Reference : -
Life sciences : Genetics & genetic processes
Human health sciences : Neurology
Syrbe, Steffen []
Hedrich, Ulrike B.S. []
Riesch, Erik []
Djémié, Tanja []
Müller, Stephan []
Møller, Rikke S. [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Maher, Bridget []
Hernandez-Hernandez, Laura []
Synofzik, Matthis []
Caglayan, Hande S. []
Arslan, Mutluay []
Serratosa, José M. []
Nothnagel, Michael []
May, Patrick mailto []
Krause, Roland mailto []
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
Balling, Rudi mailto
Gonzalez, Michael
Züchner, Stefan
Palotie, Aarno
Suls, Arvid
De Jonghe, Peter
Helbig, Ingo
Biskup, Saskia
Wolff, Markus
Maljeviv, Snezana
Schüle, Rebecca
Sisodoya, Sanjay M.
Weckhuysen, Sarah
Lerche, Holger
Lemke, Johannes R.
Nature Genetics
Nature Publishing Group
Yes (verified by ORBilu)
New York
[en] Genetics ; Epilepsy ; Mutation
[en] Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and other neurodevelopmental features1–6. Using next-generation sequencing, we identified four different de novo mutations in KCNA2, encoding the
potassium channel KV1.2, 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 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.
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) ; Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group)
Researchers ; Professionals

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