Abstract
Voltage‐gated sodium channels are responsible for the upstroke of the action potential and thereby play an important role in propagation of the electrical impulse in excitable tissues like muscle, nerve and the heart. Duplication of the sodium channels encoding genes during evolution generated the sodium channel gene family with the different isoforms differing in biophysical properties and tissue distribution. In this review article, mutations in these genes leading to various inherited disorders are discussed.
| Abbreviations | ||
| BFNIS | = | benign familial neonatal‐infantile seizures |
| BrS | = | Brugada syndrome |
| CMD1E | = | dilated cardiomyopathy‐1E |
| FEB3 | = | familial febrile convulsions‐3 |
| FHM | = | familial hemiplegic migraine |
| FRP | = | familial rectal pain |
| GEFS+ | = | generalized epilepsy with febrile seizures plus |
| HOKPP | = | hypokalemic periodic paralysis |
| HYPP | = | hyperkalemic periodic paralysis |
| ICEGTC | = | intractable childhood epilepsies and frequent generalized tonic‐clonic seizures |
| LQT3 | = | long QT syndrome type 3 |
| LQTS | = | long QT syndrome |
| PCCD | = | progressive cardiac conduction defect |
| PMC | = | paramyotonia congenital |
| SIDS | = | sudden infant death syndrome |
| SMEB | = | borderline SMEI |
| SMEI | = | severe myoclonic epilepsy of infancy |
| SSS | = | sick sinus syndrome |
Introduction
Voltage‐gated sodium (Na+) channels are responsible for the upstroke of the action potential and thereby play an important role in propagation of the electrical excitable impulse in tissues including muscle, nerve and the heart. The channels are composed of pore‐forming α‐subunits of ∼260 kDa associated with one or two β‐subunits of 30–40 kDa that alter the properties of the channel. The α‐subunit gene family consists of nine genes (and one additional sodium channel‐like gene, see below) that are highly conserved across species. The channels are characterized by differential sensitivities to the sodium channel blocker tetrodotoxin (TTX) and inactivation kinetics: highly TTX‐sensitive α‐subunits (encoded by SCN1A, SCN2A, SCN3A, SCN4A, SCN8A, SCN9A) have faster inactivation kinetics compared to α‐subunits that are less sensitive to TTX (encoded by SCN5A, SCN10A, SCN11A).
Mutations in these genes cause various inherited disorders, which will be discussed in this review article.
The sodium channel genes
Duplication of genes encoding the α‐subunits during evolution generated the sodium channel gene family with the different genes differing in their biophysical properties and tissue distribution () Citation1. SCN9A, SCN10A and SCN11A are expressed in the peripheral nervous system. SCN1A, SCN2A, SCN3A and SCN8A are also expressed in the peripheral nervous system, but are more abundant in the central nervous system (including the brain). SCN4A and SCN5A are highly expressed in muscle: SCN4A is expressed in adult skeletal muscle and SCN5A in embryonic and denervated skeletal muscle and heart muscle. SCN6A/SCN7A (probably referring to the same gene) is expressed in a diversity of tissues, including peripheral nervous system, heart, uterus and skeletal muscle Citation2,3. Since SCN6A/SCN7A is the only sodium channel encoding gene that has not been expressed in an exogenous system and consensus amino acid sequences essential for voltage sensitivity and channel inactivation are not well conserved Citation4, it was debated whether this gene encodes a functional voltage‐gated Na+ channel. On the other hand, SCN6A/SCN7A has been implicated in regulation of salt‐intake behavior in a knockout mouse model Citation5,6.
Table I. The voltage‐gated sodium channel gene family: tissue specificity and clinical association of mutations in these genes.
Alternative RNA‐splicing has been described for several α‐subunits (): SCN1A (extended exon 11), SCN3A (three different variants of exon 12), SCN5A (exon 18, difference of one amino acid), SCN8A (extended exon 12), SCN9A (extended exon 11) and SCN11A (lacking exon 16) Citation7–13. Additionally, developmentally regulated splice variants of SCN2A (exon 5N and 5A), SCN3A (exon 5N and 5A), SCN8A (exon 5N and 5A) and SCN9A (exon 5N and 5A) that differ in a few amino acids and are either predominantly expressed neonatally (N) or in adults (A) have been described Citation10,Citation14–16. In the case of SCN8A, another splice variant (exon 18N and 18A) contains an in‐frame stop‐codon in the neonatally expressed variant which encodes a truncated two‐domain protein, the function of which is unknown Citation8. In addition, four alternatively spliced noncoding exons which generate alternative 5′UTRs for transcripts of this gene have been reported Citation17.
