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.

Public Health Relevance

An estimated one in twenty-six Americans will develop epilepsy during their lifetime, making it the fourth most common neurological disorder in the United States. Epilepsy is often caused by mutations in genes that are critical for neuronal communication in the brain. Understanding how genetic mutations lead to epilepsy can improve diagnosis and treatment of this disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Whittemore, Vicky R
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Northwestern University at Chicago
Schools of Medicine
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Calhoun, Jeffrey D; Vanoye, Carlos G; Kok, Fernando et al. (2017) Characterization of a KCNB1 variant associated with autism, intellectual disability, and epilepsy. Neurol Genet 3:e198
Calhoun, Jeffrey D; Hawkins, Nicole A; Zachwieja, Nicole J et al. (2017) Cacna1g is a genetic modifier of epilepsy in a mouse model of Dravet syndrome. Epilepsia 58:e111-e115
Lamar, Tyra; Vanoye, Carlos G; Calhoun, Jeffrey et al. (2017) SCN3A deficiency associated with increased seizure susceptibility. Neurobiol Dis 102:38-48
Thompson, Christopher H; Hawkins, Nicole A; Kearney, Jennifer A et al. (2017) CaMKII modulates sodium current in neurons from epileptic Scn2a mutant mice. Proc Natl Acad Sci U S A 114:1696-1701
Calhoun, Jeffrey D; Hawkins, Nicole A; Zachwieja, Nicole J et al. (2016) Cacna1g is a genetic modifier of epilepsy caused by mutation of voltage-gated sodium channel Scn2a. Epilepsia 57:e103-7
Hawkins, Nicole A; Zachwieja, Nicole J; Miller, Alison R et al. (2016) Fine Mapping of a Dravet Syndrome Modifier Locus on Mouse Chromosome 5 and Candidate Gene Analysis by RNA-Seq. PLoS Genet 12:e1006398
Hawkins, Nicole A; Kearney, Jennifer A (2016) Hlf is a genetic modifier of epilepsy caused by voltage-gated sodium channel mutations. Epilepsy Res 119:20-3
Vanoye, Carlos G; Gurnett, Christina A; Holland, Katherine D et al. (2014) Novel SCN3A variants associated with focal epilepsy in children. Neurobiol Dis 62:313-22
Miller, A R; Hawkins, N A; McCollom, C E et al. (2014) Mapping genetic modifiers of survival in a mouse model of Dravet syndrome. Genes Brain Behav 13:163-72
Anderson, Lyndsey L; Thompson, Christopher H; Hawkins, Nicole A et al. (2014) Antiepileptic activity of preferential inhibitors of persistent sodium current. Epilepsia 55:1274-83

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