biostudies-literatureUnknownAbreo TJNICHD NIH HHSNHLBI NIH HHSNIMH NIH HHSNINDS NIH HHSNCI NIH HHSNIH HHSNIGMS NIH HHS<i>KCNQ2</i> 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 <i>KCNQ2</i> 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. G256W/+ mice have epilepsy leading to premature deaths. Hippocampal CA1 pyramidal cells from G256W/+ brain slices showed hyperexcitability. G256W/+ pyramidal cell KCNQ2 and KCNQ3 immbioRxiv : the preprint server for biology2024.01.04.574177https://www.ebi.ac.uk/biostudies/studies/S-EPMC10802467biostudies-literaturePlural molecular and cellular mechanisms of pore domain <i>KCNQ2</i> encephalopathy.PMC10802467R01 GM143380U54 NS108874R01 NS101596K08 NS096029P30 CA125123K08 NS110924U54 OD020351R01 NS029709S10 OD026804R01 NS049119R56 MH126953P30 CA034196P50 HD103555R01 HL162842Springer KJohnson JVarghese NLutz CPark KLTzingounis AVEinsele-Scholz SMaheshwari ASoh HJankovic MJVanoye CGSims SThompson ECHabte BWang ZDudler LAbreo TJKrishnan VCooper ECMadabushi AGeorge ALNoebels JLChavez AGZuberi ARJi ZfalsePlural molecular and cellular mechanisms of pore domain <i>KCNQ2</i> encephalopathy.<i>KCNQ2</i> 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 <i>KCNQ2</i> 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. G256W/+ mice have epilepsy leading to premature deaths. Hippocampal CA1 pyramidal cells from G256W/+ brain slices showed hyperexcitability. G256W/+ pyramidal cell KCNQ2 and KCNQ3 imm2024-01-01T00:00:00Z2024 Jun2025-09-01T03:17:05.924Z2025-09-01T03:08:14.61ZS-EPMC108024673826060810.1101/2024.01.04.574177