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
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
A mutation in the voltage-gated sodium-channel Scn2a results in moderate epilepsy in transgenic Scn2aQ54 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 (IKM) 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 Scn2aQ54 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 Scn2aQ54 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.
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