Epilepsy is a complex genetic disorder that affects about 2% of the global population. 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. 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. Spontaneous epileptic convulsions were observed in few Göttingen Minipigs (GMPs), which may provide a valuable alternative animal model for the characterisation of epilepsy-type diseases and for testing new treatments. We have characterised affected GMPs at the genome level and have taken advantage of primary fibroblast cultures to validate the functional impact of fixed genetic variants on the transcriptome level. We found numerous genes connected to calcium metabolism that have not been associated with epilepsy before, such as ADORA2B, CAMK1D, ITPKB, MCOLN2, MYLK, NFATC3, PDGFD, and PHKB. Our results have identified two transcription factor genes, EGR3 and HOXB6, as potential key regulators of CACNA1H, which was previously linked to epilepsy-type disorders in humans. Our findings provide the first set of conclusive results to support the use of affected subsets of GMPs as an alternative and more reliable model system to study human epilepsy. Further neurological and pharmacological validation of the suitability of GMPs as an epilepsy model is therefore warranted.

癫痫是一种复杂的遗传性疾病，影响全球约 2% 的人口。尽管可以通过一系列药物干预来降低癫痫发作的频率和严重程度，但目前还没有针对癫痫的疾病缓解疗法。由于缺乏合适的动物模型，新的更有效药物的开发受到阻碍。现有的啮齿动物模型可能无法概括该疾病的所有关键方面。在少数哥廷根小型猪（GMP）中观察到自发性癫痫性惊厥，这可能为表征癫痫类疾病和测试新疗法提供有价值的替代动物模型。我们在基因组水平上表征了受影响的 GMP，并利用原代成纤维细胞培养物来验证固定遗传变异对转录组水平的功能影响。我们发现了许多与钙代谢相关的基因，但以前与癫痫无关，例如ADORA2B、CAMK1D、ITPKB、MCOLN2、MYLK、NFATC3、PDGFD和PHKB。我们的结果确定了两个转录因子基因EGR3和HOXB6是CACNA1H的潜在关键调节因子，而 CACNA1H 先前被认为与人类癫痫型疾病有关。我们的研究结果提供了第一组结论性结果，支持使用受影响的 GMP 子集作为研究人类癫痫的替代且更可靠的模型系统。因此，有必要对 GMP 作为癫痫模型的适用性进行进一步的神经学和药理学验证。