Table II. Different splice variants of voltage‐gated sodium channels.
Electrophysiological studies on splice variants of SCN2A did not show any functional differences Citation18, while splice variants of SCN3A, SCN5A and SCN8A resulted in channels that have altered kinetics Citation7,Citation12,Citation19. The functional significance of the other alternative splicing events is still unknown.
The four β‐subunit isoforms can be divided into two groups. β1 (SCN1B; localized in brain, skeletal and cardiac muscle Citation20) and β3 (SCN3B; localized primarily in neuronal tissue Citation21,22, but also detected in the heart Citation22–24) are most similar in amino acid sequence and are noncovalently associated with α‐subunits Citation22,Citation25. β2 (SCN2B; localized in the central nervous system and cardiac muscle) and β4 (SCN4B; localized in many tissues, including brain, heart, and skeletal muscle Citation26) subunits are also closely related in amino acid sequence to one another but as opposed to β1 and β3 are disulfide‐linked to the α‐subunits Citation21,Citation26. Alternative RNA‐splicing has also been described for β‐subunits: SCN1Ba and SCN1Bb differ beyond the immunoglobulin (Ig)‐loop region, resulting in a distinct C‐terminal cytoplasmic domain and a longer SCN1Bb transcript Citation27,28.
Key messages
Voltage‐gated sodium channels are expressed in excitable tissues namely heart, muscle and nerve.
Mutations in the genes encoding these channels lead to various clinical phenotypes.
Our understanding of the sodium channelopathies is complicated by several factors, among which is the complexity of the clinical phenotypes, the allelic heterogeneity involved, the diverse impact of the different mutations on channel function, and the contribution of other (yet‐unknown) genetic and environmental factors to the final form or severity of the disease.
Structure and function of sodium channel subunits
α‐Subunits
The pore‐forming α‐subunits are large transmembrane proteins that contain four structurally homologous domains (DI–DIV), each composed of six helical transmembrane segments (S1–S6) (see Catterall et al. for review Citation29; see ). The S5 and S6 segments and the P‐loop between them from each domain line the channel pore. The pore contains the selectivity filter also referred to as the DEKA ring (consisting of aspartic acid, glutamate, lysine, alanine; one of these amino acids per P‐loop), which attracts positive Na+ ions and excludes negatively charged ions Citation30. The lysine residue in the P‐loop of DIII is important for discrimination for Na+ over Ca2+Citation31,32.
Figure 1. Diagrammatic representation of voltage‐gated sodium channels showing locations of mutations causing channelopathies. A: SCN1A; generalized epilepsy with febrile seizures plus (blue), severe myoclonic epilepsy of infancy (red), intractable childhood epilepsy and frequent generalized tonic‐clonic seizures (orange), borderline severe myoclonic epilepsy of infancy (green), familial febrile convulsions‐3 (purple), familial autism (light blue), familial hemiplegic migraine (yellow) and mixed phenotypes (white). B: SCN2A; benign familial neonatal‐infantile seizures (red), severe myoclonic epilepsy of infancy (green), febrile and afebrile seizures (blue), and familial autism (orange). C: SCN4A; hyperkalemic periodic paralysis (red), hypokalemic periodic paralysis (green), paramyotonia congenita (orange), potassium‐aggravated myotonia (blue) and mixed phenotypes (white). D: SCN5A; Brugada syndrome (red), long QT syndrome type 3 (green), (progressive) cardiac conduction defects (orange), sick sinus syndrome (blue), atrial standstill (purple), sudden infant death syndrome (light blue), drug‐induced torsades de pointes (yellow), AV block (black), dilated cardiomyopathy (brown) and mixed phenotype (white). E: SCN8A; ataxia. F: SCN9A; primary erythermalgia.
