Human Molecular Genetics

Human Molecular Genetics Advance Access originally published online on February 7, 2006
Human Molecular Genetics 2006 15(6):1043-1048; doi:10.1093/hmg/ddl019

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Severe epilepsy resulting from genetic interaction between Scn2a and Kcnq2

Jennifer A. Kearney^1,*, Yan Yang², Barbara Beyer², Sarah K. Bergren¹, Lieve Claes³, Peter DeJonghe^3,4 and Wayne N. Frankel²

¹Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA, ²The Jackson Laboratory, Bar Harbor, MN 04609, USA, ³Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerp, Belgium and ⁴Division of Neurology, University Hospital of Antwerp, Antwerp, Belgium

^* To whom correspondence should be addressed at: Department of Human Genetics, 4909 Buhl Building 0618, 1241 E. Catherine Street, Ann Arbor, MI 48109-0618, USA. Tel: +1 7347631053; Fax: +1 7347639691; Email: jkearney{at}umich.edu

Received December 20, 2005; Accepted February 3, 2006

	ABSTRACT

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A mutation in the voltage-gated sodium-channel Scn2a results in moderate epilepsy in transgenic Scn2a^Q54 mice maintained on a C57BL/6J strain background. The onset of progressive epilepsy begins in adults with short-duration partial seizures that originate in the hippocampus. The underlying abnormality is an increase in persistent sodium current in hippocampal neurons. The voltage-gated potassium channel Kcnq2 is responsible for generating M current (I_KM) that is thought to control excitability and limit repetitive firing of hippocampal neurons. To determine whether impaired M current would exacerbate the seizure phenotype of Scn2a^Q54 mice, we carried out genetic crosses with two mutant alleles of Kcnq2. Szt1 mice carry a spontaneous deletion that removes the C-terminal domain of Kcnq2. A novel Kcnq2 missense mutation V182M was identified by screening the offspring of ENU-treated males for reduced threshold to electrically evoked minimal clonic seizures. Double mutant mice carrying the Scn2a^Q54 transgene together with either of the Kcnq2 mutations exhibited severe epilepsy with early onset, generalized tonic–clonic seizures and juvenile lethality by 3 weeks of age. This dramatic exacerbation of the sodium-channel mutant phenotype indicates that M current plays a critical role in preventing seizure initiation and spreading in this animal model. The genetic interaction between Scn2a and Kcnq2 demonstrates that combinations of mild alleles of monogenic epilepsy genes can result in severe disease and provides a model for complex inheritance of human epilepsy. The data suggest that interaction between these genes might contribute to the variable expressivity observed in human families with sodium-channel mutations. In a screen of 23 SMEI patients with missense mutations of SCN1A, no second-site mutations in KCNQ2 were identified.

	INTRODUCTION

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Epilepsy is a common neurological disorder affecting 1% of the population. During the last few years, there has been significant progress in identifying mutations responsible for monogenic epilepsy. Many of the responsible genes are components of neuronal signaling, including voltage-gated sodium and potassium channels (1,2). Generalized epilepsy with febrile seizures plus (GEFS+), a benign childhood-onset syndrome with autosomal dominant inheritance (OMIM 604233 [OMIM] ), can result from mutations in the sodium-channel genes SCN1A, SCN2A or SCN1B (2). Missense mutations in SCN2A have also been identified in benign familial neonatal-infantile seizures (2). More than 150 de novo mutations of SCN1A have been identified in the sporadic disorder severe myoclonic epilepsy of infancy (SMEI) (2,3).

A mouse model of sodium-channel-dependent epilepsy is provided by the Scn2a^Q54 transgenic line (4). On the C57BL/6J strain background, Scn2a^Q54 heterozygotes exhibit adult-onset, progressive epilepsy that begins with short-duration partial seizures of hippocampal origin. The causal mutation GAL879-881QQQ in the cytoplasmic S4–S5 linker of domain 2 results in delayed channel inactivation and increased persistent current (4). The level of persistent current in hippocampal neurons of Scn2a^Q54 mice (2% of total peak current) is comparable to that produced by mutations such as SCN1A^R1648H in families with GEFS+ (5). The severity of the Scn2a^Q54 phenotype is influenced by strain background, demonstrating that genetic modifiers can influence the clinical severity of sodium-channel-dependent epilepsy (6).

