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Title: A Role of SCN9A in Human Epilepsies, As a Cause of Febrile Seizures and As a Potential Modifier of Dravet Syndrome}
Article:
Abstract:
A follow-up study of a large Utah family with significant linkage to chromosome 2q24 led us to identify a new febrile seizure( FS) gene, SCN9A encoding Nav1. 7. In 21 affected members, we uncovered a potential mutation in a highly conserved amino acid, p. N641Y, in the large cytoplasmic loop between transmembrane domains I and II that was absent from 586 ethnically matched population control chromosomes. To establish a functional role for this mutation in seizure susceptibility, we introduced the orthologous mutation into the murine Scn9a ortholog using targeted homologous recombination. Compared to wild-type mice, homozygous Scn9aN641Y/N641Y knockin mice exhibit significantly reduced thresholds to electrically induced clonic and tonic-clonic seizures, and increased corneal kindling acquisition rates. Together, these data strongly support the SCN9A p. N641Y mutation as disease-causing in this family. To confirm the role of SCN9A in FS, we analyzed a collection of 92 unrelated FS patients and identified additional highly conserved Nav1. 7 missense variants in 5% of the patients. After one of these children with FS later developed Dravet syndrome( severe myoclonic epilepsy of infancy), we sequenced the SCN1A gene, a gene known to be associated with Dravet syndrome, and identified a heterozygous frameshift mutation. Subsequent analysis of 109 Dravet syndrome patients yielded nine Nav1. 7 missense variants( 8% of the patients), all in highly conserved amino acids. Six of these Dravet syndrome patients with SCN9A missense variants also harbored either missense or splice site SCN1A mutations and three had no SCN1A mutations. This study provides evidence for a role of SCN9A in human epilepsies, both as a cause of FS and as a partner with SCN1A mutations.
Introduction:
Febrile seizures( FS) are the most common seizure disorder of early childhood, and exhibit a prevalence of 2–5% in European and North American children[1]. Large FS families reported in the clinical literature support a genetic etiology for febrile seizures, as does the 31% incidence of FS in first-degree relatives[2]. Individuals who experience FS have a 2–9% chance of developing afebrile seizures later in life[1] and this incidence is four times higher if there is a family history of FS[3]. These later-onset epileptic phenomena include generalized convulsive, as well as simple and complex partial seizures that can be resistant to currently available anticonvulsant therapy[1]. Notably, FS occur in up to 75% of children with the catastrophic early-onset epilepsy disorder of ‘severe myoclonic epilepsy of infancy’ or Dravet syndrome. In Dravet syndrome, a normally developing child at 2 to12 months of age has convulsive seizures that are prolonged and indiscriminately lateralized. In the second or third year of life, these children have frequent myoclonic, partial and atypical absences as well. While the myoclonic attacks disappear after 4–7 years, these children continue to have generalized tonic-clonic, clonic and complex partial seizures with common episodes of nonconvulsive status epilepticus[1]. The hypothesis that alleles predisposing to FS may be found in Dravet syndrome patients led Claes et al. to find a high frequency of SCN1A gene mutations in patients with Dravet syndrome[1],[4],[5]. Since then, others have proposed a complex genetic etiology for Dravet syndrome. This is based on the observation that over 50% of Dravet syndrome patients have de novo SCN1A mutations yet belong to families with a history of FS[6]–[9]. In addition, identical SCN1A missense or truncation mutations are associated with widely different seizure severities, including intractable seizures of Dravet syndrome, comparatively benign FS, and even asymptomatic family members in some cases[10]–[12]. However, definitive genetic evidence supporting a multifactorial hypothesis of Dravet syndrome is lacking[8],[13]. We previously reported linkage( LOD = 8. 1) to a 10 centimorgan( cM) region on chromosome 2q24 in a large Utah kindred( K4425) with FS before the age of six years in 21 individuals, including 10 individuals with subsequent afebrile seizures[14]. This region contains five sodium channel α subunit genes including SCN1A, SCN2A and SCN3A that share over 85% identity and are highly expressed in brain[15]. SCN1A is commonly mutated in Dravet syndrome and mutations in either SCN2A or SCN1A are associated with the generalized( genetic) epilepsy febrile seizure plus( GEFS+) syndrome[4],[16]–[18]. Mutations in SCN2A have also been reported in patients with benign familial neonatal-infantile seizures and a single SCN3A mutation has recently been identified in a pediatric patient with partial epilepsy[19],[20]. Clearly, this genomic region contains several important genes that impact seizure susceptibility in children.