Depending on the membrane potential, voltage‐gated Na+ channels can switch between three functional states: resting (closed), activated (open), and inactivated (closed). The highly conserved S4 region in each domain has a positive amino acid at every third position, and is considered the voltage sensor. The transition from the resting state to the activated state occurs when a change in transmembrane voltage moves S4 from within the pore towards the extracellular side of the cell, activating the channel which becomes permeable to ions Citation33. Inactivation is mediated mainly by the inactivation gate (DIII–DIV linker), that blocks the inside of the channel shortly after it has been activated, and the C‐terminal cytoplasmic domain Citation34–36. During an action potential the channel normally remains open for only a few milliseconds after depolarization before it is being inactivated. When the membrane potential becomes negative after the repolarization phase of the action potential, the channels return to their resting state and can be activated again during the next action potential.
β‐Subunits
β‐Subunits consist of one transmembrane segment, an intracellular domain and a glycosylated extracellular domain. The structure of the extracellular domain resembles the structure of the V‐like family of Ig‐fold proteins, containing domains similar to the variable regions of antibodies and including motifs as found in cell adhesion molecules Citation37.
The multifunctional β‐subunits control channel‐gating, regulate the level of expression of the α‐subunit at the plasma membrane Citation38,39 and are involved in cell adhesion through interaction with the cytoskeleton, extracellular matrix, and other cell adhesion molecules that regulate cell migration and aggregation Citation40.
Channelopathies: Cardiac sodium channelopathies
SCN5A (Figure)
Mutations in the cardiac voltage‐gated Na+ channel α‐subunit gene SCN5A result in multiple arrhythmia syndromes Citation41. Mutations leading to loss of Nav1.5 channel function can result in Brugada syndrome (BrS; MIM 601144) Citation42, (progressive) cardiac conduction defect (PCCD; MIM 113900) Citation43, sick sinus syndrome (SSS; MIM 608567) Citation44, sudden infant death syndrome (SIDS; MIM 272120) Citation45 and dilated cardiomyopathy associated with conduction defects and arrhythmias (CMD1E; MIM 601154) Citation46. In combination with modifier genes, a loss‐of‐function defect causes atrial standstill Citation47. Mutations leading to a gain‐of‐function of the channel cause long QT syndrome type 3 (LQT3; MIM 603830) Citation48. Some mutations in this gene lead to more than one disease phenotype, referred to as overlap syndromes of cardiac Na+ channelopathy, which are usually only recognized in large families Citation49,50.
Loss‐of‐function mutations: Brugada syndrome and conduction defects
The Brugada syndrome, with an estimated 5–50 cases per 10,000 individuals (with a higher incidence in Asia than in the United States and Europe Citation51), is an autosomal dominant disorder characterized by sudden cardiac death from ventricular tachyarrhythmias, in combination with a typical electrocardiogram (ECG) pattern of ST segment elevation in leads V1–V3. It is believed to cause 4%–12% of all sudden cardiac deaths and ∼20% of deaths in patients without structural abnormalities. To date, 80 mutations in SCN5A (of which 14% are nonsense or frameshift mutations, leading to truncation of the protein) have been described in BrS patients or in BrS patients with a mixed (overlap) phenotype (Inherited Arrhythmias Database: http://www.fsm.it/cardmoc/) Citation52. These loss‐of‐function mutations are associated with dysfunctional channels or with a reduction of membrane expression of the channel due to a trafficking defect. Loss of Na+ channel function reduces the upstroke of the action potential and may slow down action potential propagation. Thus, not surprisingly, patients with BrS often present with (progressive) conduction defects Citation53,54. Loss‐of‐function mutations in SCN5A can also cause isolated cardiac conduction disease, i.e. without ECG features of BrS. Recently, a haplotype in the promoter region of SCN5A that occurs frequently in Asians was found to be associated with slower cardiac conduction Citation55, suggesting that decreased expression of SCN5A transcripts may contribute to differences in BrS prevalence as a function of ethnicity.
