RT Journal Article SR Electronic T1 Deletion of a non-canonical promoter regulatory element causes loss of Scn1a expression and epileptic phenotypes in mice JF bioRxiv FD Cold Spring Harbor Laboratory SP 766634 DO 10.1101/766634 A1 Jessica L. Haigh A1 Anna Adhikari A1 Nycole A. Copping A1 Tyler Stradleigh A1 A. Ayanna Wade A1 Rinaldo Catta-Preta A1 Linda Su-Feher A1 Iva Zdilar A1 Sarah Morse A1 Timothy A Fenton A1 Anh Nguyen A1 Diana Quintero A1 Michael Sramek A1 Jasmine Carter A1 Andrea Gompers A1 Jason Lambert A1 Cesar P. Canales A1 Len A. Pennacchio A1 Axel Visel A1 Diane E. Dickel A1 Jill L. Silverman A1 Alex S. Nord YR 2019 UL http://biorxiv.org/content/early/2019/09/12/766634.abstract AB Genes with multiple co-active promoters appear common in brain, yet little is known about functional requirements for these potentially redundant genomic regulatory elements. SCN1A, which encodes the NaV1.1 sodium channel alpha subunit, is one such gene with two co-active promoters. Mutations in SCN1A are associated with epilepsy, including Dravet Syndrome (DS). The majority of DS patients harbor coding mutations causing SCN1A haploinsufficiency, however putative causal non-coding promoter mutations have been identified. To model the functional role of potentially redundant Scn1a promoters, we focused on the non-coding Scn1a 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 Scn1a and NaV1.1 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.