Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia

Background Since 1994, over 50 families affected by the episodic ataxia type 1 disease spectrum have been described with mutations in KCNA1, encoding the voltage-gated K+ channel subunit Kv1.1. All of these mutations are either transmitted in an autosomal-dominant mode or found as de novo events. Me...

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Autores: Verdura E, Fons C, Schlüter A, Ruiz M, Fourcade S, Casasnovas C, Castellano A, Pujol A
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Fundació Sant Joan de Déu
Repositorio:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
OAI Identifier:oai:fsjd.fundanetsuite.com:p16713
Acceso en línea:https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=16713
Access Level:acceso abierto
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spelling Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesiaVerdura EFons CSchlüter ARuiz MFourcade SCasasnovas CCastellano APujol ABackground Since 1994, over 50 families affected by the episodic ataxia type 1 disease spectrum have been described with mutations in KCNA1, encoding the voltage-gated K+ channel subunit Kv1.1. All of these mutations are either transmitted in an autosomal-dominant mode or found as de novo events. Methods A patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy was sequenced by whole-exome sequencing (WES). A candidate variant was tested using cellular assays and patch-clamp recordings. Results WES revealed a homozygous variant (p.Val368Leu) in KCNA1, involving a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG). Functional analysis showed that mutant protein alone failed to produce functional channels in homozygous state, while coexpression with wild-type produced no effects on K+ currents, similar to wild-type protein alone. Treatment with oxcarbazepine, a sodium channel blocker, proved effective in controlling seizures. Conclusion This newly identified variant is the first to be reported to act in a recessive mode of inheritance in KCNA1. These findings serve as a cautionary tale for the diagnosis of channelopathies, in which an unreported phenotypic presentation or mode of inheritance for the variant of interest can hinder the identification of causative variants and adequate treatment choice.BMJ PUBLISHING GROUP2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=16713JOURNAL OF MEDICAL GENETICSISSN: 00222593ISSNe: 14686244reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déuinstname:Fundació Sant Joan de DéuInglésinfo:eu-repo/semantics/openAccessoai:fsjd.fundanetsuite.com:p167132026-05-27T12:37:41Z
dc.title.none.fl_str_mv Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia
title Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia
spellingShingle Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia
Verdura E
title_short Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia
title_full Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia
title_fullStr Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia
title_full_unstemmed Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia
title_sort Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia
dc.creator.none.fl_str_mv Verdura E
Fons C
Schlüter A
Ruiz M
Fourcade S
Casasnovas C
Castellano A
Pujol A
author Verdura E
author_facet Verdura E
Fons C
Schlüter A
Ruiz M
Fourcade S
Casasnovas C
Castellano A
Pujol A
author_role author
author2 Fons C
Schlüter A
Ruiz M
Fourcade S
Casasnovas C
Castellano A
Pujol A
author2_role author
author
author
author
author
author
author
description Background Since 1994, over 50 families affected by the episodic ataxia type 1 disease spectrum have been described with mutations in KCNA1, encoding the voltage-gated K+ channel subunit Kv1.1. All of these mutations are either transmitted in an autosomal-dominant mode or found as de novo events. Methods A patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy was sequenced by whole-exome sequencing (WES). A candidate variant was tested using cellular assays and patch-clamp recordings. Results WES revealed a homozygous variant (p.Val368Leu) in KCNA1, involving a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG). Functional analysis showed that mutant protein alone failed to produce functional channels in homozygous state, while coexpression with wild-type produced no effects on K+ currents, similar to wild-type protein alone. Treatment with oxcarbazepine, a sodium channel blocker, proved effective in controlling seizures. Conclusion This newly identified variant is the first to be reported to act in a recessive mode of inheritance in KCNA1. These findings serve as a cautionary tale for the diagnosis of channelopathies, in which an unreported phenotypic presentation or mode of inheritance for the variant of interest can hinder the identification of causative variants and adequate treatment choice.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=16713
url https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=16713
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv BMJ PUBLISHING GROUP
publisher.none.fl_str_mv BMJ PUBLISHING GROUP
dc.source.none.fl_str_mv JOURNAL OF MEDICAL GENETICS
ISSN: 00222593
ISSNe: 14686244
reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
instname:Fundació Sant Joan de Déu
instname_str Fundació Sant Joan de Déu
reponame_str r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
collection r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
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