Gain‐of‐function mutations: long QT syndrome
Multiple genes have been associated with LQTS, an inherited cardiac arrhythmia associated with syncope and sudden death from torsades de pointes polymorphic ventricular tachycardia, estimated to affect 1 per 5,000 individuals. One subtype of this syndrome is associated with mutations in SCN5A (LQT3). Gain‐of‐function mutations in Nav1.5 result in an increase in the late component of the Na+ current by slowing of inactivation or an increase in the reversibility of inactivation, resulting in a slow and constant entry of Na+ in the plateau phase of the action potential, leading to a prolonged QT interval on the surface electrocardiogram (ECG) Citation56. Because in SCN5A‐related LQTS QT‐prolongation is most pronounced at lower heart rates, bradycardia presents an important factor in developing lethal arrhythmias in LQTS families with mutations in SCN5ACitation57. Thus far, 62 LQTS‐causing missense mutations and small (in frame) insertions and deletions have been identified in SCN5A (Inherited Arrhythmias Database: http://www.fsm.it/cardmoc/).
SCN4B
Very recently, the first mutation in the SCN4B gene encoding Navβ.4 was presented Citation58. This missense mutation functionally disturbs Nav1.5 in a LQTS patient and therefore SCN4B very likely is a new LQTS susceptibility gene.
Neuronal channelopathies
Brain sodium channelopathies
SCN1A (Figure)
SCN1A, the neuronal voltage‐gated Na+ channel α‐subunit gene encoding Nav1.1, is part of the SCN1A‐SCN2A‐SCN3A gene cluster on chromosome 2q24. Missense mutations have been identified in patients with generalized epilepsy with febrile seizures plus (GEFS+; MIM 604233) Citation59, an autosomal dominant epilepsy characterized by febrile seizures in children, and afebrile seizures in adults Citation60,61. A large number of mutations of SCN1A have been identified in patients with severe myoclonic epilepsy of infancy (SMEI; MIM 607208) Citation62, a rare disorder characterized by various types of generalized and partial seizures, including myoclonic seizures. Many of the mutations characterized in children with SMEI are de novo (69 out of 75 cases) Citation63. Also, many of the observed mutations in SMEI patients are nonsense or frameshift mutations that cause protein truncation Citation64, with deletion of the C‐terminal cytoplasmic domain resulting in disease of similar severity to deletion of the N‐terminal cytoplasmic domain Citation63. No nonsense or frameshift mutations in SCN1A have been described so far in patients with GEFS+. One report suggests that in SMEI, pore region missense mutations are associated with a more severe phenotype Citation65.
SCN1A mutations have also been associated with intractable childhood epilepsies and frequent generalized tonic‐clonic seizures (ICEGTC) Citation66, familial febrile convulsions‐3 (FEB3; MIM: 604403) Citation67, and borderline SMEI (SMEB, when not all the SMEI criteria are fulfilled) Citation68.
In 2005, Dichgans et al. Citation69 described a mutation in SCN1A leading to familial hemiplegic migraine (FHM; MIM 141500), an autosomal dominant severe subtype of migraine with aura. This gain‐of‐function missense mutation in the inactivation gate of the channel was present in three families with the same disorder. This finding underlines the molecular links between migraine and epilepsy, two common paroxysmal disorders.
The association of SCN1A mutations with familial autism is also being investigated Citation70.
SCN2A (Figure)
Despite the fact that SCN1A and SCN2A are closely related genes, only a few epilepsy mutations have been identified in SCN2A encoding Nav1.2 Citation14,Citation71,72. Loss‐of‐function missense mutations in SCN2A were found in patients with benign familial neonatal‐infantile seizures (BFNIS; MIM 607745), a mild autosomal dominant syndrome in which afebrile seizures occur in clusters during the first year of life but which does not progress to adult epilepsy. Interestingly, one mutation (located in the conserved transmembrane segment S4 of DIII) was identified in affected members of three families, which occurred independently according to haplotype analysis Citation73.
Unlike SCN1A, SCN2A does not show evidence of haploinsufficiency. Only one (de novo) truncation mutation has been identified in SCN2A in a patient with intractable epilepsy and mental decline, a severe form of epilepsy resembling SMEI Citation71. In this case the truncated protein had a dominant‐negative effect possibly arising from direct or indirect cytoskeletal interactions of the mutant protein.
One mutation in SCN2A has been described that might play a role in autism, but needs to be further analyzed Citation70.
