Journal article
Characterization of a complex Duchenne muscular dystrophy-causing dystrophin gene inversion and restoration of the reading frame by induced exon skipping
Human Mutation, Vol.30(1), pp.22-28
2009
Abstract
Out of three mutations in the dystrophin gene that cause Duchenne muscular dystrophy (DMD), the most common, serious childhood muscle wasting disease, two are genomic deletions of one or more exons that disrupt the reading frame. Specific removal of an exon flanking a genomic deletion using antisense oligonucleotide intervention during pre-RNA processing can restore the reading frame and could potentially reduce disease severity. We describe a rare dystrophin gene rearrangement; inversion of ∼28 kb, flanked by a 10-bp duplication and an 11-kb deletion, which led to the omission of exons 49 and 50 from the mature mRNA and the variable inclusion of several pseudoexons. In vitro transfection of cultured patient cells with antisense oligonucleotides directed at exon 51 induced efficient removal of that exon, as well as one of the more commonly included pseudoexons, suggesting closely coordinated splicing of these exons. Surprisingly, several antisense oligonucleotides (AOs) directed at this pseudoexon had no detectable effect on the splicing pattern, while all AOs directed at the other predominant pseudoexon efficiently excised that target. Antisense oligomers targeting dystrophin exon 51 for removal are currently undergoing clinical trials. Despite the unique nature of the dystrophin gene rearrangement described here, a personalized multiexon skipping treatment is applicable and includes one compound entering clinical trials for DMD.
Details
- Title
- Characterization of a complex Duchenne muscular dystrophy-causing dystrophin gene inversion and restoration of the reading frame by induced exon skipping
- Authors/Creators
- H.R. Madden (Author/Creator) - The University of Western AustraliaS. Fletcher (Author/Creator) - The University of Western AustraliaM.R. Davis (Author/Creator) - Royal Perth HospitalS.D. Wilton (Author/Creator) - The University of Western Australia
- Publication Details
- Human Mutation, Vol.30(1), pp.22-28
- Publisher
- John Wiley & Sons Inc.
- Identifiers
- 991005542719007891
- Copyright
- © 2008 Wiley-Liss, Inc.
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Journal article
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Source: InCites
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- Collaboration types
- Domestic collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.255 Musculoskeletal Disorders
- 1.255.628 Duchenne Muscular Dystrophy
- Web Of Science research areas
- Genetics & Heredity
- ESI research areas
- Molecular Biology & Genetics