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Open AccessArticle

In or Out? New Insights on Exon Recognition through Splice-Site Interdependency

1
Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
2
Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
3
Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA
4
Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(7), 2300; https://doi.org/10.3390/ijms21072300
Received: 7 February 2020 / Revised: 13 March 2020 / Accepted: 23 March 2020 / Published: 26 March 2020
(This article belongs to the Collection Feature Papers in Molecular Genetics and Genomics)
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′- and 3′-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 “splicing interdependency”, 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. View Full-Text
Keywords: Pre-mRNA; splicing; 5′ and 3′ splice sites; interdependency Pre-mRNA; splicing; 5′ and 3′ splice sites; interdependency
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Khan, M.; S. Cornelis, S.; Sangermano, R.; J.M. Post, I.; Janssen Groesbeek, A.; Amsu, J.; Gilissen, C.; Garanto, A.; W.J. Collin, R.; P.M. Cremers, F. In or Out? New Insights on Exon Recognition through Splice-Site Interdependency. Int. J. Mol. Sci. 2020, 21, 2300.

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