Na channel gene mutations in epilepsy—The functional consequences

Epilepsy Research 70S (2006) S218–S222

Mini review

Na channel gene mutations in epilepsy—The functional consequences Kazuhiro Yamakawa ∗ Laboratory for Neurogenetics, RIKEN Brain Science Institute, Hirosawa 2-1, Wako-shi, Saitama 351-0198, Japan Received 31 October 2005; received in revised form 7 November 2005; accepted 7 November 2005 Available online 27 June 2006

Abstract Mutations of voltage-gated sodium channel genes SCN1A, SCN2A, and SCN1B have been identified in several types of epilepsies including generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy in infancy (SMEI). In both SCN1A and SCN2A, missense mutations tend to result in benign idiopathic epilepsy, whereas truncation mutations lead to severe and intractable epilepsy. However, the results obtained by the biophysical analyses using cultured cell systems still remain elusive. Now studies in animal models harboring sodium channel gene mutations should be eagerly pursued. © 2006 Elsevier B.V. All rights reserved. Keywords: Sodium channel gene; SCN1A; SCN2A; SCN1B

In these several years, mutations in voltage-gated sodium channel genes have been reported to be associated with several types of epilepsies (Table 1). Generalized epilepsy with febrile seizures plus (GEFS+), displaying autosomal-dominant inheritance, is characterized by febrile seizures that persist beyond the age of 6 years as well as variable afebrile seizures including generalized tonic–clonic, myoclonic, and absence seizures. A genetic linkage analysis mapped Abbreviations: BFNIS, benign familial neonatal-infantile seizures; GEFS+, generalized epilepsy with febrile seizures plus; SCN1A, sodium channel ␣-subunit type-1; SCN2A, sodium channel ␣-subunit type-2; SCN1B, sodium channel ␤1-subunit; SMEI, severe myoclonic epilepsy in infancy ∗ Tel.: +81 48 467 9703; fax: +81 48 467 7095. E-mail address: [email protected]. 0920-1211/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.eplepsyres.2005.11.025

one of GEFS+ loci at 19q13.1, and mutations in the SCN1B gene, which encodes the ␤1 subunit and locates at 19q13.1, have been described in several GEFS+ families (Wallace et al., 1998; Audenaert et al., 2003). However, the number of the GEFS+ families with SCN1B mutations remains a few. In contrast, a significant number of mutations, almost exclusively missense, in the SCN1A gene encoding the ␣1-subunit have been described in GEFS+ families (Escayg et al., 2000, 2001; Sugawara et al., 2001a; Wallace et al., 2001; Annesi et al., 2003; Nagao et al., 2005). So far, approximately 10% of GEFS+ patients showed SCN1A missense mutations that mostly located at the transmembrane segments of the channel protein. We also reported a missense mutation in another voltagegated sodium channel gene, SCN2A, encoding the

K. Yamakawa / Epilepsy Research 70S (2006) S218–S222 Table 1 Sodium channel genes for epilepsy Gene

Epilepsy syndrome

Reference

SCN1A

GEFS+ SMEI

Escayg et al. (2000), etc. Claes et al. (2001), etc.

SCN2A

GEFS+ (?) BFNIS Intractable epilepsy + mental decline GEFS+

Sugawara et al. (2001b) Heron et al. (2002), etc. Kamiya et al. (2004)

SCN1B

Wallace et al. (1998), etc.

␣2-subunit in a patient with atypical GEFS+ (Sugawara et al., 2001b), although we could not identify further number of SCN2A missense mutations in more than 50 consecutive GEFS+ cases who did not show SCN1A mutations. Meanwhile, multiple missense mutations in SCN2A have since been described in another milder type of epilepsy, benign familial neonatal-infantile seizures (BFNIS) (Heron et al., 2002; Berkovic et al., 2004). Severe myoclonic epilepsy in infancy (SMEI) is an intractable epilepsy first described by Dravet (1978) that is much severer than GEFS+. SMEI patients often experience fever-induced tonic, clonic, and tonic–clonic seizures, beginning in the first year of life. In subsequent years, myoclonic and absence seizures follow. Seizures are intractable and often prolonged, frequently resulting in convulsive status epilepticus. Early psychomoter development is normal, but patients show acquired severe mental decline and ataxia by age 2. Clinically, GEFS+ and SMEI may present a continuum, with SMEI being proposed as the most severe phenotype within the GEFS+ spectrum (Singh et al., 2001). In fact, a significant number of mutations in SCN1A have also been reported in patients with SMEI (Claes et al., 2001, 2003; Sugawara et al., 2002; Ohmori et al., 2002; Fujiwara et al., 2003; Gennaro et al., 2003; Nabbout et al., 2003; Fukuma et al., 2004; Kimura et al., 2005). The number of reported SMEI-associated mutations of SCN1A now exceeds 100. In our study (Fujiwara et al., 2003), SCN1A mutations were detected in approximately 80% of SMEI patients; one third of the mutations were missense and two thirds of these were truncation mutations such as nonsense and frameshift. Missense mutations in SCN1A were also found in 70% of patients having intractable childhood epilepsy with generalized

