{"id":13278,"date":"2024-01-09T08:26:00","date_gmt":"2024-01-09T08:26:00","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&#038;p=13278"},"modified":"2025-02-03T17:57:55","modified_gmt":"2025-02-03T17:57:55","slug":"2025-plural-molecular-and-cellular-mechanisms-of-pore-domain-kcnq2-encephalopathy","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/ja\/resource_library\/2025-plural-molecular-and-cellular-mechanisms-of-pore-domain-kcnq2-encephalopathy\/","title":{"rendered":"2025 &#8211; Plural molecular and cellular mechanisms of pore domain KCNQ2 encephalopathy"},"content":{"rendered":"<p><em>KCNQ2<\/em>\u00a0variants in children with neurodevelopmental impairment are difficult to assess due their heterogeneity and unclear pathogenic mechanisms. We describe a child with neonatal-onset epilepsy, developmental impairment of intermediate severity, and\u00a0<em>KCNQ2<\/em>\u00a0G256W heterozygosity. Analyzing prior KCNQ2 channel cryoelectron microscopy models revealed G256 as keystone 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 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 reveal pore \u201cturret arch\u201d bonding as a KCNQ structural novelty and introduce a valid animal model of\u00a0<em>KCNQ2<\/em>\u00a0encephalopathy. Our results, spanning structure to behavior, may be broadly applicable because the majority of\u00a0<em>KCNQ2<\/em>\u00a0encephalopathy patients share variants near the selectivity filter.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[42],"resource_type":[75],"application_areas":[50,53],"therapeutic_areas":[55,143],"target_categories":[61],"target_families":[333],"targets":[295],"resource_keyword":[],"class_list":["post-13278","resource_library","type-resource_library","status-publish","hentry","products_tags-syncropatch-384","resource_type-publication","application_areas-ion-channels","application_areas-assay-development-and-validation","therapeutic_areas-cns","therapeutic_areas-assay-development-and-validation","target_categories-voltage-gated-ion-channels","target_families-kv-channels","targets-kv7-2"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library\/13278","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/media?parent=13278"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/products_tags?post=13278"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_type?post=13278"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/application_areas?post=13278"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/therapeutic_areas?post=13278"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_categories?post=13278"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_families?post=13278"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/targets?post=13278"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_keyword?post=13278"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}