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

Steffen Syrbe, Ulrike B S Hedrich, Erik Riesch, Tania Djémié, Stephan Müller, Rikke S. Møller, Bridget Maher, Laura Hernandez-Hernandez, Matthis Synofzik, Hande S. Caglayan, Mutluay Arslan, José M. Serratosa, Michael Nothnagel, Patrick May, Roland Krause, Heidrun Löffler, Katja Detert, Thomas Dorn, Heinrich Vogt, Günter KrämerLudger Schöls, Primus E. Mullis, Tarja Linnankivi, Anna Elina Lehesjoki, Katalin Sterbova, Dana C. Craiu, Dorota Hoffman-Zacharska, Christian M. Korff, Yvonne G. Weber, Maja Steinlin, Sabina Gallati, Astrid Bertsche, Matthias K. Bernhard, Andreas Merkenschlager, Wieland Kiess, Michael Gonzalez, Stephan L Zuchner, Aarno Palotie, Arvid Suls, Peter De Jonghe, Ingo Helbig, Saskia Biskup, Markus Wolff, Snezana Maljevic, Rebecca Schüle, Sanjay M. Sisodiya, Sarah Weckhuysen, Holger Lerche, Johannes R. Lemke

Research output: Contribution to journalArticle

100 Citations (Scopus)

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 K V 1.2, 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 K V 1.2-expressing neurons.

Original languageEnglish (US)
Pages (from-to)393-399
Number of pages7
JournalNature Genetics
Volume47
Issue number4
DOIs
StatePublished - Apr 28 2015

Fingerprint

Brain Diseases
Mutation
Intellectual Disability
Kv1.2 Potassium Channel
Phenotype
Ataxia
Epilepsy
Sleep
Seizures
Fever
Neurons
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Syrbe, S., Hedrich, U. B. S., Riesch, E., Djémié, T., Müller, S., Møller, R. S., ... Lemke, J. R. (2015). De novo loss-or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. Nature Genetics, 47(4), 393-399. https://doi.org/10.1038/ng.3239

De novo loss-or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. / Syrbe, Steffen; Hedrich, Ulrike B S; Riesch, Erik; Djémié, Tania; Müller, Stephan; Møller, Rikke S.; Maher, Bridget; Hernandez-Hernandez, Laura; Synofzik, Matthis; Caglayan, Hande S.; Arslan, Mutluay; Serratosa, José M.; Nothnagel, Michael; May, Patrick; Krause, Roland; 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; Gonzalez, Michael; Zuchner, Stephan L; Palotie, Aarno; Suls, Arvid; De Jonghe, Peter; Helbig, Ingo; Biskup, Saskia; Wolff, Markus; Maljevic, Snezana; Schüle, Rebecca; Sisodiya, Sanjay M.; Weckhuysen, Sarah; Lerche, Holger; Lemke, Johannes R.

In: Nature Genetics, Vol. 47, No. 4, 28.04.2015, p. 393-399.

