Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy

Abstract

Objective Mutations in KCNQ2 and KCNQ3, encoding the voltage-gated potassium channels KV7.2 and KV7.3, are known to cause benign familial neonatal seizures mainly by haploinsufficiency. Here, we set out to determine the disease mechanism of 7 de novo missense KCNQ2 mutations that were recently described in patients with a severe epileptic encephalopathy including pharmacoresistant seizures and pronounced intellectual disability. Methods Mutations were inserted into the KCNQ2 cDNA. Potassium currents were recorded using 2-microelectrode voltage clamping, and surface expression was analyzed by a biotinylation assay in cRNA-injected Xenopus laevis oocytes. Results We observed a clear loss of fu..