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Open AccessArticle

Nonsequential Splicing Events Alter Antisense-Mediated Exon Skipping Outcome in COL7A1

1
Centre for Molecular Medicine and Innovative Therapeutics, Health Futures Institute, Murdoch University, Murdoch 6150, Australia
2
Perron Institute for Neurological and Translational Science, Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands 6009, Australia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(20), 7705; https://doi.org/10.3390/ijms21207705
Received: 2 September 2020 / Revised: 6 October 2020 / Accepted: 14 October 2020 / Published: 18 October 2020
(This article belongs to the Special Issue Precision Nucleic Acid Therapeutics)
The COL7A1 gene encodes homotrimer fibrils essential for anchoring dermal and epidermal layers, and pathogenic mutations in COL7A1 can cause recessive or dominant dystrophic epidermolysis bullosa. As a monogenic disease gene, COL7A1 constitutes a potential target for antisense oligomer-mediated exon skipping, a therapy applicable to a growing number of other genetic disorders. However, certain characteristics of COL7A1: many exons, low average intron size, and repetitive and guanine-cytosine rich coding sequence, present challenges to the design of specific and effective antisense oligomers. While targeting COL7A1 exons 10 and 73 for excision from the mature mRNA, we discovered that antisense oligomers comprised of 2′-O-methyl modified bases on a phosphorothioate backbone and phosphorodiamidate morpholino oligomers produced similar, but distinctive, splicing patterns including excision of adjacent nontargeted exons and/or retention of nearby introns in some transcripts. We found that the nonsequential splicing of certain introns may alter pre-mRNA processing during antisense oligomer-mediated exon skipping and, therefore, additional studies are required to determine if the order of intron removal influences multiexon skipping and/or intron retention in processing of the COL7A1 pre-mRNA. View Full-Text
Keywords: COL7A1; dystrophic epidermolysis bullosa; antisense oligonucleotides; splice-switching; exon skipping; intron retention; morpholino; 2′-O-methyl COL7A1; dystrophic epidermolysis bullosa; antisense oligonucleotides; splice-switching; exon skipping; intron retention; morpholino; 2′-O-methyl
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Ham, K.A.; Aung-Htut, M.T.; Fletcher, S.; Wilton, S.D. Nonsequential Splicing Events Alter Antisense-Mediated Exon Skipping Outcome in COL7A1. Int. J. Mol. Sci. 2020, 21, 7705.

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