The Interaction of UBR4, LRP1, and OPHN1 in Refractory Epilepsy: Drosophila Model to Investigate the Oligogenic Effect on Epilepsy

Refractory epilepsy is an intractable neurological disorder that is currently difficult to achieve effective pharmacological control in clinical practice and can result in poor quality of life as well as increased mortality. Genetic factors are important causes of epilepsy, especially idiopathic epilepsy. In the clinical gene sequencing work, we identified one refractory epileptic patient who carried three epileptogenic candidate genes: UBR4, LRP1, and OPHN1 variants. To clarify the epileptogenicity and interactions of UBR4, LRP1, and OPHN1 variants, as well as explore the role of each mutant gene in eliciting epilepsy, we established single-knockdown, double-knockdown, and triple-knockdown Drosophila models by suppressing the gene expression of these three epileptogenic candidate genes. After conducting behavioral testing for epilepsy in the seven Drosophila knockdown models, regression equations illustrating the causal connection between genotype and phenotype were developed. The mutations of the three epileptogenic candidate genes: UBR4, LRP1, and OPHN1, were proved to be epileptogenic at the animal level both in seizure rates and logistic regression results. Moreover, significant negative interactions in UBR4-OPHN1 KD and LRP1-OPHN1 KD were found in the trigenic KD system as well as the UBR4-OPHN1 and LRP1-OPHN1 digenic KD system according to the logistic regression analysis result. However, despite the existence of negative interaction, three groups of digenic KD flies and one group of trigenic KD flies presented higher seizure rates than that of the corresponding monogenic KD flies. LRP1-OPHN1 KD together with its negative interaction was regarded as the main causative factors for seizure in the UBR4-LRP1-OPHN1 KD.