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De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy

Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and other neurodevelopmental features(1-6). Using next generation sequencing, we identified four different de novo mutations in KCNA2, encoding the potassiu...

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Autores principales: Syrbe, Steffen, Hedrich, Ulrike B.S., Riesch, Erik, Djémié, Tania, Müller, Stephan, Møller, Rikke S., Maher, Bridget, Hernandez-Hernandez, Laura, Synofzik, Matthis, Caglayan, Hande S., Arslan, Mutluay, Serratosa, José M., Nothnagel, Michael, May, Patrick, Krause, Roland, Löffler, Heidrun, Detert, Katja, Dorn, Thomas, Vogt, Heinrich, Krämer, Günter, Schöls, Ludger, Mullis, Primus E., Linnankivi, Tarja, Lehesjoki, Anna-Elina, Sterbova, Katalin, Craiu, Dana C., Hoffman-Zacharska, Dorota, Korff, Christian M., Weber, Yvonne G., Steinlin, Maja, Gallati, Sabina, Bertsche, Astrid, Bernhard, Matthias K., Merkenschlager, Andreas, Kiess, Wieland, Gonzalez, Michael, Züchner, Stephan, Palotie, Aarno, Suls, Arvid, De Jonghe, Peter, Helbig, Ingo, Biskup, Saskia, Wolff, Markus, Maljevic, Snezana, Schüle, Rebecca, Sisodiya, Sanjay M., Weckhuysen, Sarah, Lerche, Holger, Lemke, Johannes R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380508/
https://www.ncbi.nlm.nih.gov/pubmed/25751627
http://dx.doi.org/10.1038/ng.3239
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author Syrbe, Steffen
Hedrich, Ulrike B.S.
Riesch, Erik
Djémié, Tania
Müller, Stephan
Møller, Rikke S.
Maher, Bridget
Hernandez-Hernandez, Laura
Synofzik, Matthis
Caglayan, Hande S.
Arslan, Mutluay
Serratosa, José M.
Nothnagel, Michael
May, Patrick
Krause, Roland
Löffler, Heidrun
Detert, Katja
Dorn, Thomas
Vogt, Heinrich
Krämer, Günter
Schöls, Ludger
Mullis, Primus E.
Linnankivi, Tarja
Lehesjoki, Anna-Elina
Sterbova, Katalin
Craiu, Dana C.
Hoffman-Zacharska, Dorota
Korff, Christian M.
Weber, Yvonne G.
Steinlin, Maja
Gallati, Sabina
Bertsche, Astrid
Bernhard, Matthias K.
Merkenschlager, Andreas
Kiess, Wieland
Gonzalez, Michael
Züchner, Stephan
Palotie, Aarno
Suls, Arvid
De Jonghe, Peter
Helbig, Ingo
Biskup, Saskia
Wolff, Markus
Maljevic, Snezana
Schüle, Rebecca
Sisodiya, Sanjay M.
Weckhuysen, Sarah
Lerche, Holger
Lemke, Johannes R.
author_facet Syrbe, Steffen
Hedrich, Ulrike B.S.
Riesch, Erik
Djémié, Tania
Müller, Stephan
Møller, Rikke S.
Maher, Bridget
Hernandez-Hernandez, Laura
Synofzik, Matthis
Caglayan, Hande S.
Arslan, Mutluay
Serratosa, José M.
Nothnagel, Michael
May, Patrick
Krause, Roland
Löffler, Heidrun
Detert, Katja
Dorn, Thomas
Vogt, Heinrich
Krämer, Günter
Schöls, Ludger
Mullis, Primus E.
Linnankivi, Tarja
Lehesjoki, Anna-Elina
Sterbova, Katalin
Craiu, Dana C.
Hoffman-Zacharska, Dorota
Korff, Christian M.
Weber, Yvonne G.
Steinlin, Maja
Gallati, Sabina
Bertsche, Astrid
Bernhard, Matthias K.
Merkenschlager, Andreas
Kiess, Wieland
Gonzalez, Michael
Züchner, Stephan
Palotie, Aarno
Suls, Arvid
De Jonghe, Peter
Helbig, Ingo
Biskup, Saskia
Wolff, Markus
Maljevic, Snezana
Schüle, Rebecca
Sisodiya, Sanjay M.
