Generic placeholder image

CNS & Neurological Disorders - Drug Targets


ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Review Article

Understanding Genotypes and Phenotypes of the Mutations in Voltage- Gated Sodium Channel α Subunits in Epilepsy

Author(s): Yijun Feng, Shuzhang Zhang, Zhiping Zhang, Jingkang Guo, Zhiyong Tan, Yudan Zhu*, Jie Tao* and Yong-Hua Ji*

Volume 18, Issue 4, 2019

Page: [266 - 272] Pages: 7

DOI: 10.2174/1871527317666181026164825

Price: $65


Background & Objective: Voltage-gated sodium channels (VGSCs) are responsible for the generation and propagation of action potentials in most excitable cells. In general, a VGSC consists of one pore-forming α subunit and two auxiliary β subunits. Genetic alterations in VGSCs genes, including both α and β subunits, are considered to be associated with epileptogenesis as well as seizures. This review aims to summarize the mutations in VGSC α subunits in epilepsy, particularly the pathophysiological and pharmacological properties of relevant VGSC mutants.

Conclusion: The review of epilepsy-associated VGSC α subunits mutants may not only contribute to the understanding of disease mechanism and genetic modifiers, but also provide potential theoretical targets for the precision and individualized medicine for epilepsy.

Keywords: Voltage-gated sodium channels, α subunits, mutation, epilepsy, seizures, pathophysiological.

