This proposal describes a rational system for the identification of genes that control seizure susceptibility in mice using a combination of quantitative trait locus (QTL) mapping and bioinformatic approaches. The proposed project builds on results of an ongoing K02-funded study in our laboratory in which we used B6 (host) X A/J (donor) chromosome substitution strains (B6.A CSS) to identify QTLs on five chromosomes that confer increased susceptibility to pilocarpine-induced limbic seizures, a rodent model of human temporal lobe epilepsy. We will use breeding and mapping strategies--including the creation of F2 populations and interval-specific congenics--in combination with bioinformatics techniques to fine map seizure susceptibility QTLs and identify candidate genes (QTGs). These QTGs can later be tested in human populations ascertained by the PI (Winawer) under separate K02 funding, or examined in experimental functional systems. We will apply similar strategies to map susceptibility QTLs for Electroconvulsive Threshold (ECT), to identify both model-specific and broadly-acting (generalized hyperexcitability) QTLs and QTGs. The combination of experimental and bioinformatics strategies is extremely powerful for identifying epilepsy candidate genes. This approach is made possible by the availability of databases derived from published literature, strain-specific sequence data, estimates of the density of inter-strain single nucleotide polymorphisms (SNPs) across the genome, and strain and region-specific expression databases. Relevance: Epilepsy, defined as recurrent seizures occurring without acute provocation, affects approximately 50 million people worldwide at any given time. There is substantial evidence for a genetic contribution to human epilepsy, but most epilepsy remains unexplained by genes discovered to date. Our proposal aims to identify genes associated with increased susceptibility to seizures. These genes can be examined in human populations as well as be investigated with functional experimental models. Discovery of susceptibility genes can provide insight into epilepsy pathophysiology and transform therapeutic strategies. PROJECT NARRATIVE Epilepsy affects approximately 50 million people worldwide at any given time, and many patients have epilepsy refractory to currently available treatment. Most epilepsy remains unexplained by genes discovered to date. Our proposal aims to identify genes associated with increased susceptibility to seizures, thereby providing insight into pathophysiology and transforming therapeutic strategies.

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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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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Winawer, M R; Klassen, T L; Teed, S et al. (2014) A locus on mouse Ch10 influences susceptibility to limbic seizure severity: fine mapping and in silico candidate gene analysis. Genes Brain Behav 13:341-9
Brooks-Kayal, Amy R; Bath, Kevin G; Berg, Anne T et al. (2013) Issues related to symptomatic and disease-modifying treatments affecting cognitive and neuropsychiatric comorbidities of epilepsy. Epilepsia 54 Suppl 4:44-60
Distler, Margaret G; Gorfinkle, Naomi; Papale, Ligia A et al. (2013) Glyoxalase 1 and its substrate methylglyoxal are novel regulators of seizure susceptibility. Epilepsia 54:649-57
Winawer, Melodie R; Gildersleeve, Sandra S; Phillips, Austin G et al. (2011) Mapping a mouse limbic seizure susceptibility locus on chromosome 10. Epilepsia 52:2076-83
Winawer, Melodie R; Hesdorffer, Dale C (2010) Migraine, epilepsy, and psychiatric comorbidity: partners in crime. Neurology 74:1166-8
Santoro, Bina; Lee, Janet Y; Englot, Dario J et al. (2010) Increased seizure severity and seizure-related death in mice lacking HCN1 channels. Epilepsia 51:1624-7