The novel KCNQ2 E140Q variant caused dramatic loss-of-function effects in Kv7.2 channels, which were restored by retigabine in vitro.
Case Report (n=1)
Does retigabine restore function in Kv7.2 channels with the E140Q mutation?
Retigabine restores function in a novel Kv7.2 E140Q loss-of-function variant associated with neonatal onset epileptic encephalopathy, supporting the use of Kv7 activators as personalized therapy.
Kv7.2 subunits encoded by the KCNQ2 gene provide a major contribution to the M-current (IKM), a voltage-gated K+ current crucially involved in the regulation of neuronal excitability. Heterozygous missense variants in Kv7.2 are responsible for epileptic diseases characterized by highly heterogeneous genetic transmission and clinical severity, ranging from autosomal-dominant Benign Familial Neonatal Seizures (BFNS) to sporadic cases of severe epileptic and developmental encephalopathy (DEE). Here, we describe a patient with neonatal onset DEE, carrying a previously undescribed heterozygous KCNQ2 c.418G > C, p.Glu140Gln (E140Q) variant. Patch-clamp recordings in CHO cells expressing the E140Q mutation reveal dramatic loss of function (LoF) effects. Multistate structural modelling suggested that the E140Q substitution impeded an intrasubunit electrostatic interaction occurring between the E140 side chain in S2 and the arginine at position 210 in S4 (R210); this interaction is critically involved in stabilizing the activated configuration of the voltage-sensing domain (VSD) of Kv7.2. Functional results from coupled charge reversal or disulfide trapping experiments supported such a hypothesis. Finally, retigabine restored mutation-induced functional changes, reinforcing the rationale for the clinical use of Kv7 activators as personalized therapy for DEE-affected patients carrying Kv7.2 LoF mutations.
Soldovieri et al. (Wed,) conducted a case report in Epileptic and developmental encephalopathy (DEE) (n=1). KCNQ2 E140Q variant was evaluated on Functional effects of the E140Q mutation on Kv7.2 channels. The novel KCNQ2 E140Q variant caused dramatic loss-of-function effects in Kv7.2 channels, which were restored by retigabine in vitro.