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Open AccessArticle

Single Exon Skipping Can Address a Multi-Exon Duplication in the Dystrophin Gene

1
Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch 6150, Australia
2
Perron Institute for Neurological and Translational Science, Perth 6009, Australia
3
Institute of Neurology, Schneider Children’s Medical Center of Israel, Tel-Aviv University, Tel-Aviv 62919, Israel
4
Pathology Department, Hadassah-Hebrew-University Medical Center, Jerusalem 91120, Israel;
5
Centre for Neuromuscular & Neurological Disorders, University of Western Australia, Perth 6009, Australia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(12), 4511; https://doi.org/10.3390/ijms21124511
Received: 10 June 2020 / Revised: 22 June 2020 / Accepted: 23 June 2020 / Published: 25 June 2020
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease typically caused by protein-truncating mutations that preclude synthesis of a functional dystrophin. Exonic deletions are the most common type of DMD lesion, however, whole exon duplications account for between 10–15% of all reported mutations. Here, we describe in vitro evaluation of antisense oligonucleotide-induced splice switching strategies to re-frame the transcript disrupted by a multi-exon duplication within the DMD gene. Phosphorodiamidate morpholino oligomers and phosphorodiamidate morpholino oligomers coupled to a cell penetrating peptide were evaluated in a Duchenne muscular dystrophy patient cell strain carrying an exon 14–17 duplication. Two strategies were employed; the conventional approach was to remove both copies of exon 17 in addition to exon 18, and the second strategy was to remove only the first copy of exon 17. Both approaches result in a larger than normal but in-frame DMD transcript, but surprisingly, the removal of only the first exon 17 appeared to be more efficient in restoring dystrophin, as determined using western blotting. The emergence of a normal sized DMD mRNA transcript that was not apparent in untreated samples may have arisen from back splicing and could also account for some of the dystrophin protein being produced. View Full-Text
Keywords: Duchenne muscular dystrophy; dystrophin; antisense oligomers; duplication mutations; exon skipping; splicing Duchenne muscular dystrophy; dystrophin; antisense oligomers; duplication mutations; exon skipping; splicing
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Greer, K.; Johnsen, R.; Nevo, Y.; Fellig, Y.; Fletcher, S.; Wilton, S.D. Single Exon Skipping Can Address a Multi-Exon Duplication in the Dystrophin Gene. Int. J. Mol. Sci. 2020, 21, 4511.

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