Epilepsy is a chronic condition of recurrent seizures. Although epilepsy can be caused by non- genetic factors including stroke, traumatic brain injuries, and brain infections, genetic causes remain a significant component in epilepsy etiology. Elucidating the functions of genes and mutations associated with epilepsy would provide a better understanding of seizure disorders in the general population and be informative to therapies that reduce or offset seizure incidences. While the causative gene mutations in dozens of Mendelian epilepsy families have been identified, there are a few examples where these genes have been found to contribute to epilepsy in the general population. Moreover, even when genes involved in epilepsy have been implicated, we lack tractable animal models to rapidly translate these findings into mechanistic insights and ultimately new anti-epileptic therapies. The zebrafish shows high genetic and physiologic homology to humans and displays a seizure-like behavior in response to various pharmacological and genetic manipulations. With high throughput sequencing of human DNA samples, a significant number of genes are now being identified, yet their role in the disease state are unknown. There is considerable interest i developing a rapid method to elucidate the underlying genetics, biochemistry and pathophysiology of newly diagnosed diseases in the context of a living vertebrate organism. Here we propose to use the zebrafish as a model to rapidly characterize the function of gene variants identified in the NIH Undiagnosed Diseases Program (UDP), specifically 15 genes for which mutations have been associated with epilepsy. Successful completion of these aims will functionally characterize the genes associated with epilepsy and will determine the contribution of the gene variant to the phenotype providing valuable insight for the development of new detection methods and disease-modifying therapies. Our long- term goal is to employ the information gained from this and following applications to develop new therapies for the effective management of epilepsy and the reduction of its toll on the individual, and society.

Public Health Relevance

Epilepsy is a disabling disease that affects ~1% of the general population and requires long-term treatment. Most forms of epilepsy are inheritable, but for over 70% of patients, the underlying genetic basis for their condition remains unknown, impeding effective diagnosis and treatment. To develop new ways to diagnose and treat epilepsy, we aim to characterize gene mutations not yet known to be involved, and to explore how these mutations can cause the disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZHG1)
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Krasnewich, Donna M
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University of Iowa
Schools of Arts and Sciences
Iowa City
United States
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Fuller, Tyson D; Westfall, Trudi A; Das, Tirthasree et al. (2018) High-throughput behavioral assay to investigate seizure sensitivity in zebrafish implicates ZFHX3 in epilepsy. J Neurogenet 32:92-105