Research output: Contribution to journalArticle

Syrbe, S, Hedrich, UBS, Riesch, E, Djémié, T, Müller, S, Møller, RS, Maher, B, Hernandez-Hernandez, L, Synofzik, M, Caglayan, HS, Arslan, M, Serratosa, JM, Nothnagel, M, May, P, Krause, R, Löffler, H, Detert, K, Dorn, T, Vogt, H, Krämer, G, Schöls, L, Mullis, PE, Linnankivi, T, Lehesjoki, AE, Sterbova, K, Craiu, DC, Hoffman-Zacharska, D, Korff, CM, Weber, YG, Steinlin, M, Gallati, S, Bertsche, A, Bernhard, MK, Merkenschlager, A, Kiess, W, Gonzalez, M, Zuchner, SL, Palotie, A, Suls, A, De Jonghe, P, Helbig, I, Biskup, S, Wolff, M, Maljevic, S, Schüle, R, Sisodiya, SM, Weckhuysen, S, Lerche, H & Lemke, JR 2015, 'De novo loss-or gain-of-function mutations in KCNA2 cause epileptic encephalopathy', Nature Genetics, vol. 47, no. 4, pp. 393-399. https://doi.org/10.1038/ng.3239
Syrbe S, Hedrich UBS, Riesch E, Djémié T, Müller S, Møller RS et al. De novo loss-or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. Nature Genetics. 2015 Apr 28;47(4):393-399. https://doi.org/10.1038/ng.3239
Syrbe, Steffen ; Hedrich, Ulrike B S ; Riesch, Erik ; Djémié, Tania ; Müller, Stephan ; Møller, Rikke S. ; Maher, Bridget ; Hernandez-Hernandez, Laura ; Synofzik, Matthis ; Caglayan, Hande S. ; Arslan, Mutluay ; Serratosa, José M. ; Nothnagel, Michael ; May, Patrick ; Krause, Roland ; 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 ; Gonzalez, Michael ; Zuchner, Stephan L ; Palotie, Aarno ; Suls, Arvid ; De Jonghe, Peter ; Helbig, Ingo ; Biskup, Saskia ; Wolff, Markus ; Maljevic, Snezana ; Schüle, Rebecca ; Sisodiya, Sanjay M. ; Weckhuysen, Sarah ; Lerche, Holger ; Lemke, Johannes R. / De novo loss-or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. In: Nature Genetics. 2015 ; Vol. 47, No. 4. pp. 393-399.
@article{056da40961204758a27db1f651f9e2e3,
title = "De novo loss-or gain-of-function mutations in KCNA2 cause epileptic encephalopathy",
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 K V 1.2, 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 K V 1.2-expressing neurons.",
author = "Steffen Syrbe and Hedrich, {Ulrike B S} and Erik Riesch and Tania Dj{\'e}mi{\'e} and Stephan M{\"u}ller and M{\o}ller, {Rikke S.} and Bridget Maher and Laura Hernandez-Hernandez and Matthis Synofzik and Caglayan, {Hande S.} and Mutluay Arslan and Serratosa, {Jos{\'e} M.} and Michael Nothnagel and Patrick May and Roland Krause and Heidrun L{\"o}ffler and Katja Detert and Thomas Dorn and Heinrich Vogt and G{\"u}nter Kr{\"a}mer and Ludger Sch{\"o}ls and Mullis, {Primus E.} and Tarja Linnankivi and Lehesjoki, {Anna Elina} and Katalin Sterbova and Craiu, {Dana C.} and Dorota Hoffman-Zacharska and Korff, {Christian M.} and Weber, {Yvonne G.} and Maja Steinlin and Sabina Gallati and Astrid Bertsche and Bernhard, {Matthias K.} and Andreas Merkenschlager and Wieland Kiess and Michael Gonzalez and Zuchner, {Stephan L} and Aarno Palotie and Arvid Suls and {De Jonghe}, Peter and Ingo Helbig and Saskia Biskup and Markus Wolff and Snezana Maljevic and Rebecca Sch{\"u}le and Sisodiya, {Sanjay M.} and Sarah Weckhuysen and Holger Lerche and Lemke, {Johannes R.}",
year = "2015",
month = "4",
day = "28",
doi = "10.1038/ng.3239",
language = "English (US)",
volume = "47",
pages = "393--399",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "4",

}

TY - JOUR

T1 - De novo loss-or gain-of-function mutations in KCNA2 cause epileptic encephalopathy

AU - Syrbe, Steffen

AU - Hedrich, Ulrike B S

AU - Riesch, Erik

AU - Djémié, Tania

AU - Müller, Stephan

AU - Møller, Rikke S.

AU - Maher, Bridget

AU - Hernandez-Hernandez, Laura

AU - Synofzik, Matthis

AU - Caglayan, Hande S.

AU - Arslan, Mutluay

AU - Serratosa, José M.

AU - Nothnagel, Michael

AU - May, Patrick

AU - Krause, Roland

AU - Löffler, Heidrun

AU - Detert, Katja

AU - Dorn, Thomas

AU - Vogt, Heinrich

AU - Krämer, Günter

AU - Schöls, Ludger

AU - Mullis, Primus E.

AU - Linnankivi, Tarja

AU - Lehesjoki, Anna Elina

AU - Sterbova, Katalin

AU - Craiu, Dana C.

AU - Hoffman-Zacharska, Dorota

AU - Korff, Christian M.

AU - Weber, Yvonne G.

AU - Steinlin, Maja

AU - Gallati, Sabina

AU - Bertsche, Astrid

AU - Bernhard, Matthias K.

AU - Merkenschlager, Andreas

AU - Kiess, Wieland

AU - Gonzalez, Michael

AU - Zuchner, Stephan L

AU - Palotie, Aarno

AU - Suls, Arvid

AU - De Jonghe, Peter

AU - Helbig, Ingo

AU - Biskup, Saskia

AU - Wolff, Markus

AU - Maljevic, Snezana

AU - Schüle, Rebecca

AU - Sisodiya, Sanjay M.

AU - Weckhuysen, Sarah

AU - Lerche, Holger

AU - Lemke, Johannes R.

PY - 2015/4/28

Y1 - 2015/4/28

N2 - 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 K V 1.2, 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 K V 1.2-expressing neurons.

AB - 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 K V 1.2, 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 K V 1.2-expressing neurons.

UR - http://www.scopus.com/inward/record.url?scp=84930937943&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84930937943&partnerID=8YFLogxK

U2 - 10.1038/ng.3239

DO - 10.1038/ng.3239

M3 - Article

C2 - 25751627

AN - SCOPUS:84930937943

VL - 47

SP - 393

EP - 399

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 4

ER -