Graphical Abstract
Radhakrishnan K. Challenges in the management of epilepsy in resource-poor countries. Nat Rev Neurol 2009; 5: 323-30.
Carrizosa Moog J, Kakooza-Mwesige A, Tan CT. Epilepsy in the tropics: Emerging etiologies. Seizure 2017; 44: 108-12.
Chen R, Spencer DC, Weston J, Nolan SJ. Transcranial magnetic stimulation for the treatment of epilepsy. Cochrane Database Syst Rev 2016.Cd011025
Ngugi AK, Kariuki SM, Bottomley C, Kleinschmidt I, Sander JW, Newton CR. Incidence of epilepsy: A systematic review and meta-analysis. Neurology 2011; 77: 1005-12.
Ngugi AK, Bottomley C, Kleinschmidt I, Sander JW, Newton CR. Estimation of the burden of active and life-time epilepsy: A meta-analytic approach. Epilepsia 2010; 51: 883-90.
Audenaert D, Claes L, Ceulemans B, Lofgren A, Van Broeckhoven C, De Jonghe P. A deletion in SCN1B is associated with febrile seizures and early-onset absence epilepsy. Neurology 2003; 61: 854-6.
Catterall WA. From ionic currents to molecular mechanisms: The structure and function of voltage-gated sodium channels. Neuron 2000; 26: 13-25.
Fozzard HA, Hanck DA. Structure and function of voltage-dependent sodium channels: Comparison of brain II and cardiac isoforms. Physiol Rev 1996; 76: 887-926.
Goldin AL, Barchi RL, Caldwell JH, et al. Nomenclature of voltage-gated sodium channels. Neuron 2000; 28: 365-8.
Goldin AL, Snutch T, Lubbert H, et al. Messenger RNA coding for only the alpha subunit of the rat brain Na channel is sufficient for expression of functional channels in Xenopus oocytes. Proc Natl Acad Sci USA 1986; 83: 7503-7.
Catterall WA, Goldin AL, Waxman SG. International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev 2005; 57: 397-409.
Sato C, Ueno Y, Asai K, et al. The voltage-sensitive sodium channel is a bell-shaped molecule with several cavities. Nature 2001; 409: 1047-51.
Stuhmer W, Conti F, Suzuki H, et al. Structural parts involved in activation and inactivation of the sodium channel. Nature 1989; 339: 597-603.
Bosmans F, Martin-Eauclaire MF, Swartz KJ. Deconstructing voltage sensor function and pharmacology in sodium channels. Nature 2008; 456: 202-8.
Payandeh J, Gamal El-Din TM, Scheuer T, Zheng N, Catterall WA. Crystal structure of a voltage-gated sodium channel in two potentially inactivated states. Nature 2012; 486: 135-9.
Vassilev PM, Scheuer T, Catterall WA. Identification of an intracellular peptide segment involved in sodium channel inactivation. Science 1988; 241: 1658-61.
Vassilev P, Scheuer T, Catterall WA. Inhibition of inactivation of single sodium channels by a site-directed antibody. Proc Natl Acad Sci USA 1989; 86: 8147-51.
Rohl CA, Boeckman FA, Baker C, Scheuer T, Catterall WA, Klevit RE. Solution structure of the sodium channel inactivation gate. Biochemistry 1999; 38: 855-61.
West JW, Patton DE, Scheuer T, Wang Y, Goldin AL, Catterall WA. A cluster of hydrophobic amino acid residues required for fast Na(+)-channel inactivation. Proc Natl Acad Sci USA 1992; 89: 10910-4.
Catterall WA. Cellular and molecular biology of voltage-gated sodium channels. Physiol Rev 1992; 72: S15-48.
Shen H, Zhou Q, Pan X, Li Z, Wu J, Yan N. Structure of a eukaryotic voltage-gated sodium channel at near-atomic resolution. Science 2017; 355.
Meng H, Xu HQ, Yu L, et al. The SCN1A mutation database: Updating information and analysis of the relationships among genotype, functional alteration, and phenotype. Hum Mutat 2015; 36: 573-80.
Sawyer NT, Helvig AW, Makinson CD, Decker MJ, Neigh GN, Escayg A. Scn1a dysfunction alters behavior but not the effect of stress on seizure response. Genes Brain Behav 2016; 15: 335-47.
Mantegazza M, Gambardella A, Rusconi R, et al. Identification of an Nav1.1 sodium channel (SCN1A) loss-of-function mutation associated with familial simple febrile seizures. Proc Natl Acad Sci USA 2005; 102: 18177-82.
Yu FH, Mantegazza M, Westenbroek RE, et al. Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nat Neurosci 2006; 9: 1142-9.
