# Genomic evidence for the suitability of Göttingen Minipigs with a rare seizure phenotype as a model for human epilepsy

## TL;DR

This study shows that Göttingen Minipigs with a rare seizure phenotype could serve as a better animal model for studying human epilepsy.

## Contribution

The study identifies new genes linked to calcium metabolism and epilepsy and validates Göttingen Minipigs as a potential model for human epilepsy.

## Key findings

- Genes like ADORA2B, CAMK1D, and ITPKB were found to be connected to calcium metabolism and epilepsy for the first time.
- EGR3 and HOXB6 are potential regulators of CACNA1H, a gene previously linked to epilepsy-type disorders.
- Göttingen Minipigs with seizures may offer a more reliable model for studying human epilepsy than current rodent models.

## Abstract

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.

The online version contains supplementary material available at 10.1007/s10048-024-00750-2.