Forty-eight different mutations in the voltage-gated potassium channel genes KCNQ2 and KCNQ3 have been identified in the syndrome benign familial neonatal convulsions, a mild, autosomal dominant epilepsy with incomplete penetrance (OMIM nos 121 200 and 121 201) (1). A mouse model is provided by the Szt1 mutation, a spontaneous 300 kb deletion on mouse chromosome 2 that includes Kcnq2 (7). Mice heterozygous for the Szt1 mutation have increased susceptibility to seizures induced by electroconvulsive shock, but untreated Szt1 mice do not exhibit spontaneous seizures.

Variable expressivity is a common feature of inherited epilepsy caused by ion channel mutations in human patients, and family members carrying the same mutation often exhibit differences in clinical severity (2). It has been hypothesized that differences in genetic background, including sub-clinical ‘susceptibility’ alleles at other loci, may account for some of this variability. As a test of this hypothesis, we examined the effect of ‘susceptibility’ alleles of Kcnq2 on the epilepsy phenotype of Scn2a^Q54 mice.

	RESULTS

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A novel ENU-induced missense mutation in Kcnq2
C57BL/6J mice were mutagenized with ethyl-nitrosourea (ENU) and screened for response to electroconvulsive shock at The Jackson Laboratory Neuroscience Mutagenesis Facility (NMF) (8). The Nmf134 mutation was identified in this screen by its reduced seizure threshold. Nmf134 mice displayed low thresholds for minimal clonic seizures when compared with electroconvulsive thresholds obtained previously from wild-type C57BL/6J mice (9). Nmf134 mice also appear to have reduced threshold to seizures induced by petylenetetrazol (40 mg/kg, s.c.) (data not shown).

The Nmf134 mutation was genetically mapped as a binary dominant trait using 17 affected and 24 unaffected N2 backcross mice. The mutation was mapped to distal chromosome 2 by linkage with the markers D2Mit148 and D2Frk1. A peak LOD score of 4.2 was obtained with marker D2Frk1 located in an intron of the Kcnq2 gene. The coding exons of Kcnq2 were amplified by PCR of genomic DNA and analyzed by SSCP. Exon 4 exhibited an aberrant SSCP pattern and was sequenced. Comparison with the sequence from strain C57BL/6J identified a single G to A substitution in codon 182, which results in the amino acid substitution of methionine for valine (V182M) (Fig. 1A). Valine 182 is located in the S3 transmembrane segment of the potassium channel (Fig. 1D) and is evolutionarily invariant in homologous channels from other mammals, chicken and Drosophila and in paralogous channels of the Kcnq family (Fig. 1B and C).

View larger version (37K): [in this window] [in a new window]   Figure 1. Identification of the Nmf134 mutation. (A) The G>A substitution is demonstrated as G/A heterozygosity in a sequence chromatogram from an Nmf134/+ mouse. (B and C) Valine 182 is evolutionarily invariant in paralogous mouse channels of the Kcnq family (B) and in homologous channels from other species (C). (D) The V182M mutation is located in the S3 transmembrane segment of Kcnq2. (E) CSGE is used for genotyping to determine heterozygosity for the Kcnq2Nmf134 mutation.

