De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy.
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.
Department of Women and Child Health, Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.
Steffen
S
Syrbe
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Ulrike B S
UBS
Hedrich
Center for Genomics and Transcriptomics (CeGaT) GmbH, Tübingen, Germany.|Division of Human Genetics, University Children's Hospital Inselspital, Bern, Switzerland.|Swiss Epilepsy Center, Zürich, Switzerland.
Erik
E
Riesch
Neurogenetics group, Department of Molecular Genetics, VIB, Antwerp, Belgium.|Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
Tania
T
Djémié
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Stephan
S
Müller
Danish Epilepsy Center, Dianalund, Denmark.|Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
Rikke S
RS
Møller
Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, Queen Square, London, WC1N 3BG, UK.|Epilepsy Society, Chalfont-St-Peter, Bucks, SL9 0RJ, UK.
Bridget
B
Maher
Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, Queen Square, London, WC1N 3BG, UK.|Epilepsy Society, Chalfont-St-Peter, Bucks, SL9 0RJ, UK.
Laura
L
Hernandez-Hernandez
Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.|German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
Matthis
M
Synofzik
Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey.
Hande S
HS
Caglayan
Gulhane Military Medical School, Division of Child Neurology, Ankara, Turkey.
Mutluay
M
Arslan
Neurology Lab and Epilepsy Unit, Department of Neurology, IIS - Fundación Jiménez Díaz, UAM, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
José M
JM
Serratosa
Cologne Center for Genomics, University of Colgone, Cologne, Germany.
Michael
M
Nothnagel
Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg.
Patrick
P
May
Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg.
Roland
R
Krause
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Heidrun
H
Löffler
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Katja
K
Detert
Swiss Epilepsy Center, Zürich, Switzerland.
Thomas
T
Dorn
Swiss Epilepsy Center, Zürich, Switzerland.
Heinrich
H
Vogt
Swiss Epilepsy Center, Zürich, Switzerland.
Günter
G
Krämer
Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.|German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
Ludger
L
Schöls
Division of Pediatric Endocrinology, University Children's Hospital Inselspital, Bern, Switzerland.
Primus E
PE
Mullis
Pediatric Neurology, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Tarja
T
Linnankivi
Folkhälsan Institute of Genetics, Helsinki, Helsinki, Finland.|Neuroscience Center, University of Helsinki, Helsinki, Finland.|Research Program's Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
Anna-Elina
AE
Lehesjoki
Child Neurology Department, 2nd Faculty of Medicine, Charles University, Motol Hospital, Prague, Czech Republic.
Katalin
K
Sterbova
Pediatric Neurology Clinic II, Department of Neurology, Pediatric Neurology, Psychiatry, and Neurosurgery, "Carol Davila" University of Medicine, Sector 4, Bucharest, Romania.|Pediatric Neurology Clinic, "Professor Doctor Alexandru Obregia" Clinical Hospital, Sector 4, Bucharest, Romania.
Dana C
DC
Craiu
Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
Dorota
D
Hoffman-Zacharska
Child and Adolescent Department, Pediatric Neurology, University Hospitals, Geneva, Switzerland.
Christian M
CM
Korff
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Yvonne G
YG
Weber
Division of Neuropediatrics, University Children's Hospital Inselspital, Bern, Switzerland.
Maja
M
Steinlin
Division of Human Genetics, University Children's Hospital Inselspital, Bern, Switzerland.
Sabina
S
Gallati
Department of Women and Child Health, Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.
Astrid
A
Bertsche
Department of Women and Child Health, Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.
Matthias K
MK
Bernhard
Department of Women and Child Health, Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.
Andreas
A
Merkenschlager
Department of Women and Child Health, Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.
Wieland
W
Kiess
Dr. JT MacDonald Department for Human Genetics, Hussman Institute for Human Genomics, University of Miami, Miami, USA.
Michael
M
Gonzalez
Dr. JT MacDonald Department for Human Genetics, Hussman Institute for Human Genomics, University of Miami, Miami, USA.
Stephan
S
Züchner
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.|Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.|Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, 02114, USA.
Aarno
A
Palotie
Neurogenetics group, Department of Molecular Genetics, VIB, Antwerp, Belgium.|Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
Arvid
A
Suls
Neurogenetics group, Department of Molecular Genetics, VIB, Antwerp, Belgium.|Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Department of Neurology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
Peter
P
De Jonghe
Department of Neuropediatrics, Christian-Albrechts-University of Kiel, Germany.|Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, USA.
Ingo
I
Helbig
Center for Genomics and Transcriptomics (CeGaT) GmbH, Tübingen, Germany.
Saskia
S
Biskup
Department of Neuropediatrics, University of Tübingen, Tübingen, Germany.
Markus
M
Wolff
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Snezana
S
Maljevic
Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.|German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.|Division of Neuropediatrics, University Children's Hospital Inselspital, Bern, Switzerland.
Rebecca
R
Schüle
Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, Queen Square, London, WC1N 3BG, UK.|Epilepsy Society, Chalfont-St-Peter, Bucks, SL9 0RJ, UK.
Sanjay M
SM
Sisodiya
Neurogenetics group, Department of Molecular Genetics, VIB, Antwerp, Belgium.|Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
Sarah
S
Weckhuysen
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Holger
H
Lerche
Department of Women and Child Health, Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.|Division of Human Genetics, University Children's Hospital Inselspital, Bern, Switzerland.|Department of Diagnostics, Institute of Human Genetics, University of Leipzig, Leipzig, Germany.
Johannes R
JR
Lemke
D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D051663:Kv1.2 Potassium Channel / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D013036:Spasms, Infantile / Q000235:genetics*; D055815:Young Adult
C496969:KCNA2 protein, human; D051663:Kv1.2 Potassium Channel