Abstract.
Most cases of Duchenne muscular dystrophy are caused by dystrophin gene mutations that disrupt the mRNA reading frame. Artificial exclusion (skipping) of a single exon would often restore the reading frame, giving rise to a shorter, but still functional dystrophin protein. Here, we analyzed the ability of antisense U7 small nuclear (sn)RNA derivatives to alter dystrophin pre-mRNA splicing. As a proof of principle, we first targeted the splice sites flanking exon 23 of dystrophin pre-mRNA in the wild-type muscle cell line C2C12 and showed precise exon 23 skipping. The same strategy was then successfully adapted to dystrophic immortalized mdx muscle cells where exon-23-skipped dystrophin mRNA rescued dystrophin protein synthesis. Moreover, we observed a stimulation of antisense U7 snRNA expression by the murine muscle creatine kinase enhancer. These results demonstrate that alteration of dystrophin pre-mRNA splicing could correct dystrophin gene mutations by expression of specific U7 snRNA constructs.
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Received 2 December 2002; received after revision 15 January 2003; accepted 22 January 2003
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Brun, C., Suter, D., Pauli, C. et al. U7 snRNAs induce correction of mutated dystrophin pre-mRNA by exon skipping. CMLS, Cell. Mol. Life Sci. 60, 557–566 (2003). https://doi.org/10.1007/s000180300047
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DOI: https://doi.org/10.1007/s000180300047