SCN3A
Studies in rats have indicated that seizure activity induces alterations in the developmental splicing of neonatal and adult SCN2A and SCN3A transcripts Citation74, whose genes are located side by side on the chromosome: seizures were found to re‐activate the neonatal splicing event, causing an increase in the presence of the neonatal SCN2A and SCN3A transcripts in localized regions of the adult rat brain. In contrast to SCN2A, SCN3A mRNA was found to be expressed at significantly higher levels in CA4 hilar cells in the epileptic hippocampus when compared with control, and therefore possibly contributes to the pathophysiology of epilepsy Citation75. However, no mutations in this gene have been reported.
SCN8A (Figure)
Mutations in the mouse ortholog of SCN8A cause ataxia and other movement disorders Citation76. So far, only one protein truncation mutation has been described in humans, causing cerebellar atrophy, ataxia and mental retardation Citation77. This loss‐of‐function frameshift mutation was located in the pore loop of domain IV, resulting in truncation of the C‐terminal cytoplasmic domain. Interestingly, Wasserman et al. described a single‐nucleotide polymorphism in SCN8A that may contribute to the risk for suicide attempts, possibly through alterations in neuronal conduction which hypothetically could lead to disturbed analysis of incoming information in periods of emotional and physical stress Citation78.
SCN1B
Mutations in the Navβ.1 encoding SCN1B gene are associated with GEFS+ Citation79. The loss‐of‐function mutation C121W has been described in two families with GEFS+ Citation80. In another family with febrile seizures plus and early‐onset absence epilepsy, a mutation in the splice acceptor site of SCN1B that predicts a deletion of five amino acids in the extracellular Ig‐loop region was identified that could lead to loss‐of‐function Citation81. Both mutations are expected to disrupt proper folding of the protein and therefore can inhibit interaction with α‐subunits or impair subcellular distribution, which will reduce the inactivation rate of Na+ channels and results in neuronal hyperexcitability Citation81,82.
To study the loss‐of‐function effects of SCN1B in vivo, knockout mice were generated, which appear ataxic and reveal spontaneous seizures, growth retardation and premature death Citation83. These phenotypes were the result of slowing of neuronal action potential conduction, reduced number of mature nodes of Ranvier, alterations in nodal architecture, loss of Na+ channel‐contactin interactions, and abnormalities in the expression of SCN1A and SCN3A. From this, it was clear that SCN1B regulates Na+ channel density and localization, is involved in axo‐glial communication at nodes of Ranvier, and is required for normal action potential conduction and control of excitability in vivo.
Peripheral nerve sodium channelopathies
SCN9A (Figure)
Mutations in the SCN9A gene encoding the Nav1.7 channel cause primary erythermalgia (MIM 133020), a rare autosomal dominant disorder characterized by sporadic intense burning pain with redness and heat in the extremities Citation84. These gain‐of‐function mutations modify thresholds of activation and are therefore likely to contribute to increased excitability of spinal sensory neurons that express the channels and may cause the abnormal pain sensations in patients suffering from this disorder Citation85,86. Missense mutations in SCN9A have also been associated with familial rectal pain (FRP; MIM 167400), a disorder characterized by brief episodes of excruciating pain of the submandibular, ocular, and rectal areas with flushing of the surrounding skin Citation87. Additionally, conditional inactivation of SCN9A in sensory neurons of the mouse resulted in increased threshold for mechanical, thermal, and inflammatory pain Citation88. The association of SCN9A mutations with pain syndromes shows that this Na+ channel could be a target for local anesthetics.
SCN10A
SCN10A encodes Nav1.8, a channel that is restricted to the peripheral sensory nervous system Citation89. The down‐regulation of SCN10A expression in rat can 1) prevent thermal hyperalgesia (hypersensitivity to noxious stimuli) and allodynia (pain response to non‐noxious stimuli) in a rat model of neuropathic pain Citation90, and can 2) suppress responses caused by pain in a rat model of visceral pain Citation91. No mutations in humans have been described thus far, but SCN10A could be a potential target for analgesic drugs.
SCN11A
The Nav1.9 channel encoded by SCN11A is expected to contribute to setting the resting membrane potential and modulating subthreshold electrogenesis in nociceptive neurons Citation92. Its expression is adjusted in response to axotomy Citation92 and inflammation Citation93. Priest et al. Citation94 observed no differences in passive membrane properties and action potential characteristics between acutely dissociated peripheral sensory neurons in the dorsal root ganglia between wildtype and NaV1.9 knockout mice. However, expression of SCN11A contributes to the persistent thermal hypersensitivity and spontaneous pain behavior after peripheral administration of inflammatory agents Citation94. Although no mutations in SCN11A in humans have been described to date, this gene can possibly act as a target for analgesic drugs.
