Therapeutic potential and mechanism of kinetin as a treatment for the human splicing disease familial dysautonomia
| Autor: | Sandra Gill, Conxi Lázaro, Lijuan Liu, Robin Reed, El Chérif Ibrahim, Matthew M. Hims, Ranjit S. Shetty, James F. Gusella, Maire Leyne, James Mull, Susan A. Slaugenhaupt |
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| Přispěvatelé: | Center for humana genetic research, Harvard Medical School [Boston] (HMS), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Reed laboratory |
| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
MESH: Cell Line
Tumor Neurofibromatoses RNA Splicing MESH: Carrier Proteins MESH: Dysautonomia Familial Biology chemistry.chemical_compound Exon Cell Line Tumor Drug Discovery Dysautonomia Familial medicine Humans RNA Messenger Genetics (clinical) MESH: RNA Messenger Genetics MESH: Humans IKBKAP Intron Exons Kinetin medicine.disease Exon skipping chemistry MESH: Kinetin Familial dysautonomia RNA splicing Molecular Medicine [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Transcriptional Elongation Factors Carrier Proteins MESH: Exons MESH: Neurofibromatoses MESH: RNA Splicing Minigene |
| Zdroj: | Journal of Molecular Medicine Journal of Molecular Medicine, 2007, 85 (2), pp.149-61. ⟨10.1007/s00109-006-0137-2⟩ |
| ISSN: | 0946-2716 1432-1440 |
| DOI: | 10.1007/s00109-006-0137-2⟩ |
| Popis: | Mutations that affect the splicing of pre-mRNA are a major cause of human disease. Familial dysautonomia (FD) is a recessive neurodegenerative disease caused by a T to C transition at base pair 6 of IKBKAP intron 20. This mutation results in variable tissue-specific skipping of exon 20. Previously, we reported that the plant cytokinin kinetin dramatically increases exon 20 inclusion in RNA isolated from cultured FD cells. The goal of the current study was to investigate the nature of the FD splicing defect and the mechanism by which kinetin improves exon inclusion, as such knowledge will facilitate the development of future therapeutics aimed at regulating mRNA splicing. In this study, we demonstrate that treatment of FD lymphoblast cell lines with kinetin increases IKBKAP mRNA and IKAP protein to normal levels. Using a series of minigene constructs, we show that deletion of a region at the end of IKBKAP exon 20 disrupts the ability of kinetin to improve exon inclusion, pinpointing a kinetin responsive sequence element. We next performed a screen of endogenously expressed genes with multiple isoforms resulting from exon skipping events and show that kinetin's ability to improve exon inclusion is not limited to IKBKAP. Lastly, we highlight the potential of kinetin for the treatment of other human splicing disorders by showing correction of a splicing defect in neurofibromatosis. |
| Databáze: | OpenAIRE |
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