Deletion of a non-canonical promoter regulatory element causes loss of Scn1a expression and epileptic phenotypes in mice

Genes with multiple co-active promoters appear common in brain, yet little is known about functional requirements for these potentially redundant genomic regulatory elements. which encodes the Na1.1 sodium channel alpha subunit, is one such gene with two co-active promoters. Mutations in are associated with epilepsy, including Dravet Syndrome (DS). The majority of DS patients harbor coding mutations causing haploinsufficiency, however putative causal non-coding promoter mutations have been identified. To model the functional role of potentially redundant promoters, we focused on the non-coding 1b regulatory region, previously described as a non-canonical alternative transcriptional start site. Mice harboring deletion of the extended evolutionarily-conserved 1b non-coding interval exhibited surprisingly severe reduction of and Na1.1 expression in brain with accompanying seizures and behavioral deficits. This identified the 1b region as a critical disease-relevant regulatory element and provides evidence that non-canonical and apparently redundant promoters can have essential function.