{"id":6106,"date":"2023-02-17T06:56:16","date_gmt":"2023-02-17T06:56:16","guid":{"rendered":"https:\/\/beta.nanion.de\/resource_library\/2014-physiological-and-genetic-analysis-of-multiple-sodium-channel-variants-in-a-model-of-genetic-absence-epilepsy\/"},"modified":"2023-02-17T06:56:16","modified_gmt":"2023-02-17T06:56:16","slug":"2014-physiological-and-genetic-analysis-of-multiple-sodium-channel-variants-in-a-model-of-genetic-absence-epilepsy","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/zh-hans\/resource_library\/2014-physiological-and-genetic-analysis-of-multiple-sodium-channel-variants-in-a-model-of-genetic-absence-epilepsy\/","title":{"rendered":"2014 &#8211; Physiological and genetic analysis of multiple sodium channel variants in a model of genetic absence epilepsy"},"content":{"rendered":"<p>In excitatory neurons, SCN2A (NaV1.2) and SCN8A (NaV1.6) sodium channels are enriched at the axon initial segment. NaV1.6 is implicated in several mouse models of absence epilepsy, including a missense mutation identified in a chemical mutagenesis screen (Scn8aV929F). Here, we confirmed the prior suggestion that\u00a0Scn8aV929F\u00a0exhibits a striking genetic background-dependent difference in phenotypic severity, observing that spike-wave discharge (SWD) incidence and severity are significantly diminished when\u00a0Scn8aV929F\u00a0is fully placed onto the C57BL\/6J strain compared with C3H. Examination of sequence differences in NaV\u00a0subunits between these two inbred strains suggested NaV1.2V752F\u00a0as a potential source of this modifier effect. Recognising that the spatial co-localisation of the NaV\u00a0channels at the axon initial segment (AIS) provides a plausible mechanism for functional interaction, we tested this idea by undertaking biophysical characterisation of the variant NaV\u00a0channels and by computer modelling. NaV1.2V752F\u00a0functional analysis revealed an overall gain-of-function and for NaV1.6V929F\u00a0revealed an overall loss-of-function. A biophysically realistic computer model was used to test the idea that interaction between these variant channels at the AIS contributes to the strain background effect. Surprisingly this modelling showed that neuronal excitability is dominated by the properties of NaV1.2V752F\u00a0due to \u201cfunctional silencing\u201d of NaV1.6V929F\u00a0suggesting that these variants do not directly interact. Consequent genetic mapping of the major strain modifier to Chr 7, and not Chr 2 where\u00a0Scn2a\u00a0maps, supported this biophysical prediction. While a NaV1.6V929F\u00a0loss of function clearly underlies absence seizures in this mouse model, the strain background effect is apparently not due to an otherwise tempting\u00a0Scn2a\u00a0variant, highlighting the value of combining physiology and genetics to inform and direct each other when interrogating genetic complex traits such as absence epilepsy.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[44],"resource_type":[75],"application_areas":[50],"therapeutic_areas":[55],"target_categories":[61],"target_families":[332],"targets":[212,244],"resource_keyword":[],"class_list":["post-6106","resource_library","type-resource_library","status-publish","hentry","products_tags-patchliner","resource_type-publication","application_areas-ion-channels","therapeutic_areas-cns","target_categories-voltage-gated-ion-channels","target_families-nav-channels","targets-nav1-2","targets-nav1-6"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library\/6106","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=6106"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/products_tags?post=6106"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_type?post=6106"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/application_areas?post=6106"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/therapeutic_areas?post=6106"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_categories?post=6106"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_families?post=6106"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/targets?post=6106"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_keyword?post=6106"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}