Abstract
Mutations in voltage-gated sodium channels are associated with several types of human epilepsy. Variable expressivity and penetrance are common features of inherited epilepsy caused by sodium channel mutations, suggesting that genetic modifiers may influence clinical severity. The mouse model Scn2a Q54 has an epilepsy phenotype due to a mutation in Scn2a that results in elevated persistent sodium current. Phenotype severity in Scn2a Q54 mice is dependent on the genetic background. Congenic C57BL/6J.Q54 mice have delayed onset and low seizure frequency compared to (C57BL/6J × SJL/J)F1.Q54 mice. Previously, we identified two modifier loci that influence the Scn2a Q54 epilepsy phenotype: Moe1 (modifier of epilepsy 1) on Chromosome 11 and Moe2 on Chromosome 19. We have constructed interval-specific congenic strains to further refine the position of Moe2 on Chromosome 19 to a 5-Mb region. Sequencing and expression analyses of genes in the critical interval suggested two potential modifier candidates: (1) voltage-gated potassium channel subunit subfamily V, member 2 (Kcnv2), and (2) SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 2 (Smarca2). Based on its biological role in regulating membrane excitability and the association between ion channel variants and seizures, Kcnv2 is a strong functional candidate for Moe2. Modifier genes affecting the epilepsy phenotype of Scn2a Q54 mice may contribute to variable expressivity and penetrance in human epilepsy patients with sodium channel mutations.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abou-Khalil B, Ge Q, Desai R, Ryther R, Bazyk A et al (2001) Partial and generalized epilepsy with febrile seizures plus and a novel SCN1A mutation. Neurology 57:2265–2272
Adamska M, MacDonald BT, Meisler MH (2003) Doubleridge, a mouse mutant with defective compaction of the apical ectodermal ridge and normal dorsal–ventral patterning of the limb. Dev Biol 255:350–362
Beck JA, Lloyd S, Hafezparast M, Lennon-Pierce M, Eppig JT et al (2000) Genealogies of mouse inbred strains. Nat Genet 24:23–25
Bergren SK, Chen S, Galecki A, Kearney JA (2005) Genetic modifiers affecting severity of epilepsy caused by mutation of sodium channel Scn2a. Mamm Genome 16:683–690
Buchner DA, Trudeau M, Meisler MH (2003) SCNM1, a putative RNA splicing factor that modifies disease severity in mice. Science 301:967–969
Cartegni L, Wang J, Zhu Z, Zhang MQ, Krainer AR (2003) ESEfinder: a web resource to identify exonic splicing enhancers. Nucleic Acids Res 31:3568–3571
Catterall WA, Dib-Hajj S, Meisler MH, Pietrobon D (2008) Inherited neuronal ion channelopathies: new windows on complex neurological diseases. J Neurosci 28:11768–11777
Colosimo E, Gambardella A, Mantegazza M, Labate A, Rusconi R et al (2007) Electroclinical features of a family with simple febrile seizures and temporal lobe epilepsy associated with SCN1A loss-of-function mutation. Epilepsia 48:1691–1696
Cutler G, Marshall LA, Chin N, Baribault H, Kassner PD (2007) Significant gene content variation characterizes the genomes of inbred mouse strains. Genome Res 17:1743–1754
Czirjak G, Toth ZE, Enyedi P (2007) Characterization of the heteromeric potassium channel formed by kv2.1 and the retinal subunit kv8.2 in Xenopus oocytes. J Neurophysiol 98:1213–1222
Escayg A, MacDonald B, Meisler M, Baulac S, Huberfeld G et al (2000) Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS + 2. Nat Genet 24:343–345
Frankel WN, Taylor L, Beyer B, Tempel BL, White HS (2001) Electroconvulsive thresholds of inbred mouse strains. Genomics 74:306–312
Grupe A, Germer S, Usuka J, Aud D, Belknap JK et al (2001) In silico mapping of complex disease-related traits in mice. Science 292(5523):1915–1918
Holland KD, Kearney JA, Glauser TA, Buck G, Keddache M et al (2008) Mutation of sodium channel SCN3A in a patient with cryptogenic pediatric partial epilepsy. Neurosci Lett 433:65–70