 
Scn2a–Kcnq2 double mutants
In order to test the effect of combining epilepsy-associated mutations at different loci, we generated mice carrying mutations in both Scn2a and Kcnq2. Scn2a^Q54 heterozygotes were crossed with heterozygotes carrying the Kcnq2 mutations Szt1 or V182M. Offspring were monitored daily beginning at P7 to detect spontaneous seizures. The double heterozygotes exhibited a phenotype of much greater severity than the single mutants, with seizures beginning at 12 days of age and resulting in >90% lethality by 3 weeks of age (Fig. 2). We observed some double mutant mice dying during a seizure (Supplementary Material, Video S1); others died during the prolonged period of inactivity following a behavioral seizure presumed to be the post-ictal phase. The time between behavioral seizure onset and death is within 1–2 days. The prolonged generalized tonic–clonic seizures in the double heterozygotes can be seen in Supplementary Material, Videos S1 and S2. In contrast, the partial seizures of single mutant Scn2a^Q54 mice are of short duration and begin in adulthood (Supplementary Material, Video S3), and Szt1 and V182M single mutants do not exhibit any spontaneous seizures. Thus, age of onset, seizure type and seizure severity of mice carrying the Scn2a^Q54 mutation are all significantly exacerbated by combination with seizure-susceptible alleles of Kcnq2 (Table 1).

View larger version (14K): [in this window] [in a new window]   Figure 2. Increased lethality of the seizure disorder in (Scn2aQ54, Kcnq2) double heterozygous mutant mice. Prolonged, generalized tonic–clonic seizures in the double mutants begin at 12 days of age and result in >90% lethality by 21 days (Supplementary Material, Videos S1 and S2).

 

View this table: [in this window] [in a new window]   Table 1. Comparison of Scn2aQ54 and Kcnq2 single and double heterozygous mutant phenotypes

 
At 2 weeks of age, the morphology of the hippocampus in double mutant mice with seizures was normal (Fig. 3A), but there was a marked decrease of NeuN immunoreactivity in granule cells of the dentate gyrus (Fig. 3B). Loss of NeuN immunoreactivity can be considered a surrogate marker for severe neuronal injury, suggesting that the dentate granule cells are compromised in double mutant mice (10). There was no evidence of gliosis by glial fibrillary acidic protein (GFAP) immunohistochemistry in double mutant mice (Fig. 3C). The rapid clinical course between seizure onset and death (1–2 days) may limit the development of neuropathology. No abnormalities were observed in the V182M/+ (Fig. 3), Szt1 or Scn2a^Q54 single mutants (data not shown).

View larger version (82K): [in this window] [in a new window]   Figure 3. Hippocampal histopathology in (Scn2aQ54, Kcnq2Nmf134) double heterozygous mutant mice. (B and C) Brain sections from 2-week-old double mutant mice and littermate controls were stained with antibodies to NeuN and GFAP. (A) Adjacent sections were stained with cresyl violet. Double mutant mice exhibit a marked decrease of NeuN immunoreactivity in the granule cells of the dentate gyrus (DG). Scale bar, 100 µm.

 
KCNQ2 screening of patients with mutations in SCN1A
We studied seven SMEI patients who inherited SCN1A mutations from an unaffected parent. Six of these inherited cases were missense mutations and one was a nonsense mutation. We hypothesized that the affected individuals might carry a variant of KCNQ2 that was not present in the unaffected parent. We also screened 16 sporadic SMEI patients with de novo missense mutations of SCN1A. The 17 exons of KCNQ2 were amplified from genomic DNA and screened for variants by CSGE and sequencing. No missense or splice-site mutations were detected other than the previously described polymorphic variant T780N. The frequency of this variant in the SMEI patients did not differ from the previously reported control values (11,12). This small screen did not provide direct evidence for a role of KCNQ2 in the variable expressivity of human SCN1A missense mutations.

	DISCUSSION

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Mutations in voltage-gated sodium and potassium channels have been identified in human epilepsy. We report the identification of a new mutant allele of Kcnq2 that exhibits increased seizure susceptibility. It has been suggested that sub-clinical variants at other loci may underlie the variable expressivity that is common among family members with the same primary epilepsy mutation. To test this hypothesis, we examined the effect two Kcnq2 seizure-susceptible alleles, Szt1 and Kcnq2^V182M, on severity of epilepsy due to a sodium-channel mutation.

