Differential stabilities of alternative exon-skipped rod motifs of dystrophin.

Exon skipping repair is a strategy being investigated in early stage clinical trials to treat Duchenne muscular dystrophy. This is most applicable to the majority of cases which arise when genetic defects cause frame shift mutations, and induced exon skipping of out-of-phase exons restores the reading frame. However, the consequences to the edited protein so produced have not been considered. In many cases alternative routes to restoring the reading frame are possible, and we show in a test case involving exon 44 that the resulting differently edited proteins greatly vary in stability, with one of them very similar to normal unskipped dystrophin, and the other much less stable as assessed by the thermodynamics of folding as well as resistance to proteolysis. This has implications for the design of optimal therapeutic exon skipping strategies, which presumably wish to result repairs with as much fidelity to normal dystrophin as possible.