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Mechanisms underlying epilepsies associated with sodium channel mutations

Ortrud K. Steinlein1 Institute of Human Genetics, University Hospital, Ludwig-Maximilians-University, Munich, Germany 1 Corresponding author: Tel.: +49-89-5160-4468; Fax: +49-89-5160-4470, e-mail address: [email protected]

Abstract Voltage-gated sodium channels provide the molecular basis for the generation and propagation of action potentials. It is therefore not surprising that mutations in different subunits of this ion channel family are the most common cause of genetic epilepsies. Voltage-gated sodium channel mutations are associated with different seizure phenotypes including benign familial neonatal–infantile convulsions, genetic epilepsy with febrile seizures plus, and Dravet syndrome. Unraveling the pathomechanisms that underlie these genetic epilepsies is challenging, and the complex genotype–phenotype correlations are still not fully understood.

Keywords voltage-gated sodium channels, epilepsy, SCN1A, Dravet syndrome, GEFS+

1 INTRODUCTION Voltage-gated sodium channels have a crucial role with regard to neuronal function. They control the sodium exchange between the extracellular and intracellular spaces, and are essential for the initiation and firing of action potentials (Hu et al., 2009). Their important role in neuronal excitability renders them prime candidates for episodic neurological disorders such as epilepsy. It is therefore not surprising that mutations in various voltage-gated sodium channel subtypes have been found to cause different forms of epileptic disorders, and that such mutations are recognized as one of the most important causes of genetic epilepsy (Mulley et al., 2005). The seizure phenotypes caused by voltage-gated sodium channel mutations are heterogeneous and range from benign to severe if not even devastating, reflecting the importance of this ion channel superfamily for the regulation of cellular excitability on several functional levels (Table 1). Typical examples for the clinical Progress in Brain Research, Volume 213, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63326-2.00005-3 © 2014 Elsevier B.V. All rights reserved.

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Table 1 Epilepsy phenotypes caused by voltage-gated sodium channel mutations Subunit class

Gene

Channel subunit

SCN1A

Nav1.1

SCN2A

Nav1.2

SCN8A

Nav1.6

Febrile seizures GEFS+ Dravet syndrome SMEB West syndrome (infantile spasms) Doose syndrome (myoclonic astatic epilepsy) Intractable childhood epilepsy with generalized tonic–clonic seizures (ICEGTC) Rasmussens’s encephalitis Lennox–Gastaut syndrome Benign familial neonatal–infantile seizures Early infantile epileptic encephalopathy Benign familial infantile seizure Infantile epileptic encephalopathy

SCN1B

Navb1

GEFS+

Epilepsy phenotypesa

a-Subunits

b-Subunits

a

Nonepileptic phenotypes are not listed.

phenotypes caused by voltage-gated sodium channel mutations are benign familial neonatal–infantile seizures and the severe and sometimes fatal Dravet syndrome (also known as severe myoclonic epilepsy of infancy (SMEI)) (Baulac et al., 1999; Escayg et al., 2000; Heron et al., 2010; Kaplan and Lacey, 1983; Marini et al., 2011; Meisler and Kearney, 2005; Reid et al., 2009). These two epilepsy syndromes represent the extreme ends of the spectrum of clinical severity, while a third one, genetic epilepsy with febrile seizures plus (GEFS+), presents with a more intermediate phenotype that can include both benign and severe manifestations (Baulac et al., 1999; Escayg et al., 2000; Scheffer and Berkovic, 1997; Scheffer et al., 2009) (Table 1).

2 VOLTAGE-GATED SODIUM CHANNELS The superfamily of voltage-gated sodium channel genes comprises nine homologous members (SCN1A to SCN5A and SCN8A to SCN11A) that encode the sodiumselective ion channel subunits NaV1.1 to NaV1.9. The large a-subunits are characterized by four homologous domains, with each of these domains containing six transmembrane regions. The a-subunits are able to form functional channels by themselves but usually associate with the much smaller b-subunits (encoded by