Kearney JA, Plummer NW, Smith MR, Kapur J, Cummins TR et al (2001) A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities. Neuroscience 102:307–317
Kearney JA, Yang Y, Beyer B, Bergren SK, Claes L et al (2006) Severe epilepsy resulting from genetic interaction between Scn2a and Kcnq2. Hum Mol Genet 15:1043–1048
Kitami T, Ernest S, Gallaugher L, Friedman L, Frankel WN et al (2004) Genetic and phenotypic analysis of seizure susceptibility in PL/J mice. Mamm Genome 15:698–703
Letwin NE, Kafkafi N, Benjamini Y, Mayo C, Frank BC et al (2006) Combined application of behavior genetics and microarray analysis to identify regional expression themes and gene–behavior associations. J Neurosci 26:5277–5287
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25(4):402–408
Lossin C, Wang DW, Rhodes TH, Vanoye CG, George AL Jr (2002) Molecular basis of an inherited epilepsy. Neuron 34:877–884
MacDonald BT, Adamska M, Meisler MH (2004) Hypomorphic expression of Dkk1 in the doubleridge mouse: dose dependence and compensatory interactions with Lrp6. Development 131:2543–2552
Meisler MH, Kearney JA (2005) Sodium channel mutations in epilepsy and other neurological disorders. J Clin Invest 115:2010–2017
Misonou H, Mohapatra DP, Trimmer JS (2005) Kv2.1: a voltage-gated K+ channel critical to dynamic control of neuronal excitability. Neurotoxicology 26:743–752
Moloney FJ, Lyons JG, Bock VL, Huang XX, Bugeja MJ et al (2009) Hotspot mutation of brahma in non-melanoma skin cancer. J Invest Dermatol 129(4):1012–1015
Ottschytsch N, Raes A, Van HD, Snyders DJ (2002) Obligatory heterotetramerization of three previously uncharacterized Kv channel alpha-subunits identified in the human genome. Proc Natl Acad Sci USA 99:7986–7991
Pandey N, Mittal U, Srivastava AK, Mukerji M (2004) SMARCA2 and THAP11: potential candidates for polyglutamine disorders as evidenced from polymorphism and protein-folding simulation studies. J Hum Genet 49:596–602
Park YG, Clifford R, Buetow KH, Hunter KW (2003) Multiple cross and inbred strain haplotype mapping of complex trait candidate genes. Genome Res 13:118–121
Pfaffl MW, Horgan GW, Dempfle L (2002) Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res 30(9):e36
Pletcher MT, McClurg P, Batalov S, Su AI, Barnes SW et al (2002) Use of a dense single nucleotide polymorphism map for in silico mapping in the mouse. PLoS Biol 2(12):e393
Plummer NW, Galt J, Jones JM, Burgess DL, Sprunger LK et al (1998) Exon organization, coding sequence, physical mapping, and polymorphic intragenic markers for the human neuronal sodium channel gene SCN8A. Genomics 54:287–296
Ramensky V, Bork P, Sunyaev S (2002) Human non-synonymous SNPs: server and survey. Nucleic Acids Res 30:3894–3900
Reyes JC, Barra J, Muchardt C, Camus A, Babinet C et al (1998) Altered control of cellular proliferation in the absence of mammalian brahma (SNF2alpha). EMBO J 17:6979–6991
Szatkiewicz JP, Beane GL, Ding Y, Hutchins L, Pardo-Manuel de Villena F et al (2008) An imputed genotype resource for the laboratory mouse. Mamm Genome 19(3):199–208
Wallace RH, Wang DW, Singh R, Scheffer IE, George AL et al (1998) Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B. Nat Genet 19:366–370
Acknowledgments
We thank Rebecca Somershoe for technical assistance and Dr. Miriam Meisler for providing the Dblr mice. This work was supported by a National Institutes of Neurological Disorders and Stroke grant NS053792 (JK) and The Partnership for Pediatric Epilepsy Research (JK).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bergren, S.K., Rutter, E.D. & Kearney, J.A. Fine mapping of an epilepsy modifier gene on mouse Chromosome 19. Mamm Genome 20, 359–366 (2009). https://doi.org/10.1007/s00335-009-9193-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00335-009-9193-6