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Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants

BACKGROUND AND OBJECTIVES: KCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyze the clini...

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Autores principales: Schwarz, Niklas, Seiffert, Simone, Pendziwiat, Manuela, Rademacher, Annika Verena, 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, Phillip S., Rosenow, Felix, Rothschild, Annick, Scudieri, Paolo, Striano, Pasquale, Tinuper, Paolo, Tanteles, George A., Vetro, Annalisa, Zahnert, Felix, Goldberg, Ethan M., Zara, Federico, Lal, Dennis, May, Patrick, Muhle, Hiltrud, Helbig, Ingo, Weber, Yvonne
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9162046/
https://www.ncbi.nlm.nih.gov/pubmed/35314505
http://dx.doi.org/10.1212/WNL.0000000000200660
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author Schwarz, Niklas
Seiffert, Simone
Pendziwiat, Manuela
Rademacher, Annika Verena
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, Phillip S.
Rosenow, Felix
Rothschild, Annick
Scudieri, Paolo
Striano, Pasquale
Tinuper, Paolo
Tanteles, George A.
Vetro, Annalisa
Zahnert, Felix
Goldberg, Ethan M.
Zara, Federico
Lal, Dennis
May, Patrick
Muhle, Hiltrud
Helbig, Ingo
Weber, Yvonne
author_facet Schwarz, Niklas
Seiffert, Simone
Pendziwiat, Manuela
Rademacher, Annika Verena
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, Phillip S.
Rosenow, Felix
Rothschild, Annick
Scudieri, Paolo
Striano, Pasquale
Tinuper, Paolo
Tanteles, George A.
Vetro, Annalisa
Zahnert, Felix
Goldberg, Ethan M.
Zara, Federico
Lal, Dennis
May, Patrick
Muhle, Hiltrud
Helbig, Ingo
Weber, Yvonne
author_sort Schwarz, Niklas
collection PubMed
description BACKGROUND AND OBJECTIVES: KCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyze the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants. METHODS: Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in Xenopus laevis oocytes. RESULTS: We identified novel KCNC2 variants in 18 patients with various forms of epilepsy, including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy, focal epilepsy, and myoclonic-atonic epilepsy. Of the 18 variants, 10 were de novo and 8 were classified as modifying variants. Eight drug-responsive patients became seizure-free using valproic acid as monotherapy or in combination, including severe DEE cases. Functional analysis of 4 variants demonstrated gain of function in 3 severely affected DEE cases and loss of function in 1 case with a milder phenotype (GGE) as the underlying pathomechanisms. DISCUSSION: These findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of K(V)3.2 in the regulation of brain excitability.
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spelling pubmed-91620462022-06-02 Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants Schwarz, Niklas Seiffert, Simone Pendziwiat, Manuela Rademacher, Annika Verena 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, Phillip S. Rosenow, Felix Rothschild, Annick Scudieri, Paolo Striano, Pasquale Tinuper, Paolo Tanteles, George A. Vetro, Annalisa Zahnert, Felix Goldberg, Ethan M. Zara, Federico Lal, Dennis May, Patrick Muhle, Hiltrud Helbig, Ingo Weber, Yvonne Neurology Research Article BACKGROUND AND OBJECTIVES: KCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyze the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants. METHODS: Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in Xenopus laevis oocytes. RESULTS: We identified novel KCNC2 variants in 18 patients with various forms of epilepsy, including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy, focal epilepsy, and myoclonic-atonic epilepsy. Of the 18 variants, 10 were de novo and 8 were classified as modifying variants. Eight drug-responsive patients became seizure-free using valproic acid as monotherapy or in combination, including severe DEE cases. Functional analysis of 4 variants demonstrated gain of function in 3 severely affected DEE cases and loss of function in 1 case with a milder phenotype (GGE) as the underlying pathomechanisms. DISCUSSION: These findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of K(V)3.2 in the regulation of brain excitability. Lippincott Williams & Wilkins 2022-05-17 /pmc/articles/PMC9162046/ /pubmed/35314505 http://dx.doi.org/10.1212/WNL.0000000000200660 Text en Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
spellingShingle Research Article
Schwarz, Niklas
Seiffert, Simone
Pendziwiat, Manuela
Rademacher, Annika Verena
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, Phillip S.
Rosenow, Felix
Rothschild, Annick
Scudieri, Paolo
Striano, Pasquale
Tinuper, Paolo
Tanteles, George A.
Vetro, Annalisa
Zahnert, Felix
Goldberg, Ethan M.
Zara, Federico
Lal, Dennis
May, Patrick
Muhle, Hiltrud
Helbig, Ingo
Weber, Yvonne
Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants
title Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants
title_full Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants
title_fullStr Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants
title_full_unstemmed Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants
title_short Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants
title_sort spectrum of phenotypic, genetic, and functional characteristics in patients with epilepsy with kcnc2 pathogenic variants
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9162046/
https://www.ncbi.nlm.nih.gov/pubmed/35314505
http://dx.doi.org/10.1212/WNL.0000000000200660
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