Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia
Por:
Verdura E, Fons-Estupina C, Schlüter A, Ruiz M, Fourcade S, Casasnovas C, Castellano A and Pujol A
Publicada:
1 feb 2020
Ahead of Print:
5 oct 2019
Resumen:
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.
Filiaciones:
Verdura E:
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalunya, Spain
Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
Fons-Estupina C:
Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
Pediatric Neurology Department, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Catalunya, Spain
Sant Joan de Déu Research Institute (IRSJD), Esplugues de Llobregat, Barcelona, Catalunya, Spain
Schlüter A:
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalunya, Spain
Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
Ruiz M:
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalunya, Spain
Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
Fourcade S:
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalunya, Spain
Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
Casasnovas C:
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalunya, Spain
Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
Neuromuscular Unit, Neurology Department, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Catalunya, Spain
Castellano A:
Institute of Biomedicine of Seville (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
Medical Physiology and Biophysics Departament, Universidad de Sevilla, Sevilla, Spain
Pujol A:
Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Catalunya, Spain
Green Published, hybrid
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