Hyper-SUMOylation of the Kv7 Potassium Channel Diminishes the M-Current Leading to Seizures and Sudden Death

Sudden unexplained death in epilepsy (SUDEP) is the most common cause of premature mortality in epilepsy and was linked to mutations in ion channels; however, genes within the channel protein interactome might also represent pathogenic candidates. Here we show that mice with partial deficiency of Sentrin/SUMO-specific protease 2 (SENP2) develop spontaneous seizures and sudden death. SENP2 is highly enriched in the hippocampus, often the focus of epileptic seizures. SENP2 deficiency results in hyper-SUMOylation of multiple potassium channels known to regulate neuronal excitability. We demonstrate that the depolarizing M-current conducted by Kv7 channel is significantly diminished in SENP2-deficient hippocampal CA3 neurons, primarily responsible for neuronal hyperexcitability. Following seizures, SENP2-deficient mice develop atrioventricular conduction blocks and cardiac asystole. Both seizures and cardiac conduction blocks can be prevented by retigabine, a Kv7 channel opener. Thus, we uncover a disease-causing role for hyper-SUMOylation in the nervous system and establish an animal model for SUDEP. •SENP2 deficiency causes seizures and sudden death with 100% early mortality in mice•SENP2 deficiency leads to hyper-SUMOylation of Kv7.2 and diminishes the M-current•Brain-specific deletion of SENP2 recapitulates seizures and sudden death phenotype•Seizures and AV blocks can be prevented by the Kv7 channel opener retigabine Sudden death is the most common cause of premature mortality in epilepsy. Qi et al. show that hyper-SUMOylation of the voltage-gated potassium channel Kv7.2 causes seizure and heart conduction block, which can be prevented by a third-generation antiepilepsy drug.