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Induced non-productive splicing to study muscle gene expression

Fletcher, S., Adams, A.M., Johnsen, R., Greer, K. and Wilton, S. (2009) Induced non-productive splicing to study muscle gene expression. In: 33rd HGSA Annual Scientific Meeting, 3 - 6 May 2009, Fremantle, Western Australia.


RNA silencing has been applied to suppress gene expression, with varying degrees of specificity and efficiency reported. Endogenous alternative splicing can regulate gene expression through a process called Regulated Unproductive Splicing and Translation (RUST) by either incorporating an exon carrying a nonsense mutation, or excluding an exon to disrupt the reading frame. As a result, the mature gene transcripts cannot be translated into functional gene products. We show that it is possible to efficiently disrupt the normal dystrophin mRNA reading frame and ablate dystrophin expression by the application of antisense oligomers. Total suppression of dystrophin gene expression can be induced and maintained for several weeks in vivo, and a severe dystrophic pathology observed within 4 weeks of commencing oligomer delivery in neonatal mice. This approach to gene down-regulation is very efficient and specific in suppressing dystrophin gene expression, unlike a recent attempt to induce dystrophic pathology by RNAi. Disruption of gene expression through altered splicing patterns could be applied to many different genes, and offers the opportunity to induce transient mouse models to study the consequences of gene suppression in vivo. In addition, selected exon removal to yield in-frame transcripts can allow mapping of functional protein domains, based upon exon boundaries, and provide an alternative to transgenic mouse models for the study of muscle gene expression.

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