Syrbe, Steffen, Hedrich, Ulrike B. S., Riesch, Erik, Djemie, Tania, Mueller, Stephan, Moller, Rikke S., Maher, Bridget ORCID: 0000-0002-9735-0845, Hernandez-Hernandez, Laura, Synofzik, Matthis ORCID: 0000-0002-2280-7273, Caglayan, Hande S., Arslan, Mutluay, Serratosa, Jose M., Nothnagel, Michael ORCID: 0000-0001-8305-7114, May, Patrick ORCID: 0000-0001-8698-3770, Krause, Roland ORCID: 0000-0001-9938-7126, Loeffler, Heidrun, Detert, Katja, Dorn, Thomas, Vogt, Heinrich, Kraemer, Guenter, Schoels, Ludger, Mullis, Primus E., Linnankivi, Tarja, Lehesjoki, Anna-Elina, Sterbova, Katalin, Craiu, Dana C., Hoffman-Zacharska, Dorota ORCID: 0000-0001-7367-512X, Korff, Christian M., Weber, Yvonne G., Steinlin, Maja, Gallati, Sabina, Bertsche, Astrid ORCID: 0000-0003-2832-0156, Bernhard, Matthias K., Merkenschlager, Andreas, Kiess, Wieland, Gonzalez, Michael, Zuechner, Stephan, Palotie, Aarno, Suls, Arvid ORCID: 0000-0003-0328-198X, De Jonghe, Peter, Helbig, Ingo ORCID: 0000-0001-8486-0558, Biskup, Saskia, Wolff, Markus ORCID: 0000-0001-5640-0888, Maljevic, Snezana ORCID: 0000-0003-1876-5872, Schule, Rebecca ORCID: 0000-0002-7781-2766, Sisodiya, Sanjay M., Weckhuysen, Sarah ORCID: 0000-0003-2878-1147, Lerche, Holger and Lemke, Johannes R. (2015). De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. Nature Genet., 47 (4). S. 393 - 402. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1546-1718

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Abstract

Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and other neurodevelopmental features(1-6). 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Syrbe, SteffenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hedrich, Ulrike B. S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riesch, ErikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Djemie, TaniaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moller, Rikke S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maher, BridgetUNSPECIFIEDorcid.org/0000-0002-9735-0845UNSPECIFIED
Hernandez-Hernandez, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Synofzik, MatthisUNSPECIFIEDorcid.org/0000-0002-2280-7273UNSPECIFIED
Caglayan, Hande S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arslan, MutluayUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Serratosa, Jose M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nothnagel, MichaelUNSPECIFIEDorcid.org/0000-0001-8305-7114UNSPECIFIED
May, PatrickUNSPECIFIEDorcid.org/0000-0001-8698-3770UNSPECIFIED
Krause, RolandUNSPECIFIEDorcid.org/0000-0001-9938-7126UNSPECIFIED
Loeffler, HeidrunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Detert, KatjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dorn, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vogt, HeinrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kraemer, GuenterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schoels, LudgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mullis, Primus E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Linnankivi, TarjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lehesjoki, Anna-ElinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sterbova, KatalinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Craiu, Dana C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoffman-Zacharska, DorotaUNSPECIFIEDorcid.org/0000-0001-7367-512XUNSPECIFIED
Korff, Christian M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weber, Yvonne G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steinlin, MajaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gallati, SabinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bertsche, AstridUNSPECIFIEDorcid.org/0000-0003-2832-0156UNSPECIFIED
Bernhard, Matthias K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merkenschlager, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kiess, WielandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gonzalez, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zuechner, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Palotie, AarnoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Suls, ArvidUNSPECIFIEDorcid.org/0000-0003-0328-198XUNSPECIFIED
De Jonghe, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Helbig, IngoUNSPECIFIEDorcid.org/0000-0001-8486-0558UNSPECIFIED
Biskup, SaskiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolff, MarkusUNSPECIFIEDorcid.org/0000-0001-5640-0888UNSPECIFIED
Maljevic, SnezanaUNSPECIFIEDorcid.org/0000-0003-1876-5872UNSPECIFIED
Schule, RebeccaUNSPECIFIEDorcid.org/0000-0002-7781-2766UNSPECIFIED
Sisodiya, Sanjay M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weckhuysen, SarahUNSPECIFIEDorcid.org/0000-0003-2878-1147UNSPECIFIED
Lerche, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lemke, Johannes R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-409267
DOI: 10.1038/ng.3239
Journal or Publication Title: Nature Genet.
Volume: 47
Number: 4
Page Range: S. 393 - 402
Date: 2015
Publisher: NATURE PUBLISHING GROUP
Place of Publication: NEW YORK
ISSN: 1546-1718
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
POTASSIUM CHANNEL GENE; MYOCLONIC EPILEPSY; KCNQ2 MUTATIONS; VOLTAGE SENSOR; ION CHANNELS; K+ CHANNEL; ATAXIA; KV1.2; MYOKYMIA; PROTEINSMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/40926

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