Oakley JC, Kalume F, Yu FH, Scheuer T, Catterall WA. Temperature- and age-dependent seizures in a mouse model of severe myoclonic epilepsy in infancy. Proc Natl Acad Sci USA 2009; 106: 3994-9.
Tang B, Dutt K, Papale L, et al. A BAC transgenic mouse model reveals neuron subtype-specific effects of a Generalized Epilepsy with Febrile Seizures Plus (GEFS+) mutation. Neurobiol Dis 2009; 35: 91-102.
Martin MS, Dutt K, Papale LA, et al. Altered function of the SCN1A voltage-gated sodium channel leads to gamma-aminobutyric acid-ergic (GABAergic) interneuron abnormalities. J Biol Chem 2010; 285: 9823-34.
Ceulemans BP, Claes LR, Lagae LG. Clinical correlations of mutations in the SCN1A gene: From febrile seizures to severe myoclonic epilepsy in infancy. Pediatr Neurol 2004; 30: 236-43.
Catterall WA, Kalume F, Oakley JC. NaV1.1 channels and epilepsy. J Physiol 2010; 588: 1849-59.
Liao Y, Deprez L, Maljevic S, et al. Molecular correlates of age-dependent seizures in an inherited neonatal-infantile epilepsy. Brain 2010; 133: 1403-14.
Heron SE, Crossland KM, Andermann E, et al. Sodium-channel defects in benign familial neonatal-infantile seizures. Lancet 2002; 360: 851-2.
Misra SN, Kahlig KM, George AL Jr. Impaired NaV1.2 function and reduced cell surface expression in benign familial neonatal-infantile seizures. Epilepsia 2008; 49: 1535-45.
Boiko T, Van Wart A, Caldwell JH, Levinson SR, Trimmer JS, Matthews G. Functional specialization of the axon initial segment by isoform-specific sodium channel targeting. J Neurosci 2003; 23: 2306-13.
Lauxmann S, Boutry-Kryza N, Rivier C, et al. An SCN2A mutation in a family with infantile seizures from Madagascar reveals an increased subthreshold Na(+) current. Epilepsia 2013; 54: e117-21.
Dilena R, Striano P, Gennaro E, et al. Efficacy of sodium channel blockers in SCN2A early infantile epileptic encephalopathy. Brain Dev 2017; 39: 345-8.
Gazina EV, Leaw BT, Richards KL, et al. ‘Neonatal’ Nav1.2 reduces neuronal excitability and affects seizure susceptibility and behaviour. Hum Mol Genet 2015; 24: 1457-68.
Yu FH, Catterall WA. Overview of the voltage-gated sodium channel family. Genome Biol 2003; 4: 207.
Whitaker WR, Faull RL, Waldvogel HJ, Plumpton CJ, Emson PC, Clare JJ. Comparative distribution of voltage-gated sodium channel proteins in human brain. Brain Res Mol Brain Res 2001; 88: 37-53.
Holland KD, Kearney JA, Glauser TA, et al. Mutation of sodium channel SCN3A in a patient with cryptogenic pediatric partial epilepsy. Neurosci Lett 2008; 433: 65-70.
Estacion M, Gasser A, Dib-Hajj SD, Waxman SG. A sodium channel mutation linked to epilepsy increases ramp and persistent current of Nav1.3 and induces hyperexcitability in hippocampal neurons. Exp Neurol 2010; 224: 362-8.
Vanoye CG, Gurnett CA, Holland KD, George AL Jr, Kearney JA. Novel SCN3A variants associated with focal epilepsy in children. Neurobiol Dis 2014; 62: 313-22.
Lamar T, Vanoye CG, Calhoun J, et al. SCN3A deficiency associated with increased seizure susceptibility. Neurobiol Dis 2017; 102: 38-48.
Chen YJ, Shi YW, Xu HQ, et al. Electrophysiological Differences between the Same Pore Region Mutation in SCN1A and SCN3A. Mol Neurobiol 2015; 51: 1263-70.
Blumenfeld H, Lampert A, Klein JP, et al. Role of hippocampal sodium channel Nav1.6 in kindling epileptogenesis. Epilepsia 2009; 50: 44-55.
Boiko T, Rasband MN, Levinson SR, et al. Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon. Neuron 2001; 30: 91-104.
Veeramah KR, O’Brien JE, Meisler MH, et al. De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. Am J Hum Genet 2012; 90: 502-10.
Meisler MH, Helman G, Hammer MF, et al. SCN8A encephalopathy: Research progress and prospects. Epilepsia 2016; 57: 1027-35.
Papale LA, Beyer B, Jones JM, et al. Heterozygous mutations of the voltage-gated sodium channel SCN8A are associated with spike-wave discharges and absence epilepsy in mice. Hum Mol Genet 2009; 18: 1633-41.
Martin MS, Tang B, Papale LA, Yu FH, Catterall WA, Escayg A. The voltage-gated sodium channel Scn8a is a genetic modifier of severe myoclonic epilepsy of infancy. Hum Mol Genet 2007; 16: 2892-9.