Discussion:
In this study, we have shown that a mutation in a highly conserved amino acid residue of the SCN9A sodium channel alpha subunit is associated with a wide clinical spectrum of seizure phenotypes in a single large family. These phenotypes include simple FS, self-limited afebrile seizures, and temporal lobe epilepsy. The SCN9A-N641Y segregating mutation in our large K4425 FS family, and the significantly reduced seizure threshold and enhanced kindling acquisiton rate phenotypes conferred uniquely by the same mutation introduced into the Scn9a-N641Y knockin mouse, provide strong evidence that SCN9A has a role in central excitability and is disease-causing in this family. In addition, we find supporting evidence for a multifactorial etiology of Dravet syndrome by uncovering concurrent variants in both SCN9A and SCN1A in a subset of our patients. Our findings of numerous variants in separate FS and Dravet syndrome cohorts are statistically significant( p<0. 05) when the frequency of the combined specific altered residues found in patients is compared to those same residues in controls, but not statistically significant when all variants found in FS and Dravet syndrome patients are compared to all variants found in controls. While our findings provide highly suggestive evidence of the role of SCN9A in FS and Dravet syndrome, replication in multiple cohorts, combined with functional studies, is needed to confirm a hyperexcitable role of SCN9A in unrelated epilepsy patients. The multifactorial etiology of Dravet syndrome proposed by many investigators suggests that it is very likely that genes responsible for Dravet syndrome will far outnumber SCN1A and SCN9A. The corneal stimulation paradigm is a reliable and reproducible measure for inducing seizures to test the efficacy of anticonvulsant drugs[34]. A Kcnq3 and two separate Kcnq2 mouse models as well as the models for the Wolf-Hirschhorn deletion syndrome have helped to validate the corneal stimulation paradigm as a robust seizure susceptibility test[33],[38],[39]. Here, we show that homozygous knockin Scn9aN641Y/N641Y mice are significantly more susceptible than wild-type mice to seizures that activate either the forebrain or hindbrain. Both the clonic and tonic-clonic generalized seizures characteristic of FS patients are induced by lower stimulation currents in mice that harbor the p. N641Y mutation in Scn9a. In the corneal kindling model, repeated application of an initially subconvulsive electrical stimulus results in progressive escalation of the stimulus-induced epileptic activity, culminating in a partial seizure that secondarily generalizes[35]. This model of partial epilepsy successfully validated a first-in-class neurotherapeutic agent based on galanin for treating pharmacoresistant epilepsy[40] and differentiated knockin mutations known to cause childhood epilepsy. Indeed, mutations in the Kcnq2 and Kcnq3 subunits that underlie M-current channels were recently shown to significantly increase the rate of corneal kindling[41]. Our model adds to the growing list of other specific human epilepsy knockin mice, including the Gabrg2[42], Kcnq2[33], Kcnq3[33], Scn1a[43] and Chrna4[44] mice, to report a clear-cut genotype to phenotype seizure susceptibility. In multiple published studies, some Dravet syndrome patients inherit SCN1A mutations from asymptomatic or mildly affected parents, making multiple mutations in this syndrome a likely finding[7],[11],[12]. Furthermore, modifying alleles may preferentially be found in Dravet syndrome patients with SCN1A mutations that are less deleterious when compared to complete heterozygous loss of function mutations. This is indeed that case for the majority of our Dravet syndrome patients with SCN9A variants. Six out of seven of our Dravet syndrome patients with SCN9A variants harbor either missense or splice site mutations in SCN1A while a sizable portion of published SCN1A mutations are predicted to lead to truncated proteins[8]. Our results support the idea that some SCN9A variants when found alone might be asymptomatic or cause infrequent febrile seizures due to incomplete penetrance and variable expressivity, but likely contribute in a multifactorial fashion to Dravet syndrome. Indeed, a recent finding of almost 100 unique missense SCN1A mutations