2 Voltage-gated sodium channels

the genes SCN1B to SCN4B) that modulate the channels trafficking and its biophysical characteristics (Catterall, 2000; Fozzard and Hanck, 1996; Goldin et al., 2000). Voltage-gated sodium channels are closed at resting membrane potentials and require depolarization for their activation. Once opened, they allow the rapid influx of sodium ions into the cell, causing further depolarization of the membrane potential and reinforcement of the action potential. Voltage-gated sodium channel only show very short opening times, and are closing within milliseconds after opening. This so-called fast inactivation helps to keep the action potential under stringent control. In many cells, the closing of voltage-gated sodium channels is not complete, resulting in a small persistent sodium current that exhibits a rather long inactivation time that is within the range of tens of seconds (Catterall et al., 2005; Yu and Catterall, 2003) (Fig. 1). Structurally, the large a-subunits consist of two parts with the transmembrane regions S1–S4 building the voltage sensor and S5–S6 forming the sodium-selective ion channel pore (Catterall et al., 2005; Sato et al., 2001; Stuhmer et al., 1989). The voltage sensor consists of repeated motifs of positively charged amino acids followed by hydrophobic amino acids arranged in an a-helix structure. Depolarization of the cell results in the rapid movement of the voltage sensors contributed by domains I–III, which then induces a conformational change in the protein that opens the ion channel pore (Alabi et al., 2007). The subsequent fast inactivation that follows each activation period is caused by the intrinsically slower movement of the domain IV voltage sensor (Bosmans et al., 2008; West et al., 1992). The intracellular loop between domains III and IV contains three highly conserved amino acids (isoleucine, phenylalanine, and methionine) that constitute the core of the inactivation gate which, upon inactivation, transposes into the channel pore, a phenomenon often described as a ball-and-chain type block (Payandeh et al., 2012; Vassilev et al., 1988, 1989). Extracellular

+ + + + +

Domain I S1 ………………… S6

Voltage sensor

+ + + + +

Domain II S1 ………………… S6

+ + + + +

Domain III S1 ………………… S6

+ + + + +

Domain IV S1 ………………… S6

Intracellular

FIGURE 1 Schematic representation of a sodium channel alpha-subunit. Each domain consists of six transmembrane domains (S1–S6), the fourth one containing the positively charged amino acids that constitute the voltage sensor.

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The expression pattern of the different voltage-gated sodium channel subunits not only depends on the developmental stage but also differs between brain regions and cell types. The a-subunit SCN3A is most prominently expressed in the neonatal brain and therefore seems to be important for development, while subunits such as SCN1A, SCN2A, and SCN8A display high expression in adult brains. The latter nevertheless differ with respect to their cellular localization with, for example, SCN2A showing high expression at unmyelinated axons while SCN8A is mostly found at the cell soma. Both genes are prominently expressed in the axon initial segment, which constitutes the site for action potential initiation in neurons (Gong et al., 1999; Hu et al., 2009; Westenbroek et al., 1989; Whitaker et al., 2001). SCN1A is mostly found expressed in g-aminobutyric acidergic (GABAergic) neurons, probably colocalizes with SCN8A in spinal cord neurons and, according to newer findings, is also likely to be concentrated at the axon initial segment (Duflocq et al., 2008; Hu et al., 2009; Lorincz and Nusser, 2010; Ogiwara et al., 2007a; Whitaker et al., 2001).

3 CLINICAL PHENOTYPES ASSOCIATED WITH VOLTAGEGATED SODIUM CHANNEL MUTATIONS The phenotypic spectrum associated with mutations in voltage-gated sodium channel genes SCN1A and SCN2A is characterized by three different epilepsy syndromes: benign familial neonatal–infantile seizures, Dravet syndrome (also named SMEI), and GEFS+(Baulac et al., 1999; Escayg et al., 2000; Heron et al., 2010; Kaplan and Lacey, 1983; Lewis et al., 1996; Scheffer and Berkovic, 1997; Scheffer et al., 2009; Shevell et al., 1986). Benign familial neonatal–infantile seizures are named due to the fact that their average age of onset (between 4 and 8 months of life) overlaps with both benign neonatal and benign infantile convulsion syndromes. Affected children present with afebrile seizures that occur in clusters and show spontaneous remission within the first year of life. The seizures mostly start focally but secondary generalization is commonly observed. Usually, the patients are normal with respect to their intellectual and motor development (Kaplan and Lacey, 1983; Lewis et al., 1996; Shevell et al., 1986). The syndrome can be caused by heterozygous missense mutations within the SCN2A gene that are segregating within families in an autosomal dominant manner. However, mutations are only found in a minority of families and the existence of additional, so far unknown major genes for benign familial neonatal– infantile seizures has therefore to be assumed (Berkovic et al., 2004; Kaplan and Lacey, 1983; Lewis et al., 1996; Malacarne et al., 2001; Shevell et al., 1986). Dravet syndrome is an early-onset epileptic encephalopathy that is characterized by seizures and psychomotor decline. Initially, seizures present as febrile convulsions but in the course of the disease afebrile seizures become more and more common. Different types of generalized or focal seizures might occur, including myoclonic seizures, absence seizures, and atonic or tonic seizures (Doose et al., 1998; Fujiwara et al., 2003; Jansen et al., 2006; Sugawara et al., 2002). The patients

