Reference : De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy
Scientific journals : Article
Life sciences : Genetics & genetic processes
Human health sciences : Neurology
De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy
Syrbe, Steffen []
Hedrich, Ulrike B.S. []
Riesch, Erik []
Djémié, Tanja []
Müller, Stephan []
Møller, Rikke S. []
Maher, Bridget []
Hernandez-Hernandez, Laura []
Synofzik, Matthis []
Caglayan, Hande S. []
Arslan, Mutluay []
Serratosa, José M. []
Nothnagel, Michael []
May, Patrick mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Krause, Roland mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
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 [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
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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