{"id":13234,"date":"2024-01-04T14:41:18","date_gmt":"2024-01-04T14:41:18","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&#038;p=13234"},"modified":"2024-01-04T14:41:18","modified_gmt":"2024-01-04T14:41:18","slug":"2023-pathogenic-scn2a-variants-are-associated-with-familial-and-sporadic-hemiplegic-migraine","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/ja\/resource_library\/2023-pathogenic-scn2a-variants-are-associated-with-familial-and-sporadic-hemiplegic-migraine\/","title":{"rendered":"2023 &#8211; Pathogenic SCN2A variants are associated with familial and sporadic hemiplegic migraine"},"content":{"rendered":"<p><strong>Background:<\/strong>\u00a0Familial hemiplegic migraine is a severe autosomal dominant subtype of migraine with aura characterized by transient motor weakness during attacks. Previously identified genes\u00a0<em>CACNA1A<\/em>,\u00a0<em>ATP1A2<\/em>,\u00a0<em>SCN1A<\/em>\u00a0and\u00a0<em>PRRT2<\/em>\u00a0account for less than 20% of cases with hemiplegic migraine referred for genetic diagnosis.<\/p>\n<p><strong>Objectives and Methods:\u00a0<\/strong>To identify a novel gene, we conducted a whole-genome linkage analysis combined with mini-exome sequencing in a four-generation pedigree with hemiplegic migraine. A candidate ion channel gene was analyzed for mutations in six other affected pedigrees comprising at least three available affected members, and in a large panel of unrelated probands with hemiplegic migraine referred for molecular diagnosis, all without mutations in the known genes. The functional consequences of the identified variants were determined.<\/p>\n<p><strong>Results:\u00a0<\/strong>In the discovery pedigree, we identified a heterozygous missense mutation (c.4438A&gt;G, p.Lys1480Glu) in the neuronal voltage-gated sodium channel gene\u00a0<em>SCN2A<\/em>, which cosegregated with the hemiplegic migraine phenotype. We detected another mutation (c.769T&gt;A, p.Phe257Ile) cosegregating with hemiplegic migraine in a second family, in which two members also had infantile seizures. A third variant (c.3955C&gt;G, p.Arg1319Gly) was found in a sporadic hemiplegic migraine case. All three\u00a0<em>SCN2A<\/em>\u00a0variants were absent in the genome aggregation database gnomAD. Heterologous expression in HEK293T cells coupled with automated patch clamp recording demonstrated abnormal voltage-dependent and kinetic properties of all three\u00a0<em>SCN2A<\/em>\u00a0variants.<\/p>\n<p><strong>Conclusions:<\/strong>Dysfunction of the neuronal sodium channel\u00a0<em>SCN2A<\/em>\u00a0can be associated with familial and sporadic hemiplegic migraine. Our finding expands the genetic landscape for migraine and contributes to the diverse genotype-phenotype spectrum associated with\u00a0<em>SCN2A<\/em>.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[42],"resource_type":[75],"application_areas":[50,53,76],"therapeutic_areas":[55,56,143],"target_categories":[61],"target_families":[332],"targets":[],"resource_keyword":[],"class_list":["post-13234","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-cns","therapeutic_areas-pain","therapeutic_areas-assay-development-and-validation","target_categories-voltage-gated-ion-channels","target_families-nav-channels"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library\/13234","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=13234"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/products_tags?post=13234"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_type?post=13234"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/application_areas?post=13234"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/therapeutic_areas?post=13234"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_categories?post=13234"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_families?post=13234"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/targets?post=13234"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_keyword?post=13234"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}