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Exceptions to the reading frame rule in DMD: Will exon skipping be relevant?

Greer, K., Johnsen, R., Wilton, S. and Fletcher, S. (2009) Exceptions to the reading frame rule in DMD: Will exon skipping be relevant? In: 6th Australasian Gene Therapy Society Meeting, 29 April - 1 May 2009, Kerry Packer Education Centre. Royal Prince Alfred Hospital, Sydney, NSW.


Duchenne Muscular Dystrophy (DMD) is a severe muscle wasting disease caused by the absence of a functional dystrophin protein. The majority of the mutations in the dystrophin gene cause the protein to be prematurely truncated and therefore non-functional. Mutations that result in an internally deleted protein lead to a milder allelic condition, Becker muscular dystrophy. However, not all dystrophin mutations comply with the reading frame rule. We report two small in-frame exon duplications that, while expected to show a BMD phenotype, were found to cause DMD. This genotype: phenotype inconsistency could arise from disruption of an essential functional domain, or compromised transcription across the massive intron 2, which is in excess of 170 kb. Here we describe the application of phosphorodiamidate morpholino oligomers coupled to a cell penetrating peptide (PMO) to remove selected exons during mRNA processing. Myoblasts prepared from two DMD patients, one with a duplication of exon three, and the other, exons three and four, which are both in-frame re-arrangements, were transfected with PMOs. Oligomers were targeted at either exon three or four, or the two exons together in a cocktail. RNA was analysed by RT-PCR to monitor exon skipping and RNA levels were quantitated using real-time PCR. Preliminary studies have failed to detect protein in untreated cells, suggesting a defect in gene transcript processing.

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