3 Clinical phenotypes with sodium channel mutations

are showing normal psychomotor development during the first year of life, but slowing of development or even regression usually starts in the second year of life. At the same time, the EEG starts to display generalized spike-wave activity, while the MRI is either normal or shows nonspecific findings. Status epilepticus occurs frequently, often every 1–2 months. In general, the outcome is poor, with intellectual disability in most patients and no sufficient seizure control. In the long-term patients, nocturnal convulsions and a gait deterioration that becomes most prominent in adolescence are developed (Doose et al., 1998; Fujiwara et al., 2003; Jansen et al., 2006; Sugawara et al., 2002). Dravet syndrome is mostly caused by de novo occurring mutations within the SCN1A gene (Escayg et al., 2000; Fujiwara et al., 2003; Kimura et al., 2005; Nabbout et al., 2003; Scheffer, 2003; Singh et al., 2001). Mutation types include truncation mutations including splice site and deletion mutations (Claes et al., 2001; Kanai et al., 2004). Recently, microdeletions that are either intragenic or encompass the complete gene have been described in some patients (Mulley et al., 2006; Suls et al., 2006). Furthermore, a few patients have been described in which a Dravet-like or a GEFS+ phenotype is caused by mutations in either SCN2A or in the accessory subunit gene SCN1B (Ogiwara et al., 2009; Patino et al., 2009). The latter gene has also been found to be a very rare cause of early-onset absence epilepsy (Wallace et al., 1998). Most patients with Dravet syndrome are sporadic (approximately 90%); however, a few familial cases have been described. In some of these families, parental mosaicism has been proved to be the reason for the repeated occurrence of Dravet syndrome within the same family (Depienne et al., 2010; Genmaro et al., 2006; Marini et al., 2006; Morimoto et al., 2006; Selmer et al., 2009). Mostly, the carrier parent is unaffected but might show a milder form of epilepsy if the degree of mosaicism is high. So far the frequency with which mosaicism occurs in Dravet syndrome is not known but the seven families that have been published serve as a reminder that this possibility and the recurrence risk that it implies must be kept in mind when counseling parents of an affected child (Depienne et al., 2010; Genmaro et al., 2006; Marini et al., 2006; Morimoto et al., 2006; Selmer et al., 2009). A variant of Dravet syndrome, named borderline severe myoclonic epilepsy of infancy exists that is also caused by mutations in the SCN1A gene. Clinically, this syndrome is quite similar to the Dravet syndrome but lacks key features such as myoclonic seizures or generalized spike-wave activity in the EEG (Fukuma et al., 2004; Mulley et al., 2005; Ohmori et al., 2003; Sugama et al., 1987). Apart from the already mentioned syndromes of benign familial neonatal– infantile seizures, Dravet syndrome, and GEFS+, mutations in the voltage-gated sodium channel gene SCN1A are also associated with a variety of even more rare epileptic syndromes. These include severe infantile multifocal epilepsy or the syndrome of migrating partial seizures of infancy as well as less well-defined phenotypes of unspecific epileptic encephalopathies or isolated tonic–clonic or myoclonic–atonic seizures phenotypes (Carranza Rojo et al., 2011; Harkin et al., 2007; Livingston et al., 2009).