Weckhuysen, Sarah
Lerche, Holger
Lemke, Johannes R.
author_sort Syrbe, Steffen
collection PubMed
description Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and other neurodevelopmental features(1-6). Using next generation sequencing, we identified four different de novo mutations in KCNA2, encoding the potassium channel K(V)1.2, in six patients with epileptic encephalopathy (one mutation recurred three times independently). Four individuals presented with febrile and multiple afebrile, often focal seizure types, multifocal epileptiform discharges strongly activated by sleep, mild-moderate intellectual disability, delayed speech development and sometimes ataxia. Functional studies of the two mutations associated with this phenotype revealed an almost complete loss-of-function with a dominant-negative effect. Two further individuals presented with a different and more severe epileptic encephalopathy phenotype. They carried mutations inducing a drastic gain-of-function effect leading to permanently open channels. These results establish KCNA2 as a novel gene involved in human neurodevelopmental disorders by two different mechanisms, predicting either hyperexcitability or electrical silencing of K(V)1.2-expressing neurons.
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spelling pubmed-43805082015-10-01 De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy Syrbe, Steffen Hedrich, Ulrike B.S. Riesch, Erik Djémié, Tania Müller, Stephan Møller, Rikke S. Maher, Bridget Hernandez-Hernandez, Laura Synofzik, Matthis Caglayan, Hande S. Arslan, Mutluay Serratosa, José M. Nothnagel, Michael May, Patrick Krause, Roland Löffler, Heidrun Detert, Katja Dorn, Thomas Vogt, Heinrich Krämer, Günter Schöls, Ludger Mullis, Primus E. Linnankivi, Tarja Lehesjoki, Anna-Elina Sterbova, Katalin Craiu, Dana C. Hoffman-Zacharska, Dorota Korff, Christian M. Weber, Yvonne G. Steinlin, Maja Gallati, Sabina Bertsche, Astrid Bernhard, Matthias K. Merkenschlager, Andreas Kiess, Wieland Gonzalez, Michael Züchner, Stephan Palotie, Aarno Suls, Arvid De Jonghe, Peter Helbig, Ingo Biskup, Saskia Wolff, Markus Maljevic, Snezana Schüle, Rebecca Sisodiya, Sanjay M. Weckhuysen, Sarah Lerche, Holger Lemke, Johannes R. Nat Genet Article Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and other neurodevelopmental features(1-6). Using next generation sequencing, we identified four different de novo mutations in KCNA2, encoding the potassium channel K(V)1.2, in six patients with epileptic encephalopathy (one mutation recurred three times independently). Four individuals presented with febrile and multiple afebrile, often focal seizure types, multifocal epileptiform discharges strongly activated by sleep, mild-moderate intellectual disability, delayed speech development and sometimes ataxia. Functional studies of the two mutations associated with this phenotype revealed an almost complete loss-of-function with a dominant-negative effect. Two further individuals presented with a different and more severe epileptic encephalopathy phenotype. They carried mutations inducing a drastic gain-of-function effect leading to permanently open channels. These results establish KCNA2 as a novel gene involved in human neurodevelopmental disorders by two different mechanisms, predicting either hyperexcitability or electrical silencing of K(V)1.2-expressing neurons. 2015-03-09 2015-04 /pmc/articles/PMC4380508/ /pubmed/25751627 http://dx.doi.org/10.1038/ng.3239 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Syrbe, Steffen
Hedrich, Ulrike B.S.
Riesch, Erik
Djémié, Tania
Müller, Stephan
Møller, Rikke S.
Maher, Bridget
Hernandez-Hernandez, Laura
Synofzik, Matthis
Caglayan, Hande S.
Arslan, Mutluay
Serratosa, José M.
Nothnagel, Michael
May, Patrick
Krause, Roland
Löffler, Heidrun
Detert, Katja
Dorn, Thomas
Vogt, Heinrich
Krämer, Günter
Schöls, Ludger
Mullis, Primus E.
Linnankivi, Tarja
Lehesjoki, Anna-Elina
Sterbova, Katalin
Craiu, Dana C.
Hoffman-Zacharska, Dorota
Korff, Christian M.
Weber, Yvonne G.
Steinlin, Maja
Gallati, Sabina
Bertsche, Astrid
Bernhard, Matthias K.
Merkenschlager, Andreas
Kiess, Wieland
Gonzalez, Michael
Züchner, Stephan
Palotie, Aarno
Suls, Arvid
De Jonghe, Peter
Helbig, Ingo
Biskup, Saskia
Wolff, Markus
Maljevic, Snezana
Schüle, Rebecca
Sisodiya, Sanjay M.
Weckhuysen, Sarah
Lerche, Holger
Lemke, Johannes R.
De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy
title De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy
title_full De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy
title_fullStr De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy
title_full_unstemmed De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy
title_short De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy
title_sort de novo loss- or gain-of-function mutations in kcna2 cause epileptic encephalopathy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380508/
https://www.ncbi.nlm.nih.gov/pubmed/25751627
http://dx.doi.org/10.1038/ng.3239
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