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Autor: Vogt, Heinrich

5 záznamů v Medvik Filtry

Článek online

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

Syrbe, Steffen
Autor Syrbe, Steffen Department of Women and Child Health, Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany
Hedrich, Ulrike B S
Autor Hedrich, Ulrike B S Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
Riesch, Erik
Autor Riesch, Erik ] Center for Genomics and Transcriptomics (CeGaT), Tübingen, Germany. [2] Division of Human Genetics, University Children's Hospital Inselspital, Bern, Switzerland. [3] Swiss Epilepsy Center, Zürich, Switzerland
Djémié, Tania
Autor Djémié, Tania ] Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium. [2] Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Müller, Stephan
Autor Müller, Stephan Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
Møller, Rikke S
Autor Møller, Rikke S ] Danish Epilepsy Center, Dianalund, Denmark. [2] Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark
Maher, Bridget
Autor Maher, Bridget ] Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, Queen Square, London, UK. [2] Epilepsy Society, Chalfont-St-Peter, Bucks, UK
Hernandez-Hernandez, Laura
Autor Hernandez-Hernandez, Laura ] Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, Queen Square, London, UK. [2] Epilepsy Society, Chalfont-St-Peter, Bucks, UK
Synofzik, Matthis
Autor Synofzik, Matthis ] Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. [2] German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
Caglayan, Hande S
Autor Caglayan, Hande S Department of Molecular Biology and Genetics, Bo[gcaron]aziçi University, Istanbul, Turkey

Nature genetics. 2015 ; 47 (4) : 393-9.

Nat Genet
ISSN 1546-1718
Medvik
Zdroj

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.