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Genes coding for subunits of voltage-gated sodium channels other than SCN1A and SCN2A might also be involved in the pathogenesis of epilepsies. A single mutation has been found in SCN3A causing a phenotype of cryptogenic partial epilepsy (Estacion et al., 2010). Most interesting, several SCN9A mutations have been described that either occurred allelic to SCN1A mutations in patients with Dravet syndrome, or were present in patients with febrile seizures without SCN1A mutations. These observations suggest that mutations within SCN9A can either act as modifiers in the presence of stronger mutations or cause a mild seizure phenotype by themselves (Doty, 2010). Mutations in SCN8A seem to have the potential to cause a severe epilepsy phenotype because a de novo missense mutation within this gene was found to be associated with infantile encephalopathy in one patient (Veeramah et al., 2012). However, it cannot be excluded at this point that other, unidentified mutations contributed to the epilepsy phenotype in this patient. Taken together, several subunit genes of the voltage-gated sodium channel family are not only directly involved in the pathogenesis of genetic epilepsy but are often able to cause different seizure phenotypes. A high degree of clinical heterogeneity is not only observed when comparing different mutations within the same gene but can even be found for different patients carrying the same mutation. For example, families have been described in which a SCN1A mutation causes a benign GEFS+ phenotype in a parent but is associated with a devastating neurological phenotype in the child (Depienne et al., 2010). Such observations suggest that the effects voltagegated sodium channel mutations have on brain excitability are often modulated by additional, unknown factors. These might include genetic variants in other genes, but environmental factors or epigenetic regulation also present potential mechanisms that are able to modify the impact that a given mutation has on the clinical phenotype (Doty, 2010; Kobow et al., 2013).

4 PATHOGENETIC MECHANISMS OF SODIUM CHANNEL MUTATIONS IN EPILEPSY So far, the pathophysiological mechanisms underlying the various types of epilepsy caused by mutations in voltage-gated sodium channels remain poorly understood (Oliva et al., 2012). Several different approaches are being used to shed light on the complexity of these mechanisms. Most commonly, heterologous expression experiments are utilized as a first step procedure to determine if a newly discovered genetic variation has to be considered as a disease-causing mutation or an innocent bystander. These experiments are traditionally performed in either Xenopus oocytes or mammalian cells such as the often used HEK (human embryonic kidney) or CHO (Chinese hamster ovary) cells (Catterall et al., 2010; Faisal, 2007; Mantegazza et al., 2010; Meisler et al., 2010; Ragsdale, 2008). Experiments performed in these standard cell systems have the advantage that their results are roughly comparable to each other even if conducted in different laboratories. However, even these rather simple expression systems contain pitfalls, for example, because researchers use

4 Pathogenetic mechanisms of sodium channel mutations in epilepsy

different cDNA clones for their expression experiments. In the past, these clones often contained no or only parts of the untranslated regions that flank most genes. By now, it has been recognized that these regions contain important regulatory motifs that might be able to influence the outcome of experiments ( Jia et al., 2013; Somers et al., 2013). Furthermore, most genes carry noncoding variants within their sequences (also named silent variants), which sometimes can be functionally relevant and modulate gene function (Sauna and Kimchi-Sarfaty, 2011). The presence of different alleles could therefore influence the outcome of experiments, Additionally, the choice of specific b-subunits for coexpression experiments can also be crucial with regard to the experimental outcome because b-subunits differ considerably with respect to their modulating effect. These limitations have to be kept in mind when comparing heterologous expression experiments conducted in different labs and they might be part of the explanation why studies with voltage-gated sodium channel mutations have produced conflicting results more than once. Depending on the mutation under consideration and the experimental setup, voltage-gated sodium channel mutations have been found to cause either gain-of-function or lossof-function effects, rendering it difficult to gain any reliable insight into the pathomechanisms underlying epileptogenesis from this type of experimental design (Catterall et al., 2010; Meisler et al., 2010; Ragsdale, 2008). Heterologous expression experiments can be regarded as a valuable tool for first step assessment of putative mutations, but more sophisticated methods are needed to shed light on the process of epileptogenesis started by such mutations. An often used approach for studying the in vivo effects of mutations are mouse models. So far eight mouse models have been published that carry voltage-gated sodium channel mutations previously found in human patients (Kearney et al., 2001; Martin et al., 2007, 2010; Ogiwara et al., 2007b; Papale et al., 2009; Singh et al., 2009; Tang et al., 2009; Yu et al., 2006). Comparison of two mouse models with the same SCN1A mutation demonstrates that, analogous to heterologous expression experiments, the choice of experimental procedure clearly impacts the experimental outcome. One of the SCN1A experiments used a transgenic approach with a bacterial artificial chromosome to introduce the mutation into the mouse model while the other used a gene-targeted knock-in method (Martin et al., 2010; Tang et al., 2009). Recordings from dissociated cortical GABAergic neurons showed slower recovery from inactivation and increased use-dependent inactivation in both experimental setups. The analysis of excitatory neurons, however, clearly showed differences between the two mouse models (Martin et al., 2010; Tang et al., 2009). One possible explanation for these differences could be the fact that transgenic approaches invariably cause expression of the targeted gene in cells or tissues that normally do not express this particular gene. Such a nonphysiological expression pattern is likely to produce artificial effects that render it difficult to interpret the results (Oliva et al., 2012). An interesting approach to study the effect of voltage-gated sodium channel mutations in vivo is presented by the use of patient-derived fibroblasts. Such fibroblasts can be reprogrammed by the induced pluripotent stem cell (iPSC) method to generate

