OMICs driven identification of epilepsy candidate genes in primary fibroblasts isolated from Goettingen Minipigs with a seizure phenotype

Background: Epilepsy affects about 2% of the population worldwide. Although the frequency and severity of epileptic seizures can be reduced by a range of pharmacological interventions, there are no disease-modifying treatments for epilepsy. As a complex genetic disorder, epilepsy involves the interaction of multiple genes and environmental factors that interact in complex ways. This makes epilepsy a challenging condition to understand and treat. The development of new and more effective drugs is hindered by a lack of suitable animal models. Available rodent models may not recapitulate all key aspects of the disease.Results: Spontaneous epileptic convulsions have been observed in Goettingen Minipigs (GMPs), which may provide a valuable alternative animal model for the characterization of epilepsy-type disease and in which to test new treatments. We have characterized GMPs at the genome level and have taken advantage of primary fibroblast cultures to analyse the transcriptome in healthy versus seizure phenotype GMPs to discover the seizure-associated genes. In this study, we found CACNA1H to be differentially expressed in fibroblasts from epileptic GMPs, which has previously been linked to epilepsy-type disorders in humans. Our results have identified two transcription factor genes, EGR3 and HOXB6, as potential key regulators of CACNA1H.Conclusions: Our findings provide the basis for the establishment of GMPs with a seizure phenotype as a new animal model for human epilepsy. The identification of known and novel epilepsy candidate genes is a first indicator of the potential that GMPs offer compared to rodent models for epilepsy. This study is the first step towards a more robust, more reliable, and genetically well characterized epilepsy model system.