The phenotype of Kcnq2^V182M heterozygotes and homozygotes closely resembles that seen in mice with targeted deletion of Kcnq2 (13), suggesting that the Kcnq2^V182M mutation is a loss-of-function allele. The Szt1 mutation is a 300 kb deletion on mouse chromosome 2 that includes two genes associated with human epilepsy, Kcnq2 and Chrna4. The phenotype of Szt1 heterozygotes is similar to that seen in Kcnq2 null heterozygotes (13), whereas Chrna4 null heterozygotes have not been reported to be seizure-sensitive. The Scn2a^Q54, Szt1/+ double mutant phenotype closely resembles that observed in Scn2a^Q54, Kcnq2^V182M/+ double mutants, suggesting that Kcnq2 haploinsufficiency underlies the seizure-susceptible phenotype of Szt1/+ mice. Functional studies of KCNQ2 human epilepsy mutations demonstrated that most lead to a reduction of potassium current (14,15).

The combination the Scn2a^Q54 sodium-channel mutation with a Kcnq2 seizure-susceptibility allele results in a dramatic exacerbation of epilepsy, changing the clinical manifestation from mild, late-onset epilepsy to severe, juvenile-onset disease. This effect may be understood in light of the distinct roles of SCN2A and KCNQ2 in neuronal excitability. Voltage-gated sodium channels such as SCN2A open in response to membrane depolarization, resulting in initiation and propagation of action potentials. KCNQ2 co-assembles with KCNQ3 to form the heteromeric potassium channel that is responsible for M current, a slowly activating and deactivating potassium conductance that limits excitability and repetitive firing (16). M current slowly activates in the voltage range of action potential initiation, repolarizing the membrane and suppressing repetitive firing (17). The Scn2a^Q54 mutation generates abnormal persistent sodium current that results in a lowered neuronal firing threshold. The combination of persistent sodium current with reduced M current due to a Kcnq2 mutation may facilitate further depolarization, resulting in spreading of hyperexcitability and generalized seizures. Future biophysical analyses of hippocampal slices may elucidate the neuronal pathways contributing to hyperexcitability in double mutant mice.

Our results indicate that M current is an important factor limiting seizure initiation and spreading in single mutant Scn2a^Q54 mice and suggest that Kcnq2 and Kcnq3 may be therapeutic targets for treatment of epilepsy caused by sodium-channel mutations. Functional up-regulation of these potassium channels might ameliorate the effects of a sodium-channel mutation. Recent pharmacological studies support the potential of KCNQ channel openers for treatment of disorders of neuronal excitability, including epilepsy and migraine (18).

Although most SCN1A mutations in SMEI result in loss of channel activity, recent studies have demonstrated that gain-of-function defects can also result in SMEI (19). Likewise, some GEFS+ mutations appear to result in loss-of-function defects (20). In a few cases, SMEI patients have inherited an SCN1A mutation from an unaffected or mildly affected parent. Thus, there is no simple correlation between clinical phenotype and biophysical properties of the mutated SCN1A. It has been suggested that factors such as genetic modifiers may contribute to differences in severity between individuals carrying identical or similar mutations. To determine whether second-site mutations in KCNQ2 might contribute to the more severe phenotypes in these cases, we screened a small cohort of SMEI patients with missense mutations of SCN1A, including seven cases with mutations inherited from unaffected parents. This small screen did not identify coding or splice-site variants of KCNQ2. Future analysis of a larger population might reveal interactions between human SCN1A and KCNQ2. In crosses between mouse strains C57BL/6J and SJL/J, we have mapped two epilepsy modifiers to chromosome regions corresponding to human 9p21–24, 10q21–25 and 17q21–24 (6). These and other loci may also contribute to the complex relationship between genotype and clinical severity of sodium-channel mutations.

More than 150 mutations in voltage-gated sodium channels and 48 mutations in KCNQ2 and KCNQ3 have been identified thus far in patients with epilepsy (2,21). Variable expressivity is a common feature of these disorders. Our results suggest that interaction between variants in sodium- and potassium-channel genes may contribute to the complex inheritance of human epilepsy.