Butler KM, da Silva C, Shafir Y, et al. De novo and inherited SCN8A epilepsy mutations detected by gene panel analysis. Epilepsy Res 2017; 129: 17-25.
Makinson CD, Tanaka BS, Sorokin JM, et al. Regulation of Thalamic and Cortical Network Synchrony by Scn8a Neuron 2017; 93: 1165-1179 e6.
Toledo-Aral JJ, Moss BL, He ZJ, et al. Identification of PN1, a predominant voltage-dependent sodium channel expressed principally in peripheral neurons. Proc Natl Acad Sci USA 1997; 94: 1527-32.
Rush AM, Dib-Hajj SD, Liu S, Cummins TR, Black JA, Waxman SG. A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc Natl Acad Sci USA 2006; 103: 8245-50.
Ahn HS, Black JA, Zhao P, Tyrrell L, Waxman SG, Dib-Hajj SD. Nav1.7 is the predominant sodium channel in rodent olfactory sensory neurons. Mol Pain 2011; 7: 32.
Weiss J, Pyrski M, Jacobi E, et al. Loss-of-function mutations in sodium channel Nav1.7 cause anosmia. Nature 2011; 472: 186-90.
Mechaly I, Scamps F, Chabbert C, Sans A, Valmier J. Molecular diversity of voltage-gated sodium channel alpha subunits expressed in neuronal and non-neuronal excitable cells. Neuroscience 2005; 130: 389-96.
Singh NA, Pappas C, Dahle EJ, et al. A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome. PLoS Genet 2009; 5e1000649
Doty CN. SCN9A: Another sodium channel excited to play a role in human epilepsies. Clin Genet 2010; 77: 326-8.
Merritt HH, Putnam TJ. Landmark article Sept 17, 1938: Sodium diphenyl hydantoinate in the treatment of convulsive disorders. By H. Houston Merritt and Tracy J Putnam Jama 1984; 251: 1062-7.
Yang Y, Dib-Hajj SD, Zhang J, et al. Structural modelling and mutant cycle analysis predict pharmacoresponsiveness of a Na(V)1.7 mutant channel. Nat Commun 2012; 3: 1186.
Hebeisen S, Pires N, Loureiro AI, et al. Eslicarbazepine and the enhancement of slow inactivation of voltage-gated sodium channels: A comparison with carbamazepine, oxcarbazepine and lacosamide. Neuropharmacology 2015; 89: 122-35.
Booker SA, Pires N, Cobb S, Soares-da-Silva P, Vida I. Carbamazepine and oxcarbazepine, but not eslicarbazepine, enhance excitatory synaptic transmission onto hippocampal CA1 pyramidal cells through an antagonist action at adenosine A1 receptors. Neuropharmacology 2015; 93: 103-15.
Rogawski MA, Loscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci 2004; 5: 553-64.
Mantegazza M, Curia G, Biagini G, Ragsdale DS, Avoli M. Voltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders. Lancet Neurol 2010; 9: 413-24.
White HS, Smith MD, Wilcox KS. Mechanisms of action of antiepileptic drugs. Int Rev Neurobiol 2007; 81: 85-110.
Errington AC, Stohr T, Heers C, Lees G. The investigational anticonvulsant lacosamide selectively enhances slow inactivation of voltage-gated sodium channels. Mol Pharmacol 2008; 73: 157-69.
Gil-Nagel A, Elger C, Ben-Menachem E, et al. Efficacy and safety of eslicarbazepine acetate as add-on treatment in patients with focal-onset seizures: Integrated analysis of pooled data from double-blind phase III clinical studies. Epilepsia 2013; 54: 98-107.
Sake JK, Hebert D, Isojarvi J, et al. A pooled analysis of lacosamide clinical trial data grouped by mechanism of action of concomitant antiepileptic drugs. CNS Drugs 2010; 24: 1055-68.
Zhao R, Zhang XY, Yang J, et al. Anticonvulsant effect of BmK IT2, a sodium channel-specific neurotoxin, in rat models of epilepsy. Br J Pharmacol 2008; 154: 1116-24.
Zhao R, Weng CC, Feng Q, et al. Anticonvulsant activity of BmK AS, a sodium channel site 4-specific modulator. Epilepsy Behav 2011; 20: 267-76.
Xiang J, Wen F, Zhang L, Zhou Y. FOXD3 inhibits SCN2A gene transcription in intractable epilepsy cell models. Exp Neurol 2017.
Liu S, Zheng P. Altered PKA modulation in the Na(v)1.1 epilepsy variant I1656M. J Neurophysiol 2013; 110: 2090-8.
Liu Y, Lai S, Ma W, et al. CDYL suppresses epileptogenesis in mice through repression of axonal Nav1.6 sodium channel expression. Nat Commun 2017; 8: 355.

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy