Academic Journal
Deletion of a non-canonical regulatory sequence causes loss of Scn1a expression and epileptic phenotypes in mice
| العنوان: | Deletion of a non-canonical regulatory sequence causes loss of Scn1a expression and epileptic phenotypes in mice |
|---|---|
| المؤلفون: | Haigh, JL, Adhikari, A, Copping, NA, Stradleigh, T, Wade, AA, Catta-Preta, R, Su-Feher, L, Zdilar, I, Morse, S, Fenton, TA, Nguyen, A, Quintero, D, Agezew, S, Sramek, M, Kreun, EJ, Carter, J, Gompers, A, Lambert, JT, Canales, CP, Pennacchio, LA, Visel, A, Dickel, DE, Silverman, JL, Nord, AS |
| بيانات النشر: | BioMed Central |
| سنة النشر: | 2021 |
| المجموعة: | Leeds Beckett University Repository |
| الوصف: | BACKGROUND: 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. METHODS: 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. We generated a transgenic mouse line with deletion of the extended evolutionarily conserved 1b non-coding interval and characterized changes in gene and protein expression, and assessed seizure activity and alterations in behavior. RESULTS: Mice harboring a deletion of the 1b non-coding interval exhibited surprisingly severe reductions of Scn1a and NaV1.1 expression throughout the brain. This was accompanied by electroencephalographic and thermal-evoked seizures, and behavioral deficits. CONCLUSIONS: This work contributes to functional dissection of the regulatory wiring of a major epilepsy risk gene, SCN1A. We identified the 1b region as a critical disease-relevant regulatory element and provide evidence that non-canonical and seemingly redundant promoters can have essential function. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | text |
| اللغة: | English |
| Relation: | https://eprints.leedsbeckett.ac.uk/id/eprint/9821/1/DeletionOfANoncanonicalRegulatorySequenceCausesLossOfScn1AExpressionAndEpilepticPhenotypesInMicePV-HAIGH.pdf; Haigh, JL and Adhikari, A and Copping, NA and Stradleigh, T and Wade, AA and Catta-Preta, R and Su-Feher, L and Zdilar, I and Morse, S and Fenton, TA and Nguyen, A and Quintero, D and Agezew, S and Sramek, M and Kreun, EJ and Carter, J and Gompers, A and Lambert, JT and Canales, CP and Pennacchio, LA and Visel, A and Dickel, DE and Silverman, JL and Nord, AS (2021) Deletion of a non-canonical regulatory sequence causes loss of Scn1a expression and epileptic phenotypes in mice. Genome Medicine, 13 (1). pp. 1-22. ISSN 1756-994X DOI: https://doi.org/10.1186/s13073-021-00884-0 |
| الاتاحة: | https://eprints.leedsbeckett.ac.uk/id/eprint/9821/ https://eprints.leedsbeckett.ac.uk/id/eprint/9821/1/DeletionOfANoncanonicalRegulatorySequenceCausesLossOfScn1AExpressionAndEpilepticPhenotypesInMicePV-HAIGH.pdf |
| Rights: | cc_by_4 |
| رقم الانضمام: | edsbas.1B5B64B8 |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |