{"id":13336,"date":"2023-11-18T16:22:55","date_gmt":"2023-11-18T16:22:55","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&#038;p=13336"},"modified":"2024-01-10T16:23:24","modified_gmt":"2024-01-10T16:23:24","slug":"2023-molecular-and-cellular-context-influences-scn8a-variant-function","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/zh-hans\/resource_library\/2023-molecular-and-cellular-context-influences-scn8a-variant-function\/","title":{"rendered":"2023 &#8211; Molecular and Cellular Context Influences SCN8A Variant Function"},"content":{"rendered":"<p>Pathogenic variants in\u00a0<em>SCN8A<\/em>, which encodes the voltage-gated sodium (Na<sub>V<\/sub>) channel Na<sub>V<\/sub>1.6, are associated with neurodevelopmental disorders including epileptic encephalopathy. Previous approaches to determine\u00a0<em>SCN8A<\/em>\u00a0variant function may be confounded by the use of a neonatal-expressed alternatively spliced isoform of Na<sub>V<\/sub>1.6 (Na<sub>V<\/sub>1.6N), and engineered mutations to render the channel tetrodotoxin (TTX) resistant. In this study, we investigated the impact of\u00a0<em>SCN8A<\/em>\u00a0alternative splicing on variant function by comparing the functional attributes of 15 variants expressed in two developmentally regulated splice isoforms (Na<sub>V<\/sub>1.6N, Na<sub>V<\/sub>1.6A). We employed automated patch clamp recording to enhance throughput, and developed a novel neuronal cell line (ND7\/LoNav) with low levels of endogenous Na<sub>V<\/sub>\u00a0current to obviate the need for TTX-resistance mutations. Expression of Na<sub>V<\/sub>1.6N or Na<sub>V<\/sub>1.6A in ND7\/LoNav cells generated Na<sub>V<\/sub>\u00a0currents that differed significantly in voltage-dependence of activation and inactivation. TTX-resistant versions of both isoforms exhibited significant functional differences compared to the corresponding wild-type (WT) channels. We demonstrated that many of the 15 disease-associated variants studied exhibited isoform-dependent functional effects, and that many of the studied\u00a0<em>SCN8A<\/em>\u00a0variants exhibited functional properties that were not easily classified as either gain- or loss-of-function. Our work illustrates the value of considering molecular and cellular context when investigating\u00a0<em>SCN8A<\/em>\u00a0variants.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[42],"resource_type":[75],"application_areas":[50,76],"therapeutic_areas":[55],"target_categories":[61],"target_families":[332],"targets":[244],"resource_keyword":[],"class_list":["post-13336","resource_library","type-resource_library","status-publish","hentry","products_tags-syncropatch-384","resource_type-publication","application_areas-ion-channels","application_areas-drug-discovery","therapeutic_areas-cns","target_categories-voltage-gated-ion-channels","target_families-nav-channels","targets-nav1-6"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library\/13336","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/media?parent=13336"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/products_tags?post=13336"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_type?post=13336"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/application_areas?post=13336"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/therapeutic_areas?post=13336"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_categories?post=13336"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_families?post=13336"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/targets?post=13336"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_keyword?post=13336"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}