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tonic–clonic (ICEGTC), an atypical SMEI that does not show myoclonic seizures (Fujiwara et al., 2003). These SMEI and ICEGTC mutations are mostly sporadic. However, the fact that several SCN1A mutations were found in familial SMEI cases whereby identical missense mutations were observed in family members with SMEI or ICEGTC as well as in those having idiopathic epilepsy, febrile seizures only, or even non-symptomatic individuals (Fujiwara et al., 2003; Nabbout et al., 2003; Kimura et al., 2005), suggests effects of genetic backgrounds or environmental modifiers, or more possibly mosaicisms in parents as shown in other genetic diseases (Poirier et al., 2005). We also described a sporadic and heterozygous R102X nonsense mutation of SCN2A in a patient with intractable epilepsy and severe mental decline (Kamiya et al., 2004). The phenotype of the patient with the SCN2A nonsense mutation is similar to SMEI but distinct because of partial epilepsy, delayed onset (1 year 7 months), and absence of temperature sensitivity. Thus, for both SCN1A and SCN2A voltage-gated sodium channels, missense mutations tend to result in benign idiopathic epilepsy, whereas truncation mutations lead to severe and intractable epilepsy, suggesting a similar underlying mechanism for these diseases. A significant number of biophysical studies on the GEFS+, SMEI, or ICEGTC-associated sodium channel gene mutations have been reported; however the functional consequences of those mutations still remain elusive. The proposed mechanisms, by which SCN1B mutations may increase the sodium ion current, include a slowing of inactivation (Wallace et al., 1998), an increase of sodium channel availability or a reduction of sodium current run-down during high frequency channel-activity (Meadows et al., 2002). However, a recent report of a SCN1B KO mouse with epileptic phenotypes suggested that the depletion of the ␤1 subunit affects the transport of the ␣-subunit and may consequently decrease the sodium current (Chen et al., 2004). Many biophysical studies had also been performed on SCN1A mutations (Alekov et al., 2000, 2001; Spampanato et al., 2001, 2003; Lossin et al., 2002, 2003; Sugawara et al., 2003; Rhodes et al., 2005). Some of these suggested increased activity of the channel (shortening refractory period after an action potential, persistent inward current, etc.) likely to be enhancing neuronal excitability. A computer simulation experiment also reported increased neuronal fir-

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ing with GEFS+ mutations (Spampanato et al., 2004). However, a significant number of GEFS+ missense mutations of SCN1A also showed reduced (Alekov et al., 2001; Spampanato et al., 2001) or complete absence of sodium current (Lossin et al., 2003). Analyses of SMEI-associated SCN1A mutants revealed that not only nonsense mutations, but also missense mutations, showed drastically attenuated sodium currents (Sugawara et al., 2003; Lossin et al., 2003). On the contrary, some SMEI missense mutations have been described to show non-inactivating channel activity with abnormal kinetics similar to those of GEFS+ (Rhodes et al., 2004). These data obtained by patchclamp analyses still cannot clearly explain the molecular phathogenesis of the disease phenotypes. However, the fact that the most GEFS+ mutations are missense while the major SMEI mutations are truncations (Fujiwara et al., 2003), still emphasize the importance of intrinsic nature of each SCN1A mutation. I previously proposed that the ultimate functional consequences of these mutations in the brain may be an overall reduction in channel activity, in which milder GEFS+ phenotypes may be explained by the intermediate reduction, not complete loss as in SMEI, of the channel activity (Yamakawa, 2005). Sodium channels play critical roles in generating action potentials along the axon. Characteristic properties of sodium currents in interneurons have been described including; less sensitive to inactivation, no slow recovery from iactivation that were observed in pyramidal cells, and higher density than in pyramidal neurons (Martina and Jonas, 1997; Martina et al., 2000). Therefore the reduction of sodium channel activity in interneurons may lead to a failure to suppress the hyperexcitablity of pyramidal neurons and the neural network as a whole. The abnormalities of sodium channel in GEFS+ and SMEI patients’ brain, mostly the reduction of channel proteins or their function, may lead to compromise of the function of interneurons that would lead to abnormal hyper-excitability of neural network as a whole, and would result in the epileptic seizures. Whereas the importance of biophysical analyses of disease-associated mutant voltage-gated sodium channels in cultured cells is clear, the resultant information is still elusive. It is now time to move on to the analyses on animal models with sodium channel gene mutations to answer questions on what the overall functional con-

sequences of these mutations are, within the brains of GEFS+ and SMEI-afflicted individuals, and to improve our understanding of the molecular pathologies of these epilepsies, and to develop effective therapies.

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