Muscle sodium channelopathies
SCN4A (Figure)
Mutations in the muscle voltage‐gated Na+ channel Nav1.4 encoding gene SCN4A have been identified in a group of related muscular disorders, including hyperkalemic periodic paralysis (HYPP; MIM 170500) Citation95 and hypokalemic periodic paralysis (HOKPP; MIM 170400) Citation96, paramyotonia congenita (PMC; MIM 168300) Citation97, and a group of disorders classified as potassium‐aggravated myotonia (MIM 608390) Citation98. The gain‐of‐function mutations in SCN4A associated with HYPP, PMC and myotonia cause a disruption of fast inactivation Citation99–101, which results in channel re‐opening and intracellular Na+ accumulation. In that case, muscle cells depolarize and generate recurrent action potentials. This can lead to enduring hyperexcitability which causes myotonia Citation102, or it can lead to general opening of the channel which can cause paralysis Citation103. In contrast, HOKPP is associated with loss‐of‐function mutations leading to hypoexcitability of the fiber membrane resulting in muscle weakness Citation104–106. However, the mechanism leading to this decreased excitability is still poorly understood.
Discussion
In the last decades, much research has been done to identify new phenotype‐linked mutations in voltage‐gated Na+ channels. Despite the fact that the relationship between mutations, altered Na+ channel function and disease phenotypes has become clearer, many questions still remain. Our understanding of the sodium channelopathies is complicated by several factors, among which is the complexity of the clinical phenotypes (pleiotropy), the allelic heterogeneity involved, the diverse impact of the different mutations on channel function, and the contribution of other (yet‐unknown) genetic and environmental factors to the final form or severity of the disease Citation107,108. Gain‐of‐function and loss‐of‐function mutations in the same gene lead to different diseases. In contrast to the obvious association between truncation mutations and loss of channel function, no relationships have been described so far between the locations within the channel protein of amino‐acid‐changing mutations and these mechanisms, which appear to be random. In rare instances, a given mutation may even harbor biophysical defects associated with both gain and loss of channel function Citation63.
Genetic factors other than the causal mutation itself that play a role in modulation of disease severity are starting to be uncovered. For example, the combined effect of a mutation in SCN5A and polymorphisms in the atrial‐specific gap junction protein connexin40 gene has been reported to cause familial atrial standstill Citation47. In mice, genetic variation in a putative RNA‐splicing factor (SCNM1) has been shown to modulate movement disorder severity in SCN8A mutant mice Citation109. In another mouse study, an interaction between two mild mutations, one in SCN2A and the other in the potassium channel gene KCNQ2, has been described to result in severe epilepsy Citation110. Furthermore, two modifier loci affecting epilepsy severity caused by a SCN2A mutation have been reported Citation111. The genetic factors modulating disease severity may also reside in the gene affected itself Citation55 and even on the same allele. In SCN5A, for example, a common polymorphism that attenuates the biophysical defect of a mutation on the same allele has been described Citation112.
Not all voltage‐gated Na+ channels have been linked to human disease. Although no mutations have been described in SCN3A, SCN10A and SCN11A, in vivo animal studies indicate that other Na+ channelopathies probably exist. Furthermore, the different splice variants of the Na+ channel genes could play a role in the pathogenesis of the sodium channelopathies.
Since voltage‐gated Na+ channels are action players with many faces, our understanding of how mutations cause disease has lagged somewhat behind. In the next years, our increasing knowledge may lead to better targeted treatment of patients suffering from these disorders.
Acknowledgements
The authors wish to thank A.C. Linnenbank for preparing the figure and A.C.G. van Ginneken for critical reading of the manuscript. This work is supported by Netherlands Heart Foundation grants 2003B195 (CRB) and 2003T302 (AAMW), and the Interuniversity Cardiology Institute of the Netherlands (project 27, AAMW). Connie R. Bezzina is an Established Investigator of the Netherlands Heart Foundation (Grant 2005/T024).
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