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


ABSTRACT: 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.

SUBMITTER: Ham KA 

PROVIDER: S-EPMC7590164 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Nonsequential Splicing Events Alter Antisense-Mediated Exon Skipping Outcome in <i>COL7A1</i>.

Ham Kristin A KA   Aung-Htut May Thandar MT   Fletcher Sue S   Wilton Steve D SD  

International journal of molecular sciences 20201018 20


The <i>COL7A1</i> gene encodes homotrimer fibrils essential for anchoring dermal and epidermal layers, and pathogenic mutations in <i>COL7A1</i> can cause recessive or dominant dystrophic epidermolysis bullosa. As a monogenic disease gene, <i>COL7A1</i> 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 <i>COL7A1</i>: many exons, low average intron size, and repetit  ...[more]

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