challenges the previously held notion that haploinsufficient SCN1A mutations alone are responsible for Dravet syndrome because many of these missense mutations likely confer only partial, rather than complete, heterozygous loss of function[22]. Our results now suggest that Dravet syndrome may be included in the list of disorders with “modifier” genes that include Huntington's disease and cystic fibrosis[45]. Additional new functional data that examines the two gene mutations will be required to test if the “two-hit” hypothesis is valid in certain Dravet syndrome patients. None of our FS or Dravet syndrome variants overlaps with the SCN9A disease-associated changes found in the extreme pain or insensitivity to pain disorders[24]–[26],[46]. Furthermore, in all published studies of PE, PEPD and CIP, an increased incidence of seizures is not reported in patients with SCN9A mutations[24]–[26]. After follow-up questioning, none of the 21 affected members of K4425 reported the easily recognized extreme pain phenotypes associated with some SCN9A missense mutations. PEPD is often misdiagnosed as epilepsy because tonic non-epileptic seizures are a particular feature in infancy and early childhood. However the “slow-flat-slow” ictal EEG pattern associated with profound syncope in PEPD patients is clearly not epileptiform, whereas EEGs in K4425 patients are epileptiform[14],[47]. Another distinguishing feature is that PEPD attacks are provoked by physical stimulation and not by hyperthermia as seen in FS. The notion that dysfunction in the same ion channel can be associated in distinct paroxysmal phenotypes is already known for SCN9A. In 17 of 18 patients with SCN9A missense mutations published to date, the rectal, ocular and mandibular pain seen in PEPD does not overlap with the severe burning hand and foot pain characteristic of PE[48]. We now extend the tissue specificity of paroxysmal Nav1. 7 malfunction to the central nervous system. Additional support for discrete phenotypes resulting from the same ion channel protein comes from the identification of SCN1A mutations in either epilepsy or familial hemiplegic migraine[49], and CACNA1A mutations in familial hemiplegic migraine, episodic ataxia and spinocerebellar ataxia[50]. Experimentally, the Nav1. 7 p. L858H PE mutation causes hyperexcitable sensory neurons and hypoexcitable sympathetic neurons, and these opposing electrical properties are a result of neuron specific physiologically coupled proteins[51]. A unique complement of Nav1. 7 interacting proteins or second messenger pathways in the central nervous system may also explain how the same gene previously implicated with peripheral pain can also be associated with an epilepsy phenotype, but this hypothesis will require further study.
Febrile seizures are the most common seizure disorder of early childhood , and exhibit a prevalence of 2%–5% in European and North American children . While the genetic basis of febrile seizures is well-documented , efforts to uncover these genes have yielded only a few genes in a small proportion of cases . In a genomic region on human chromosome 2 known to harbor the febrile seizure SCN1A sodium channel gene , we now report a disease-causing mutation in the adjacent gene , SCN9A ( Nav1 . 7 ) , in a large family with febrile seizures . We introduced the family mutation ( N641Y ) into the orthologous mouse gene to create a knockin mouse model , and tested seizure susceptibility in these mice . Compared to wild-type mice , our Scn9a knockin mice have a significantly lower threshold to electrically induced seizures and experience seizures at a significantly faster rate with repeated subthreshold stimulation . We also report novel missense SCN9A mutations in unrelated febrile seizure patients . Furthermore , we show that a subset of patients with the catastrophic early-onset Dravet syndrome who commonly have mutations in SCN1A also harbor mutations in SCN9A . This finding is important as it demonstrates for the first time mutational evidence for a modifying digenic mechanism of human epilepsy . For infants with Dravet syndrome , a genetic diagnosis will be of immediate benefit to guide therapeutics away from the sodium channel blocking class of anticonvulsant drugs that exacerbate seizures but are often the first administered .