle" rowspan="1" colspan="1">c.2864C>A</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">D992Y</td><td align="center" valign="middle" rowspan="1" colspan="1">c.2974G>T</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td></tr></tbody></table><table-wrap-foot><fn id="TFN1"><label>a</label><p id="P27">ATP1A3 mutation coordinates are defined based on UniProt ID P1363724 and Consensus CDS ID CCDS12594.1<sup><xref ref-type="bibr" rid="R25">25</xref></sup>.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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