KCNQ2 variants in children with neurodevelopmental impairment are difficult to assess due to their heterogeneity and unclear pathogenic mechanisms. We describe a child with neonatal-onset epilepsy, developmental impairment of intermediate severity, and KCNQ2 G256W heterozygosity. Analyzing prior KCNQ2 channel cryoelectron microscopy models revealed G256 as a node of an arch-shaped non-covalent bond network linking S5, the pore turret, and the ion path. Co-expression with G256W dominantly suppressed conduction by wild-type subunits in heterologous cells. Ezogabine partly reversed this suppression. Kcnq2^G256W/+ mice have epilepsy leading to premature deaths. Hippocampal CA1 pyramidal cells from G256W/+ brain slices showed hyperexcitability. G256W/+ pyramidal cell KCNQ2 and KCNQ3 immunolabeling was significantly shifted from axon initial segments to neuronal somata. Despite normal mRNA levels, G256W/+ mouse KCNQ2 protein levels were reduced by about 50%. Our findings indicate that G256W pathogenicity results from multiplicative effects, including reductions in intrinsic conduction, subcellular targeting, and protein stability. These studies provide evidence for an unexpected and novel role for the KCNQ2 pore turret and introduce a valid animal model of KCNQ2 encephalopathy. Our results, spanning structure to behavior, may be broadly applicable because the majority of KCNQ2 encephalopathy patients share variants near the selectivity filter.

Since the pioneering work by Moeller, Szabo, and Bullock, weakly electric fish have served as a valuable model for investigating spatial and social cognitive abilities in a vertebrate taxon usually less accessible than mammals or other terrestrial vertebrates. These fish, through their electric organ, generate low-intensity electric fields to navigate and interact with conspecifics, even in complete darkness. The brown ghost knifefish is appealing as a study subject due to a rich electric ‘vocabulary’, made by individually variable and sex-specific electric signals. These are mainly characterized by brief frequency modulations of the oscillating dipole moment continuously generated by their electric organ, and are known as chirps. Different types of chirps are believed to convey specific and behaviorally salient information, serving as behavioral readouts for different internal states during behavioral observations. Despite the success of this model in neuroethology over the past seven decades, the code to decipher their electric communication remains unknown. To this aim, in this study we re-evaluate the correlations between signals and behavior offering an alternative, and possibly complementary, explanation for why these freshwater bottom dwellers emit electric chirps. By uncovering correlations among chirping, electric field geometry, and detectability in enriched environments, we present evidence for a previously unexplored role of chirps as specialized self-directed signals, enhancing conspecific electrolocation during social encounters.