Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes

Witkowski, Grzegorz; Szulczyk, Bartlomiej; Nurowska, Ewa; Jurek, Marta; Pasierski, Michal; Lipiec, Agata; Charzewska, Agnieszka; Dawidziuk, Mateusz; Milewski, Michal; Owsiak, Szymon; Rola, Rafal; Sienkiewicz Jarosz, Halina; Hoffman-Zacharska, Dorota

doi:10.3390/ijms25031745

Open AccessArticle

Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes

by

Grzegorz Witkowski

^1,2,*,

Bartlomiej Szulczyk

³,

Ewa Nurowska

³,

Marta Jurek

⁴,

Michal Pasierski

³,

Agata Lipiec

⁵,

Agnieszka Charzewska

⁴

,

Mateusz Dawidziuk

⁴

,

Michal Milewski

⁴

,

Szymon Owsiak

¹,

Rafal Rola

²,

Halina Sienkiewicz Jarosz

¹ and

Dorota Hoffman-Zacharska

^4,6

¹

First Department of Neurology, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland

²

Military Institute of Aviation Medicine, Krasinskiego 54/56, 01-755 Warsaw, Poland

³

Chair and Department of Pharmacotherapy and Pharmaceutical Care, Faculty of Pharmacy, The Medical University of Warsaw, Banacha 1b, 02-097 Warsaw, Poland

⁴

Department of Medical Genetics, Institute of Mother and Child, Kasprzaka 17a, 01-211 Warsaw, Poland

⁵

Clinic of Pediatric Neurology, Institute of Mother and Child, Kasprzaka 17a, 01-211 Warsaw, Poland

⁶

Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Miecznikowa 1, 02-096 Warsaw, Poland

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2024, 25(3), 1745; https://doi.org/10.3390/ijms25031745

Submission received: 29 December 2023 / Revised: 20 January 2024 / Accepted: 25 January 2024 / Published: 1 February 2024

(This article belongs to the Special Issue Epilepsy: From Molecular Basis to Therapy)

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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.

Keywords: voltage gated sodium channels; SCN1A mutation; epilepsy; patch clamp; nerve excitability study

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MDPI and ACS Style

Witkowski, G.; Szulczyk, B.; Nurowska, E.; Jurek, M.; Pasierski, M.; Lipiec, A.; Charzewska, A.; Dawidziuk, M.; Milewski, M.; Owsiak, S.; et al. Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes. Int. J. Mol. Sci. 2024, 25, 1745. https://doi.org/10.3390/ijms25031745

AMA Style

Witkowski G, Szulczyk B, Nurowska E, Jurek M, Pasierski M, Lipiec A, Charzewska A, Dawidziuk M, Milewski M, Owsiak S, et al. Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes. International Journal of Molecular Sciences. 2024; 25(3):1745. https://doi.org/10.3390/ijms25031745

Chicago/Turabian Style

Witkowski, Grzegorz, Bartlomiej Szulczyk, Ewa Nurowska, Marta Jurek, Michal Pasierski, Agata Lipiec, Agnieszka Charzewska, Mateusz Dawidziuk, Michal Milewski, Szymon Owsiak, and et al. 2024. "Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes" International Journal of Molecular Sciences 25, no. 3: 1745. https://doi.org/10.3390/ijms25031745

APA Style

Witkowski, G., Szulczyk, B., Nurowska, E., Jurek, M., Pasierski, M., Lipiec, A., Charzewska, A., Dawidziuk, M., Milewski, M., Owsiak, S., Rola, R., Sienkiewicz Jarosz, H., & Hoffman-Zacharska, D. (2024). Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes. International Journal of Molecular Sciences, 25(3), 1745. https://doi.org/10.3390/ijms25031745

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Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes

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