학술논문
Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes.
Document Type
Academic Journal
Author
Witkowski G; First Department of Neurology, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland.; Military Institute of Aviation Medicine, Krasinskiego 54/56, 01-755 Warsaw, Poland.; Szulczyk B; Chair and Department of Pharmacotherapy and Pharmaceutical Care, Faculty of Pharmacy, The Medical University of Warsaw, Banacha 1b, 02-097 Warsaw, Poland.; Nurowska E; Chair and Department of Pharmacotherapy and Pharmaceutical Care, Faculty of Pharmacy, The Medical University of Warsaw, Banacha 1b, 02-097 Warsaw, Poland.; Jurek M; Department of Medical Genetics, Institute of Mother and Child, Kasprzaka 17a, 01-211 Warsaw, Poland.; Pasierski M; Chair and Department of Pharmacotherapy and Pharmaceutical Care, Faculty of Pharmacy, The Medical University of Warsaw, Banacha 1b, 02-097 Warsaw, Poland.; Lipiec A; Clinic of Pediatric Neurology, Institute of Mother and Child, Kasprzaka 17a, 01-211 Warsaw, Poland.; Charzewska A; Department of Medical Genetics, Institute of Mother and Child, Kasprzaka 17a, 01-211 Warsaw, Poland.; Dawidziuk M; Department of Medical Genetics, Institute of Mother and Child, Kasprzaka 17a, 01-211 Warsaw, Poland.; Milewski M; Department of Medical Genetics, Institute of Mother and Child, Kasprzaka 17a, 01-211 Warsaw, Poland.; Owsiak S; First Department of Neurology, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland.; Rola R; Military Institute of Aviation Medicine, Krasinskiego 54/56, 01-755 Warsaw, Poland.; Sienkiewicz Jarosz H; First Department of Neurology, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland.; Hoffman-Zacharska D; Department of Medical Genetics, Institute of Mother and Child, Kasprzaka 17a, 01-211 Warsaw, Poland.; Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Miecznikowa 1, 02-096 Warsaw, Poland.
Source
Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
Subject
Language
English
Abstract
Mutations of the SCN1A gene, which encodes the voltage-dependent Na + channel's α subunit, are associated with diverse epileptic syndromes ranging in severity, even intra-family, from febrile seizures to epileptic encephalopathy. The underlying cause of this variability is unknown, suggesting the involvement of additional factors. The aim of our study was to describe the properties of mutated channels and investigate genetic causes for clinical syndromes' variability in the family of five SCN1A gene p.Arg1596Cys mutation carriers. The analysis of additional genetic factors influencing SCN1A -associated phenotypes was conducted through exome sequencing (WES). To assess the impact of mutations, we used patch clamp analysis of mutated channels expressed in HEK cells and in vivo neural excitability studies (NESs). In cells expressing the mutant channel, sodium currents were reduced. NESs indicated increased excitability of peripheral motor neurons in mutation carriers. WES showed the absence of non-SCA1 pathogenic variants that could be causative of disease in the family. Variants of uncertain significance in three genes, as potential modifiers of the most severe phenotype, were identified. The p.Arg1596Cys substitution inhibits channel function, affecting steady-state inactivation kinetics. Its clinical manifestations involve not only epileptic symptoms but also increased excitability of peripheral motor fibers. The role of Nav1.1 in excitatory neurons cannot be ruled out as a significant factor of the clinical phenotype.