Loss-of-Function Variant Associated with Epilepsy and Neurodevelopmental Delay Enhances Kv12.2 Channel Inactivation.

A de novo missense variant in has been identified in a patient with neurological symptoms including seizures. Here, we confirm the previously reported loss-of-function features for the associated Kv12.2 mutant A371V and investigate the underlying mechanism. Loss of function was not rescued by low temperature during channel biogenesis. Elevated external K reduced the rectification of Kv12.2 conductance as predicted by the GHK current equation, allowing the detection of currents mediated by homomeric A371V Kv12.2 channels and a detailed biophysical analysis of the mutant. Compared to wild-type, the voltage dependences of activation and deactivation of A371V Kv12.2 channels were shifted in the positive direction by 15 to 20 mV. Moreover, A371V Kv12.2 channels exhibited accelerated inactivation kinetics combined with a dramatic negative shift in the voltage dependence of inactivation by more than 100 mV. Even in heteromeric wild-type + A371V Kv12.2 channels, inactivation was enhanced, leading to a significant current reduction at physiological potentials. Our Kv12.2 data show similarities to Kv11 channels regarding C-type inactivation and differences regarding the sensitivity to external K and pharmacological inhibition of inactivation. The gating modification caused by the A371V amino acid substitution in Kv12.2 renders loss of function voltage-dependent, with a possible impact on neuronal excitability and firing behavior.