Mutations in voltage-gated sodium channels have been associated with several types of human epilepsy, including Genetic (Generalized) Epilepsy with Febrile Seizure Plus (GEFS+) and Dravet Syndrome. Within these genetic epilepsies, there is variable penetrance and expressivity of the clinical phenotype, suggesting a role for genetic modifiers. We have developed mouse models with mutations in voltage-gated sodium channels and seizure-related phenotypes with different underlying mechanisms. Scn2aQ54 transgenic mice have a gain-of-function mutation that results in spontaneous, adult-onset partial motor seizures and models features of GEFS+. Heterozygous Scn1a+/- null mice are a model of Dravet Syndrome, a severe, infant-onset epilepsy with progressive worsening accompanied by psychomotor regression. A common feature of these mouse models is that epilepsy severity varies depending on the genetic strain background, suggesting that genetic modifiers influence the phenotype. Scn2aQ54 mice on the resistant C57BL/6J background have delayed onset, decreased severity and improved survival compared to the susceptible (C57BL/6J x SJL/J)F1 background. Conversely, the epilepsy phenotype of Scn1a+/- mice is more severe on the C57BL/6J background, while they have delayed onset and improved survival on the 129S6/SvEvTac strain background. Based on these observations, we hypothesize that multiple genetic modifiers act to influence penetrance and expressivity of the primary epilepsy mutation. Previously we mapped two modifier loci that are responsible for the strain difference in Scn2aQ54 mice: Moe1 (modifier of epilepsy 1) on Chromosome 11 and Moe2 on Chromosome 19. During the previous funding period we performed fine mapping and candidate gene analysis of the Moe1 region, identified the Moe2 modifier gene, and identified additional modifier loci that influence the Scn2aQ54 phenotype. We propose to continue our analysis of epilepsy modifiers using the Scn2aQ54 and Scn1a+/- mouse models. First, we will identify the responsible genes at Scn2aQ54 modifier loci. Next, we will determine the molecular basis of the Moe2 modifier effect. Finally, we will map genetic modifier loci in the Scn1a+/- mouse model and perform transcriptome analysis via RNA-seq for accelerated identification of candidate genes. The major goal of our studies is to identify and characterize modifier genes that influence epilepsy susceptibility and severity. These genes are likely to contribute to common epilepsy syndromes with more complex genetics. Identification of epilepsy modifier genes will provide insight into the basic biology of epileptogenesis and may identify novel therapeutic targets for the treatment of human patients.

Public Health Relevance

The major goal of this proposal is to identify modifier genes that influence penetrance and severity of inherited epilepsy. Identification of epilepsy modifier genes and analysis of the underlying mechanisms will provide insight into the molecular events of epileptogenesis. This will contribute to understanding the basis of epilepsy with more complex inheritance and suggest novel therapeutic targets for the improved treatment of human patients

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Whittemore, Vicky R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
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

Showing the most recent 10 out of 20 publications