학술논문
Deletion of a non-canonical regulatory sequence causes loss of Scn1a expression and epileptic phenotypes in mice
Document Type
article
Author
Haigh, Jessica L; Adhikari, Anna; Copping, Nycole A; Stradleigh, Tyler; Wade, A Ayanna; Catta-Preta, Rinaldo; Su-Feher, Linda; Zdilar, Iva; Morse, Sarah; Fenton, Timothy A; Nguyen, Anh; Quintero, Diana; Agezew, Samrawit; Sramek, Michael; Kreun, Ellie J; Carter, Jasmine; Gompers, Andrea; Lambert, Jason; Canales, Cesar P; Pennacchio, Len A; Visel, Axel; Dickel, Diane E; Silverman, Jill L; Nord, Alex S
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Subject
Language
Abstract
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 Na V 1.1 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 determine the functional role of one of these 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 a deletion of the extended evolutionarily-conserved 1b non-coding interval exhibited surprisingly severe reductions of Scn1a and Na V 1.1 expression in brain with accompanying electroencephalographic seizures and behavioral deficits. This work identified the 1b region as a critical disease-relevant regulatory element and provides evidence that non-canonical and seemingly redundant promoters can have essential function.