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Heterozygous variants in KCNC2 cause a broad spectrum of epilepsy phenotypes associated with characteristic functional alterations 2021.05.21.21257099
Schwarz, Niklas; Seiffert, Simone; Pendziwiat, Manuela et al.
2021
 

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Keywords :
KCNC2; epilepsy; potassium channel
Abstract :
[en] Background KCNC2 encodes a member of the shaw-related voltage-gated potassium channel family (KV3.2), which are important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain.Methods Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic and functional analysis. The cases were referred through clinical and research collaborations in our study. Four de novo variants were examined electrophysiologically in Xenopus laevis oocytes.Results We identified novel KCNC2 variants in 27 patients with various forms of epilepsy. Functional analysis demonstrated gain-of-function in severe and loss-of-function in milder phenotypes as the underlying pathomechanisms with specific response to valproic acid.Conclusion These findings implicate KCNC2 as a novel causative gene for epilepsy emphasizing the critical role of KV3.2 in the regulation of brain excitability with an interesting genotype-phenotype correlation and a potential concept for precision medicine.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Disciplines :
Genetics & genetic processes
Neurology
Author, co-author :
Schwarz, Niklas
Seiffert, Simone
Pendziwiat, Manuela
Rademacher, Annika
Brünger, Tobias
Hedrich, Ulrike B. S.
Augustijn, Paul B.
Baier, Hartmut
Bayat, Allan
Bisulli, Francesca
Buono, Russell J.
Bruria, Ben Zeev
Doyle, Michael G.
Guerrini, Renzo
Heimer, Gali
Iacomino, Michele
Kearney, Hugh
Klein, Karl Martin
Kousiappa, Ioanna
Kunz, Wolfram S.
Lerche, Holger
Licchetta, Laura
Lohmann, Ebba
Minardi, Raffaella
McDonald, Marie
Montgomery, Sarah
Mulahasanovic, Lejla
Oegema, Renske
Ortal, Barel
Papacostas, Savvas S.
Ragona, Francesca
Granata, Tiziana
Reif, Philipp S.
Rosenow, Felix
Rothschild, Annick
Scudieri, Paolo
Striano, Pasquale
Tinuper, Paolo
Tanteles, George A.
Vetro, Annalisa
Zahnert, Felix
Zara, Federico
Lal, Dennis
May, Patrick  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
Muhle, Hiltrud
Helbig, Ingo
Weber, Yvonne
More authors (37 more) Less
Language :
English
Title :
Heterozygous variants in KCNC2 cause a broad spectrum of epilepsy phenotypes associated with characteristic functional alterations 2021.05.21.21257099
Publication date :
21 May 2021
Publisher :
Cold Spring Harbor Laboratory Press
Focus Area :
Systems Biomedicine
FnR Project :
FNR11583046 - Epileptogenesis Of Genetic Epilepsies, 2017 (01/04/2018-30/06/2021) - Roland Krause
Funders :
BMBF Treat-ION grant (01GM1907).
Available on ORBilu :
since 26 May 2021

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