title: Deletion of Dystrophin In-Frame Exon 5 Leads to a Severe Phenotype: Guidance for Exon Skipping Strategies.
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.
authors.affiliation: Western Australian Neuroscience Research Institute, Perth, Australia.|University of Western Australia, Perth, Australia.
authors.forename: Zhi Yon Charles
authors.initials: ZY
authors.lastname: Toh
authors.affiliation: Centre for Comparative Genomics, Murdoch University, Perth, Australia.
authors.forename: May
authors.initials: M
authors.lastname: Thandar Aung-Htut
authors.affiliation: School of Anatomy, Physiology and Human Biology, University of Western Australia, Perth, Australia.
authors.forename: Gavin
authors.initials: G
authors.lastname: Pinniger
authors.affiliation: Western Australian Neuroscience Research Institute, Perth, Australia.|University of Western Australia, Perth, Australia.|Centre for Comparative Genomics, Murdoch University, Perth, Australia.
authors.forename: Abbie M
authors.initials: AM
authors.lastname: Adams
authors.affiliation: University of Western Australia, Perth, Australia.
authors.forename: Sudarsan
authors.initials: S
authors.lastname: Krishnaswarmy
authors.affiliation: Department of Paediatrics, Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Wong
authors.affiliation: Western Australian Neuroscience Research Institute, Perth, Australia.|University of Western Australia, Perth, Australia.|Centre for Comparative Genomics, Murdoch University, Perth, Australia.
authors.forename: Sue
authors.initials: S
authors.lastname: Fletcher
authors.affiliation: Western Australian Neuroscience Research Institute, Perth, Australia.|University of Western Australia, Perth, Australia.|Centre for Comparative Genomics, Murdoch University, Perth, Australia.
authors.forename: Steve D
authors.initials: SD
authors.lastname: Wilton
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002648:Child; D004195:Disease Models, Animal; D016189:Dystrophin / Q000032:analysis / Q000235:genetics*; D005091:Exons; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D010641:Phenotype; D012313:RNA / Q000737:chemistry / Q000378:metabolism; D012326:RNA Splicing; D017423:Sequence Analysis, RNA; D017384:Sequence Deletion
chemical_list: D016189:Dystrophin; D016376:Oligonucleotides, Antisense; D012313:RNA