title: Mechanism of Deletion Removing All Dystrophin Exons in a Canine Model for DMD Implicates Concerted Evolution of X Chromosome Pseudogenes.
abstract: Duchenne muscular dystrophy (DMD) is a lethal, X-linked, muscle-wasting disorder caused by mutations in the large, 2.4-Mb dystrophin gene. The majority of DMD-causing mutations are sporadic, multi-exon, frameshifting deletions, with the potential for variable immunological tolerance to the dystrophin protein from patient to patient. While systemic gene therapy holds promise in the treatment of DMD, immune responses to vectors and transgenes must first be rigorously evaluated in informative preclinical models to ensure patient safety. A widely used canine model for DMD, golden retriever muscular dystrophy, expresses detectable amounts of near full-length dystrophin due to alternative splicing around an intronic point mutation, thereby confounding the interpretation of immune responses to dystrophin-derived gene therapies. Here we characterize a naturally occurring deletion in a dystrophin-null canine, the German shorthaired pointer. The deletion spans 5.6 Mb of the X chromosome and encompasses all coding exons of theDMDandTMEM47genes. The sequences surrounding the deletion breakpoints are virtually identical, suggesting that the deletion occurred through a homologous recombination event. Interestingly, the deletion breakpoints are within loci that are syntenically conserved among mammals, yet the high homology among this subset of ferritin-like loci is unique to the canine genome, suggesting lineage-specific concerted evolution of these atypical sequence elements.
authors.affiliation: Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: D Jake
authors.initials: DJ
authors.lastname: VanBelzen
authors.affiliation: Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Alock S
authors.initials: AS
authors.lastname: Malik
authors.affiliation: Section of Medical Genetics, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA.
authors.forename: Paula S
authors.initials: PS
authors.lastname: Henthorn
authors.affiliation: Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Joe N
authors.initials: JN
authors.lastname: Kornegay
authors.affiliation: Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Corporal Michael Crescenz Veterans Administration Medical Center, Philadelphia, PA 19104, USA.
authors.forename: Hansell H
authors.initials: HH
authors.lastname: Stedman
keywords: Duchenne muscular dystrophy; German shorthaired pointer; concerted evolution; dystrophin-null; pseudogene