2. Academic Validation
  3. De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy

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

  • Nat Genet. 2015 Apr;47(4):393-399. doi: 10.1038/ng.3239.
Steffen Syrbe # 1,  Ulrike B S Hedrich # 2,  Erik Riesch # 3 4 5,  Tania Djémié # 6 7,  Stephan Müller 2,  Rikke S Møller 8 9,  Bridget Maher 10 11,  Laura Hernandez-Hernandez 10 11,  Matthis Synofzik 12 13,  Hande S Caglayan 14,  Mutluay Arslan 15,  José M Serratosa 16 17,  Michael Nothnagel 18,  Patrick May 19,  Roland Krause 19,  Heidrun Löffler 2,  Katja Detert 2,  Thomas Dorn 5,  Heinrich Vogt 5,  Günter Krämer 5,  Ludger Schöls 12 13,  Primus E Mullis 20,  Tarja Linnankivi 21,  Anna-Elina Lehesjoki 22 23 24,  Katalin Sterbova 25,  Dana C Craiu 26 27,  Dorota Hoffman-Zacharska 28,  Christian M Korff 29,  Yvonne G Weber 2,  Maja Steinlin 30,  Sabina Gallati 4,  Astrid Bertsche 1,  Matthias K Bernhard 1,  Andreas Merkenschlager 1,  Wieland Kiess 1,  EuroEPINOMICS RES consortium,  Michael Gonzalez 31,  Stephan Züchner 31,  Aarno Palotie 32 33 34,  Arvid Suls 6 7,  Peter De Jonghe 6 7 35,  Ingo Helbig 36 37,  Saskia Biskup 3,  Markus Wolff 38,  Snezana Maljevic 2,  Rebecca Schüle 12 13 30,  Sanjay M Sisodiya 10 11,  Sarah Weckhuysen 6 7,  Holger Lerche 2,  Johannes R Lemke 1 4 39
Affiliations

Affiliations

  • 1 Department of Women and Child Health, Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.
  • 2 Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
  • 3 Center for Genomics and Transcriptomics (CeGaT) GmbH, Tübingen, Germany.
  • 4 Division of Human Genetics, University Children's Hospital Inselspital, Bern, Switzerland.
  • 5 Swiss Epilepsy Center, Zürich, Switzerland.
  • 6 Neurogenetics group, Department of Molecular Genetics, VIB, Antwerp, Belgium.
  • 7 Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
  • 8 Danish Epilepsy Center, Dianalund, Denmark.
  • 9 Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
  • 10 Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
  • 11 Epilepsy Society, Chalfont-St-Peter, Bucks, SL9 0RJ, UK.
  • 12 Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
  • 13 German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
  • 14 Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey.
  • 15 Gulhane Military Medical School, Division of Child Neurology, Ankara, Turkey.
  • 16 Neurology Lab and Epilepsy Unit, Department of Neurology, IIS - Fundación Jiménez Díaz, UAM, Madrid, Spain.
  • 17 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
  • 18 Cologne Center for Genomics, University of Colgone, Cologne, Germany.
  • 19 Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg.
  • 20 Division of Pediatric Endocrinology, University Children's Hospital Inselspital, Bern, Switzerland.
  • 21 Pediatric Neurology, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
  • 22 Folkhälsan Institute of Genetics, Helsinki, Helsinki, Finland.
  • 23 Neuroscience Center, University of Helsinki, Helsinki, Finland.
  • 24 Research Program's Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
  • 25 Child Neurology Department, 2nd Faculty of Medicine, Charles University, Motol Hospital, Prague, Czech Republic.
  • 26 Pediatric Neurology Clinic II, Department of Neurology, Pediatric Neurology, Psychiatry, and Neurosurgery, "Carol Davila" University of Medicine, Sector 4, Bucharest, Romania.
  • 27 Pediatric Neurology Clinic, "Professor Doctor Alexandru Obregia" Clinical Hospital, Sector 4, Bucharest, Romania.
  • 28 Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
  • 29 Child and Adolescent Department, Pediatric Neurology, University Hospitals, Geneva, Switzerland.
  • 30 Division of Neuropediatrics, University Children's Hospital Inselspital, Bern, Switzerland.
  • 31 Dr. JT MacDonald Department for Human Genetics, Hussman Institute for Human Genomics, University of Miami, Miami, USA.
  • 32 Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
  • 33 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
  • 34 Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, 02114, USA.
  • 35 Department of Neurology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
  • 36 Department of Neuropediatrics, Christian-Albrechts-University of Kiel, Germany.
  • 37 Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, USA.
  • 38 Department of Neuropediatrics, University of Tübingen, Tübingen, Germany.
  • 39 Department of Diagnostics, Institute of Human Genetics, University of Leipzig, Leipzig, Germany.
  • # Contributed equally.
PMID: 25751627 DOI: 10.1038/ng.3239
Abstract

Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and Other neurodevelopmental features. Using next-generation Sequencing, we identified four different de novo mutations in KCNA2, encoding the Potassium Channel KV1.2, in six isolated 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 to moderate intellectual disability, delayed speech development and sometimes ataxia. Functional studies of the two mutations associated with this phenotype showed 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 new gene involved in human neurodevelopmental disorders through two different mechanisms, predicting either hyperexcitability or electrical silencing of KV1.2-expressing neurons.

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