{"id":16741,"date":"2025-01-07T15:36:35","date_gmt":"2025-01-07T15:36:35","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&#038;p=16741"},"modified":"2025-01-07T15:36:35","modified_gmt":"2025-01-07T15:36:35","slug":"2024-rare-dysfunctional-scn2a-variants-are-associated-with-malformation-of-cortical-development","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/zh-hans\/resource_library\/2024-rare-dysfunctional-scn2a-variants-are-associated-with-malformation-of-cortical-development\/","title":{"rendered":"2024 &#8211; Rare dysfunctional SCN2A variants are associated with  malformation of cortical development"},"content":{"rendered":"<section id=\"epi18234-sec-0001\" class=\"article-section__content\">\n<p id=\"epi18234-sec-0001-title\" class=\"article-section__sub-title section1\">Objective.\u00a0<i>SCN2A<\/i>\u00a0encodes the voltage-gated sodium (Na<sup>+<\/sup>) channel \u03b1 subunit Na<sub>V<\/sub>1.2, which is important for the generation and forward and back propagation of action potentials in neurons. Genetic variants in\u00a0<i>SCN2A<\/i>\u00a0are associated with a spectrum of neurodevelopmental disorders. However, the mechanisms whereby variation in\u00a0<i>SCN2A<\/i>\u00a0leads to disease remains incompletely understood, and the full spectrum of\u00a0<i>SCN2A<\/i>-related disorders may not be fully delineated.<\/p>\n<\/section>\n<p id=\"epi18234-sec-0002-title\" class=\"article-section__sub-title section1\">Methods.\u00a0Here, we identified seven de novo heterozygous variants in\u00a0<i>SCN2A<\/i> in eight individuals with developmental and epileptic encephalopathy (DEE) accompanied by prominent malformation of cortical development (MCD). We characterized the electrophysiological properties of Na<sup>+<\/sup>\u2009currents in human embryonic kidney (HEK) cells transfected with the adult (A) or neonatal (N) isoform of wild-type (WT) and variant Na<sub>V<\/sub>1.2 using manual and automated whole-cell voltage clamp recording.<\/p>\n<p id=\"epi18234-sec-0003-title\" class=\"article-section__sub-title section1\">Results.\u00a0The neonatal isoforms of all\u00a0<i>SCN2A<\/i>\u00a0variants studied exhibit gain of function (GoF) with a large depolarized shift in steady-state inactivation, creating a markedly enhanced window current common across all four variants tested. Computational modeling demonstrated that expression of the Na<sub>V<\/sub>1.2-p.Met1770Leu-N variant in a developing neocortical pyramidal neuron results in hyperexcitability.<\/p>\n<section id=\"epi18234-sec-0004\" class=\"article-section__content\">\n<p id=\"epi18234-sec-0004-title\" class=\"article-section__sub-title section1\">Significance.\u00a0These results support expansion of the clinical spectrum of\u00a0<i>SCN2A<\/i>-related disorders and the association of genetic variation in\u00a0<i>SCN2A<\/i>\u00a0with MCD, which suggests previously undescribed roles for\u00a0<i>SCN2A<\/i>\u00a0in fetal brain development.<\/p>\n<\/section>\n","protected":false},"featured_media":0,"template":"","products_tags":[42],"resource_type":[75],"application_areas":[50,53,76],"therapeutic_areas":[143,254],"target_categories":[61],"target_families":[332],"targets":[212],"resource_keyword":[],"class_list":["post-16741","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","application_areas-drug-discovery","therapeutic_areas-assay-development-and-validation","therapeutic_areas-rare-diseases","target_categories-voltage-gated-ion-channels","target_families-nav-channels","targets-nav1-2"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library\/16741","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=16741"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/products_tags?post=16741"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_type?post=16741"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/application_areas?post=16741"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/therapeutic_areas?post=16741"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_categories?post=16741"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_families?post=16741"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/targets?post=16741"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_keyword?post=16741"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}