Epilepsy is a diverse group of disorders characterized by recurrent seizures with variable age of onset and degree of severity of disease. It is a significant health problem in humans - the second most common human neurological affliction affecting about 1 percent of the human population, and it is estimated that a large fraction of all epilepsies have some genetic component. Unfortunately the genetic and phenotypic heterogeneity in many human epilepsies has often made it difficult to understand the modes of inheritance, and the precise causes and pathogenic mechanisms of many human epilepsies still remain obscure. Our proposed goal is to use a simple murine model to elucidate the primary cause of an inherited form of epilepsy. Stargazer, a murine model with spontaneous seizures, is a single autosomal gene mutant and fulfills the requirements of a simple model for idiopathic epilepsy. We have identified the stargazer gene, which encodes a new putative transmembrane-spanning protein whose function is not yet clear. From continued studies we will begin to determine why its disruption results in the observed phenotype of absence seizures. We will address the role of a functional knockout of the gene and how this mutation interacts with other mouse mutations that are also known to cause absence seizures. Stargazer also appears to be part of a gene family, and by isolating and studying the family we will begin to understand more about their conserved functional domains and expression in the mouse. The expression studies will provide preliminary evidence of possible protein subunit associations with stargazer, paving the way for future experiments to confirm these putative associations and to assess the functional role of stargazer within the protein complex, whether it is a calcium channel subunit as its modest sequence similarity would suggest, or some other neuronal protein. From these studies we will be able to determine the nature of the primary defect and ultimately apply our understanding of this relatively simple model to other more complex inherited epileptic disorders.
| Papale, Ligia A; Beyer, Barbara; Jones, Julie M et al. (2009) Heterozygous mutations of the voltage-gated sodium channel SCN8A are associated with spike-wave discharges and absence epilepsy in mice. Hum Mol Genet 18:1633-41 |
| Miki, T; Zwingman, T A; Wakamori, M et al. (2008) Two novel alleles of tottering with distinct Ca(v)2.1 calcium channel neuropathologies. Neuroscience 155:31-44 |
