Combined Approach to the Genetic Basis of Epilepsy

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 DESCRIPTION (provided by applicant) Epilepsy is a common neurological disorder that affects approximately three million people in the United States. Approximately 30-40% of patients are unable to achieve adequate seizure control with currently available treatments. Understanding the causes of intractable epilepsy may suggest alternative therapeutic strategies that will address this critical unmet need. Epilepsy is presumed to have a genetic basis in approximately 70% of cases. Numerous genes associated with epilepsy have been identified, and most are components of neuronal signaling, including ion channels, ion channel-associated proteins, and synaptic proteins. Epileptic encephalopathies are particularly severe childhood epilepsies that often include intractable seizures, and are frequently attributable to de novo single gene mutations. Studying mouse models of epilepsy have increased our understanding of the etiology and pathogenesis of epilepsy. In the previous funding period, we used mouse models with voltage-gated sodium channel mutations to examine the effect of genome variation on epilepsy severity and identified several modifier loci and genes. A number of genes influenced phenotype severity of the Scn2aQ54 mouse model, including Kcnv2, Hlf, and Cacna1g. Kcnv2 encodes the Kv8.2 voltage-gated potassium channel subunit, which modulates delayed rectifier potassium currents by co- assembling in heteromeric channels with Kv2.1, encoded by Kcnb1. Delayed rectifier potassium current is an important mediator of neuronal excitability particularly under conditions of repetitive firing. We hypothesized that genetic variation in KCNV2 or KCNB1 may contribute to epilepsy risk in humans. Recently, we identified de novo mutations of KCNB1 as a novel cause early infantile epileptic encephalopathy type 26 (EIEE26), which is characterized by pharmacoresistant seizures with associated cognitive and motor deficits. We propose to continue our research program on the genetic basis of epilepsy with a focus on this newly described syndrome, EIEE26. First, we will perform functional studies on a large series of KCNB1 patient mutations in order to determine the range of functional defects and define genotype-phenotype relationships. In addition, we will develop and characterize murine models of EIEE26 in order to better understand how KCNB1 mutations lead to epilepsy. Finally, we will determine how genome background influences disease severity in Kcnb1 mouse models and identify modifier loci. The proposed studies will provide insight into the genetic architecture of epilepsy, and improve treatment of patients by enhancing precision of molecular diagnosis and suggesting novel pathways for therapeutic intervention.