Epilepsy is a neurological disorder affecting approximately 3 million Americans of all ages. In over 30% of patients, seizures cannot be adequately controlled with existing treatments. Two-thirds of patients diagnosed with epilepsy have an underlying genetic cause for their disease. In recent years, extensive research has identified genes which contribute to monogenic epilepsy, while less progress has been made identifying genes involved in the more common, genetically-complex epilepsies. Over 700 mutations have been identified in the voltage-gated sodium channel genes SCN1A and SCN2A in human epilepsies, including Genetic Epilepsy with Febrile Seizures Plus (GEFS+) and Dravet Syndrome. Among affected family members with the same mutation, clinical severity of epilepsy can be markedly different. This suggests that additional factors modify the effect of the primary mutation, resulting in variable clinical presentation. Mouse models have been generated to study the genetic basis of epilepsy. In many of these mouse models, severity of the seizure phenotype is dependent upon strain background, suggesting a role for genetic modifiers. The Scn2a[Q54] transgenic mouse model has an epilepsy phenotype that varies depending on the genetic strain background. Scn2a[Q54] mice congenic on the C57Bl/6J (B6) strain exhibit delayed seizure onset and improved survival compared to (B6xSJL/J)F1.Q54 mice. Two dominant modifier loci of Scn2a[Q54] seizure susceptibility were mapped and designated Moe1 and Moe2. The goals of the proposed studies are to identify modifier genes at the Moe1 locus that alter seizure severity in Scn2a[Q54] mice and test candidate genes by transgenic transfer of the modified phenotype.
In Specific Aim 1, fine mapping of Moe1 will reduce the interval of interest to ≤10 Mb. RNA-Seq transcriptome analysis will then be utilized to evaluate differences in transcript expression and coding sequence between the resistant B6 and susceptible SJL/J strains. RNA-Seq data will be used to identify Moe1 candidate genes.
In Specific Aim 2, testing of candidate modifier genes identified by RNA-Seq will be performed by transgenic transfer of the modified phenotype. BAC transgenic animals will be generated and crossed to Scn2a[Q54] mice to assess the effect on phenotype severity. Altered phenotype severity is indicative that the candidate is an epilepsy modifier gene. This proposal aims to identify modifier genes which affect the phenotype in a mouse model of epilepsy. Understanding the molecular basis of genetic modifiers in a mouse model can provide insight into human epilepsy. This research has the potential to advance molecular diagnostic capabilities and identify novel therapeutic targets for the improved treatment of human patients.

Public Health Relevance

The aim of this proposal is to identify modifier genes that contribute to the variable clinical severity of inherited epilepsies. Identification of epilepsy modifier genes will increase our understanding of the molecular events of epileptogenesis and disease progression. This knowledge will ultimately advance the molecular diagnostic capabilities and identify novel therapeutic targets to improve the treatment of human patients.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F01-F (20))
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Stewart, Randall R
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Vanderbilt University Medical Center
Schools of Medicine
United States
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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
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
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
Hawkins, N A; Kearney, J A (2012) Confirmation of an epilepsy modifier locus on mouse chromosome 11 and candidate gene analysis by RNA-Seq. Genes Brain Behav 11:452-60