In or Out? New Insights on Exon Recognition through Splice-Site Interdependency
| Autor: | Jan Amsu, Stéphanie S. Cornelis, Riccardo Sangermano, Frans P.M. Cremers, Iris J M Post, Amber Janssen Groesbeek, Rob W.J. Collin, Alejandro Garanto, Mubeen Khan, Christian Gilissen |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
RNA Splicing
ABCA4 interdependency Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] Catalysis Article Inorganic Chemistry Dystrophin lcsh:Chemistry Pre-mRNA Exon splicing All institutes and research themes of the Radboud University Medical Center Humans splice Physical and Theoretical Chemistry Molecular Biology lcsh:QH301-705.5 Spectroscopy Genetics biology Organic Chemistry HEK 293 cells Membrane Proteins Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] General Medicine Exons Exon skipping Computer Science Applications HEK293 Cells 5′ and 3′ splice sites lcsh:Biology (General) lcsh:QD1-999 RNA splicing biology.protein ATP-Binding Cassette Transporters RNA Splice Sites Sequence motif Precursor mRNA |
| Zdroj: | International Journal of Molecular Sciences Volume 21 Issue 7 International Journal of Molecular Sciences, Vol 21, Iss 7, p 2300 (2020) International Journal of Molecular Sciences, 21 International Journal of Molecular Sciences, 21, 7 |
| ISSN: | 1422-0067 |
| Popis: | Noncanonical splice-site mutations are an important cause of inherited diseases. Based on in vitro and stem-cell-based studies, some splice-site variants show a stronger splice defect than expected based on their predicted effects, suggesting that other sequence motifs influence the outcome. We investigated whether splice defects due to human-inherited-disease-associated variants in noncanonical splice-site sequences in ABCA4, DMD, and TMC1 could be rescued by strengthening the splice site on the other side of the exon. Noncanonical 5&prime and 3&prime splice-site variants were selected. Rescue variants were introduced based on an increase in predicted splice-site strength, and the effects of these variants were analyzed using in vitro splice assays in HEK293T cells. Exon skipping due to five variants in noncanonical splice sites of exons in ABCA4, DMD, and TMC1 could be partially or completely rescued by increasing the predicted strengths of the other splice site of the same exon. We named this mechanism &ldquo splicing interdependency&rdquo and it is likely based on exon recognition by splicing machinery. Awareness of this interdependency is of importance in the classification of noncanonical splice-site variants associated with disease and may open new opportunities for treatments. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|