Journal article
Deletion of dystrophin In-Frame Exon 5 leads to a severe phenotype: Guidance for Exon skipping strategies
PloS one, Vol.11(1), e0145620
2016
Abstract
Duchenne and Becker muscular dystrophy severity depends upon the nature and location of the DMD gene lesion and generally correlates with the dystrophin open reading frame. However, there are striking exceptions where an in-frame genomic deletion leads to severe pathology or protein-truncating mutations (nonsense or frame-shifting indels) manifest as mild disease. Exceptions to the dystrophin reading frame rule are usually resolved after molecular diagnosis on muscle RNA. We report a moderate/severe Becker muscular dystrophy patient with an in-frame genomic deletion of DMD exon 5. This mutation has been reported by others as resulting in Duchenne or Intermediate muscular dystrophy, and the loss of this in-frame exon in one patient led to multiple splicing events, including omission of exon 6, that disrupts the open reading frame and is consistent with a severe phenotype. The patient described has a deletion of dystrophin exon 5 that does not compromise recognition of exon 6, and although the deletion does not disrupt the reading frame, his clinical presentation is more severe than would be expected for classical Becker muscular dystrophy. We suggest that the dystrophin isoform lacking the actin-binding sequence encoded by exon 5 is compromised, reflected by the phenotype resulting from induction of this dystrophin isoform in mouse muscle in vivo. Hence, exon skipping to address DMD-causing mutations within DMD exon 5 may not yield an isoform that confers marked clinical benefit. Additional studies will be required to determine whether multi-exon skipping strategies could yield more functional dystrophin isoforms, since some BMD patients with larger in-frame deletions in this region have been reported with mild phenotypes.
Details
- Title
- Deletion of dystrophin In-Frame Exon 5 leads to a severe phenotype: Guidance for Exon skipping strategies
- Authors/Creators
- D. Fraidenraich (Author/Creator)Z.Y.C. Toh (Author/Creator) - Perron Institute for Neurological and Translational ScienceM.T. Aung-Htut (Author/Creator) - Murdoch UniversityG. Pinniger (Author/Creator) - The University of Western AustraliaA.M. Adams (Author/Creator) - Murdoch UniversityS. Krishnaswarmy (Author/Creator) - The University of Western AustraliaB.L. Wong (Author/Creator) - Cincinnati Children's Hospital Medical CenterS. Fletcher (Author/Creator) - Murdoch UniversityS.D. Wilton (Author/Creator) - Murdoch University
- Publication Details
- PloS one, Vol.11(1), e0145620
- Publisher
- Public Library of Science
- Identifiers
- 991005544814407891
- Copyright
- © 2016 Toh et al.
- Murdoch Affiliation
- Centre for Comparative Genomics
- Language
- English
- Resource Type
- Journal article
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Source: InCites
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- Collaboration types
- Domestic collaboration
- International 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