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Nat Genet. 2015 Apr;47(4):393-9. doi: 10.1038/ng.3239. Epub 2015 Mar 9.

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

Author information

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
1] 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.
4
1] Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium. [2] Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
5
1] Danish Epilepsy Center, Dianalund, Denmark. [2] Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
6
1] Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, Queen Square, London, UK. [2] Epilepsy Society, Chalfont-St-Peter, Bucks, UK.
7
1] 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.
8
Department of Molecular Biology and Genetics, Bo[gcaron]aziçi University, Istanbul, Turkey.
9
Division of Child Neurology, Gulhane Military Medical School, Ankara, Turkey.
10
1] Neurology Laboratory and Epilepsy Unit, Department of Neurology, Instituto de Investigatión Sanitaria-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain. [2] Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
11
Cologne Center for Genomics, University of Cologne, Cologne, Germany.
12
Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg.
13
Swiss Epilepsy Center, Zürich, Switzerland.
14
Division of Pediatric Endocrinology, University Children's Hospital Inselspital, Bern, Switzerland.
15
Department of Pediatric Neurology, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
16
1] Folkhälsan Institute of Genetics, Helsinki, Finland. [2] Neuroscience Center, University of Helsinki, Helsinki, Finland. [3] Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
17
Department of Child Neurology, 2nd Faculty of Medicine, Charles University, Motol Hospital, Prague, Czech Republic.
18
1] Pediatric Neurology Clinic II, Department of Neurology, Pediatric Neurology, Psychiatry and Neurosurgery, 'Carol Davila' University of Medicine, Bucharest, Romania. [2] Pediatric Neurology Clinic, 'Professor Doctor Alexandru Obregia' Clinical Hospital, Bucharest, Romania.
19
Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
20
Child and Adolescent Department, Pediatric Neurology, University Hospitals, Geneva, Switzerland.
21
Division of Neuropediatrics, University Children's Hospital Inselspital, Bern, Switzerland.
22
Division of Human Genetics, University Children's Hospital Inselspital, Bern, Switzerland.
23
Dr. J.T. MacDonald Department for Human Genetics, Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA.
24
1] Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland. [2] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. [3] Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA.
25
1] Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium. [2] Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. [3] Department of Neurology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
26
1] Department of Neuropediatrics, Christian Albrechts University of Kiel, Kiel, Germany. [2] Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
27
Center for Genomics and Transcriptomics (CeGaT), Tübingen, Germany.
28
Department of Neuropediatrics, University of Tübingen, Tübingen, Germany.
29
1] 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. [3] Dr. J.T. MacDonald Department for Human Genetics, Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA.
30
1] Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. [2] Department of Neurology, University of Tübingen, Tübingen, Germany.
31
1] Department of Women and Child Health, Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany. [2] Division of Human Genetics, University Children's Hospital Inselspital, Bern, Switzerland. [3] Institute of Human Genetics, University of Leipzig, Leipzig, Germany.

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.

PMID:
25751627
PMCID:
PMC4380508
DOI:
10.1038/ng.3239
[Indexed for MEDLINE]
Free PMC Article
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