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

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.

Keywords: Epilepsy; Genomics; Göttingen Minipigs; Seizure; Transcriptomics; Voltage-gated calcium channel.

Fig. 1

A Summary of variant effect prediction of highly differentiated genetic variants between healthy and seizure-phenotype GMPs. B KEGG pathway gene clustering results of genes in close proximity (± 5 kbp) to fixed variants between healthy and seizure-phenotype GMPs

Fig. 2

A Volcano plots of DEGs in primary fibroblasts isolated from healthy and seizure-phenotype GMPs. B KEGG pathway gene clustering results and C GO molecular functions gene clustering results from DEGs between fibroblasts isolated from healthy and seizure-phenotype GMPs

Fig. 3

A Core regulatory network of DEGs in proximity to fixed genetic variants. B Transcription factor binding site enrichment results of the core network genes performed with the transcription factors in the network. C Positions of transcription factor binding sites in DEGs of the core regulatory network