	MATERIALS AND METHODS

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Mice
Scn2a^Q54 (TgN54Mm) transgenic mice were generated as described (4). The congenic line C57BL/6J.Q54 (abbreviated B6.Q54) was established by 10 successive generations of backcrossing to strain C57BL/6J as previously described (6). The Szt1 mutation arose spontaneously in the C57BL/6J stock at The Jackson Laboratory NMF. The mutation is a 300 kb genomic deletion that includes Kcnq2 and two other genes (7). Nmf134 mice were generated at The Jackson Laboratory NMF (http://nmf.jax.org) as described subsequently.

ENU mutagenesis and phenotyping
C57BL/6J males were mutagenized with ENU administered in three weekly injections of 80 mg/kg. Electroconvulsive threshold for minimal clonic seizures was determined as previously described (9). Briefly, mice were restrained, a drop of anesthetic (0.5% tetracaine/0.9% NaCl) was placed on each eye and a preset current was applied via silver transcorneal electrodes using an electroconvulsive stimulator (Ugo Basile Model 7801). The stimulator was set at the critical current for minimal seizure induction in 3% of the population for C57BL/6J mice (6.5 mA females or 8.0 mA males).

Mapping cross
The Nmf134 mutation was mapped in the backcross: (C57BL/6J-Nmf134xBALB/cByJ)F1xC57BL/6J-Nmf134. Backcross mice were assessed for minimal clonic seizures using a modified Racine scale (seizure grades: 0, no observable symptoms; 3, rearing, forelimb and jaw clonus; 5, tonic hindlimb extension). Microsatellite markers were amplified by PCR and run on 6% denaturing polyacrylamide gels.

Generation of double mutants
We generated double heterozygotes by crossing transgenic line B6.Q54 with heterozygous B6.Szt1/+ and B6.Kcnq2-V182M (Nmf134) mice. Mice were genotyped for the Scn2a^Q54 transgene and the Szt1 mutation as previously described (6,7). Heterozygosity for the Kcnq2-V182M mutation was determined by analysis of PCR products (forward-5'-AGGTGCAATGGCTGACAGG-3' and reverse-5'-CTGGGTCAGTGCTGCTCAC-3') using conformation-sensitive gel electrophoresis (CSGE) (Fig. 1E). Both types of double mutants were obtained in the expected Mendelian ratio.

Histology
Mice were perfused transcardially with phosphate-buffered saline (PBS) followed by 4% paraformaldehyde. Brains were post-fixed overnight and cryoprotected in 20% sucrose in PBS. Forty-micrometer sections were prepared with a sliding microtome. Free-floating sections were processed for immunohistochemistry with rabbit polyclonal antisera for NeuN (Chemicon, 1:1000) or GFAP (Sigma, 1:200). Immunoreactivity was visualized by the avidin–biotin conjugate technique using a Vectastain Elite kit (Vector, Burlingame, CA, USA) with NiCl₂ enhancement. Adjacent sections were stained with cresyl violet. Slides were viewed by light microscopy with an Olympus BX-51A fitted with a DP70 Digital camera.

Screening of KCNQ2
The 17 exons of KCNQ2 were amplified from genomic DNA and variants were identified by CSGE and sequencing using previously described methods (22).

	SUPPLEMENTARY MATERIAL

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Supplementary Material is available at HMG Online.

	ACKNOWLEDGEMENTS

 
We thank the patients and their families for their cooperation. We thank Kevin Seburn, Michael McCluskey and Louise Dionne for initial characterization of Nmf134 mice and Miriam Meisler for critical reading of the article. This work was supported by the NMF at The Jackson Laboratory (U01 NS41215), NIH research grant R21 NS046315 (JAK), The Fund for Scientific Research Flanders, University of Antwerp and the Interuniversity Attraction Poles program P5/19 of the Federal Science Policy Office, Belgium (P.D.J. and L.C.). L.C. is a post-doctoral fellow of The Institute for Science and Technology and D.A. of the FWO, Belgium.

Conflict of Interest statement. None declared.

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