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.

Detalhes bibliográficos
Autores: Verdura, Edgard, Font, Carme, Schlüter, Agatha, Ruiz, Montserrat, Fourcade, Stéphane, Casasnovas, Carlos, Castellano, Antonio, Pujol, Aurora
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/203895
Acesso em linha:http://hdl.handle.net/10261/203895
Access Level:acceso abierto
id ES_19cc8025f554210c3d4bd35cb3bb35be
oai_identifier_str oai:digital.csic.es:10261/203895
network_acronym_str ES
network_name_str España
repository_id_str
spelling Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesiaVerdura, EdgardFont, CarmeSchlüter, AgathaRuiz, MontserratFourcade, StéphaneCasasnovas, CarlosCastellano, AntonioPujol, Aurora[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.This study was supported by the Centre for Biomedical Research on Rare Diseases (CIBERER) (ACCI14-759), the URDCat program (PERIS SLT002/16/00174), the Hesperia Foundation and the Secretariat for Universities and Research of the Ministry of Business and Knowledge of the Government of Catalonia (2017SGR1206) to AP and Instituto de Salud Carlos III (PI14/00581) (cofunded by European Regional Development Fund. ERDF, a way to build Europe) and la Marató de TV3 (345/C/2014) to CC and AP. EV was funded by a grant from the Ministerio de Economia, Industria y Competividad (Juan de la Cierva programme FJCI-2016-28811). SF was funded by the Instituto de Salud Carlos III (Miguel Servet programme CPII16/00016, cofunded by European Social Fund. ESF investing in your future) and MR was funded by CIBERER.Peer reviewedBMJ Publishing GroupCentro de Investigación Biomédica en Red Enfermedades Raras (España)Generalitat de CatalunyaHesperia FoundationInstituto de Salud Carlos IIIEuropean CommissionFundació La Marató de TV3Ministerio de Economía y Competitividad (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202020202020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/203895reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/FJCI-2016-28811http://dx.doi.org/10.1136/jmedgenet-2019-106373Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2038952026-05-22T06:33:51Z
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, Edgard
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, Edgard
Font, Carme
Schlüter, Agatha
Ruiz, Montserrat
Fourcade, Stéphane
Casasnovas, Carlos
Castellano, Antonio
Pujol, Aurora
author Verdura, Edgard
author_facet Verdura, Edgard
Font, Carme
Schlüter, Agatha
Ruiz, Montserrat
Fourcade, Stéphane
Casasnovas, Carlos
Castellano, Antonio
Pujol, Aurora
author_role author
author2 Font, Carme
Schlüter, Agatha
Ruiz, Montserrat
Fourcade, Stéphane
Casasnovas, Carlos
Castellano, Antonio
Pujol, Aurora
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Centro de Investigación Biomédica en Red Enfermedades Raras (España)
Generalitat de Catalunya
Hesperia Foundation
Instituto de Salud Carlos III
European Commission
Fundació La Marató de TV3
Ministerio de Economía y Competitividad (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
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.
publishDate 2020
dc.date.none.fl_str_mv 2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/203895
url http://hdl.handle.net/10261/203895
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/FJCI-2016-28811
http://dx.doi.org/10.1136/jmedgenet-2019-106373
Sí
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 reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869404068145790976
score 15.198674

Registos relacionados