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Int. J. Mol. Sci. 2016, 17(10), 1722; doi:10.3390/ijms17101722

Endogenous Multiple Exon Skipping and Back-Splicing at the DMD Mutation Hotspot

1
School of Materials Science, Japan Advanced Institute of Science and Technology, Nomi, Ishikawa 923-1292, Japan
2
Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo 187-8502, Japan
3
Division of Gene Expression Mechanism, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan
4
Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyoku, Tokyo 113-0034, Japan
*
Author to whom correspondence should be addressed.
Academic Editor: Charles J. Malemud
Received: 5 August 2016 / Revised: 26 September 2016 / Accepted: 30 September 2016 / Published: 13 October 2016
(This article belongs to the Special Issue Pre-mRNA Splicing 2016)
View Full-Text   |   Download PDF [3551 KB, uploaded 13 October 2016]   |  

Abstract

Duchenne muscular dystrophy (DMD) is a severe muscular disorder. It was reported that multiple exon skipping (MES), targeting exon 45–55 of the DMD gene, might improve patients’ symptoms because patients who have a genomic deletion of all these exons showed very mild symptoms. Thus, exon 45–55 skipping treatments for DMD have been proposed as a potential clinical cure. Herein, we detected the expression of endogenous exons 44–56 connected mRNA transcript of the DMD using total RNAs derived from human normal skeletal muscle by reverse transcription polymerase chain reaction (RT-PCR), and identified a total of eight types of MES products around the hotspot. Surprisingly, the 5′ splice sites of recently reported post-transcriptional introns (remaining introns after co-transcriptional splicing) act as splicing donor sites for MESs. We also tested exon combinations to generate DMD circular RNAs (circRNAs) and determined the preferential splice sites of back-splicing, which are involved not only in circRNA generation, but also in MESs. Our results fit the current circRNA-generation model, suggesting that upstream post-transcriptional introns trigger MES and generate circRNA because its existence is critical for the intra-intronic interaction or for extremely distal splicing. View Full-Text
Keywords: pre-mRNA splicing; DMD; circular RNA; multiple exon skipping pre-mRNA splicing; DMD; circular RNA; multiple exon skipping
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Suzuki, H.; Aoki, Y.; Kameyama, T.; Saito, T.; Masuda, S.; Tanihata, J.; Nagata, T.; Mayeda, A.; Takeda, S.; Tsukahara, T. Endogenous Multiple Exon Skipping and Back-Splicing at the DMD Mutation Hotspot. Int. J. Mol. Sci. 2016, 17, 1722.

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