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Comparison of three different mutations in DMD exon 40 that influence the efficiency of AO induced exon skipping

West, K.A.ORCID: 0000-0002-7036-5334, Barrett, L., Fletcher, S. and Wilton, S.D. (2015) Comparison of three different mutations in DMD exon 40 that influence the efficiency of AO induced exon skipping. The Journal of Gene Medicine, 17 (8-9). PO10.

Link to Published Version: https://doi.org/10.1002/jgm.2834
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Abstract

Duchenne muscular dystrophy (DMD) is a recessive X‐linked disorder affecting one in 3500 boys. The disease is caused by mutations in the dystrophin gene (DMD) that result in protein truncation and ablate functional protein expression. Becker muscular dystrophy (BMD), a milder allelic form of DMD is less severe, less common and the progression is much slower, sometimes manifesting later in life. BMD is caused by mutations in the dystrophin gene that lead to reduced production of the dystrophin protein, which may be of variable quality, therefore increasing the variation of symptoms. Although there is currently no cure for DMD, antisense oligonucleotide (AO) induced exon skipping to restore the reading frame has shown promise. Clinical trials to re‐frame the transcript around the most common DMD‐causing genomic deletion are underway. Small intra‐exonic insertion/deletions and nonsense mutations account for approximately 25% of DMD mutations and, although single in‐frame skipping of an exon should generally result in a highly functional dystrophin isoform, there is the possibility of the mutation influencing pre‐mRNA processing. Here, we report three different mutations in DMD exon 40 that influence the efficiency of AO induced exon skipping. Each of the patients in this study would benefit from re‐framing of the DMD transcript by skipping of exon 40, although the AO therapy may need to be delivered on an individualized basis due to mutation specific effects on splicing. The influence of the different mutation exon 40 skipping was less pronounced when oligomers were synthesized as a phosphorodiamidate morpholino (PMO) than when 2'O methyl phosphorothioate AOs were used. The PMO demonstrated greater specificity and splice switching capability and may reduce the mutation‐specific influences on splicing.

Item Type: Journal Article
Murdoch Affiliation(s): Centre for Comparative Genomics
Publisher: Wiley
Copyright: © 2015 John Wiley & Sons, Ltd.
Other Information: Poster presentation given @ Ninth Australasian Gene and Cell Therapy Society Meeting, The University of Melbourne, Parkville, VIC 29 April - 1 May 2015
URI: http://researchrepository.murdoch.edu.au/id/eprint/59500
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