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patient-specific neurons that carry the voltage-gated sodium channel mutation within the original genomic context (Park et al., 2008; Takahashi and Yamanaka, 2006; Yu et al., 2007). This approach has the advantage that it closely models the genetic setup including the genetic variability present in other genes (genetic background) that contributed to epileptogenesis in the patient. On the other hand, whole-genome or whole-exome sequencing projects have shown that each person carries several 100 potentially pathogenic mutations and an even larger number of genetic variants within its genome (Ward and Kellis, 2012). It has therefore to be kept in mind that with the iPSC method the mutation under consideration is not analyzed alone but that any number of (unknown) additional mutations or genetic variants might influence the results (Meisler et al., 2010). The results obtained from those experiments might therefore not be representative for all patients. Another, probably not trivial limitation of the method is presented by the fact that the neurons are developed in culture and that these neurons are therefore not embedded within their normal physiological and spatial setting in the brain. Their neurophysiological characteristics might suffer from this lack of feedback from surrounding neuronal structures. Furthermore, the epigenetic programming of iPSC-derived neurons might differ from that of “true” neurons. Despite these limitations, the iPSC method nevertheless offers the advantage to study the effects of voltage-gated sodium channel mutations in a setting that comes as close to the real situation in the patients as currently possible (Itzhaki et al., 2011; Moretti et al., 2010; Park et al., 2008; Takahashi and Yamanaka, 2006; Yazawa et al., 2011). The iPSC analysis of a splice donor site mutation from a Dravet syndrome patient demonstrated that the induced neurons developed significantly increased sodium current densities, compared to controls (Auerbach et al., 2012; Harkin et al., 2007). These changes were observed both in neurons that resembled excitatory pyramidal neurons and in bipolar-shaped inhibitory neurons. Compared to iPSCderived control neurons both types of mutation-carrying neurons were hyperexcitable due to a significantly reduced action potential threshold and an increased firing frequency, together with a tendency for spontaneous repetitive firing and bursting behavior. These observations suggest that a cell autonomous mechanism of seizure generation could be the driving force behind the seizure phenotype seen in patients with Dravet syndrome caused by voltage-gated sodium channel mutations (Auerbach et al., 2012).

5 CONCLUSIONS Mutations within voltage-gated sodium channels are the most common cause of genetic epilepsies. The majority of mutations are found within the SCN1A gene that encodes the large a-subunit Nav1.1. They are associated with various genetic epilepsy syndromes that range from benign to severe, sometimes even within the same family. So far the pathomechanisms by which voltage-gated sodium channel mutations are able to cause such a broad range of different seizure disorders are not fully

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understood. The important methodical advances that have taken place over the last decade can be expected to improve our understanding of voltage-gated sodium channel induced epileptogenesis, and can be hoped to open up new directions for treatment strategies and drug development.

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