Multiple exon skipping strategies to by-pass dystrophin mutations

Adkin, Carl F.; Meloni, Penelope L.; Fletcher, Susan; Adams, Abbie M.; Muntoni, Francesco; Wong, Brenda; Wilton, Steve D.

doi:10.1016/j.nmd.2011.10.007

« Previous Next »Neuromuscular Disorders
Volume 22, Issue 4 , Pages 297-305, April 2012

Multiple exon skipping strategies to by-pass dystrophin mutations

Carl F. Adkin
- Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, WA 6009, Australia
Penelope L. Meloni
- Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, WA 6009, Australia
Susan Fletcher
- Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, WA 6009, Australia
Abbie M. Adams
- Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, WA 6009, Australia
Francesco Muntoni
- The Dubowitz Neuromuscular Centre, UCL, Institute of Child Health, London, UK
Brenda Wong
- Department of Paediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
- Department of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
Steve D. Wilton
- Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, WA 6009, Australia
- Corresponding author. Address: Centre for Neuromuscular and Neurological Disorders, M518, University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia. Tel.: +61 08 9346 2818; fax: +61 08 9346 3487.

Received 25 July 2011; received in revised form 10 October 2011; accepted 11 October 2011. published online 19 December 2011.

Abstract

Manipulation of dystrophin pre-mRNA processing offers the potential to overcome mutations in the dystrophin gene that would otherwise lead to Duchenne muscular dystrophy. Dystrophin mutations will require the removal of one or more exons to restore the reading frame and in some cases, multiple exon skipping strategies exist to restore dystrophin expression. However, for some small intra-exonic mutations, a third strategy, not applicable to whole exon deletions, may be possible. The removal of only one frame-shifting exon flanking the mutation-carrying exon may restore the reading frame and allow synthesis of a functional dystrophin isoform, providing that no premature termination codons are encountered. For these mutations, the removal of only one exon offers a simpler, cheaper and more feasible alternative approach to the dual exon skipping that would otherwise be considered. We present strategies to by-pass intra-exonic dystrophin mutations that clearly demonstrate the importance of tailoring exon skipping strategies to specific patient mutations.

Keywords: Dystrophin, Duchenne muscular dystrophy, Exon skipping, Antisense oligomers, Splice-switching, Personalised genetic therapy