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A Duchenne Muscular Dystrophy Gene Hot Spot Mutation in Dystrophin-Deficient Cavalier King Charles Spaniels Is Amenable to Exon 51 Skipping

Walmsley, GL; Arechavala-Gomeza, V; Fernandez-Fuente, M; Burke, MM; Nagel, N; Holder, A; Stanley, R; ... Piercy, RJ; + view all (2010) A Duchenne Muscular Dystrophy Gene Hot Spot Mutation in Dystrophin-Deficient Cavalier King Charles Spaniels Is Amenable to Exon 51 Skipping. PLOS ONE , 5 (1) , Article e8647. 10.1371/journal.pone.0008647. Green open access

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Abstract

Background: Duchenne muscular dystrophy (DMD), which afflicts 1 in 3500 boys, is one of the most common genetic disorders of children. This fatal degenerative condition is caused by an absence or deficiency of dystrophin in striated muscle. Most affected patients have inherited or spontaneous deletions in the dystrophin gene that disrupt the reading frame resulting in unstable truncated products. For these patients, restoration of the reading frame via antisense oligonucleotide-mediated exon skipping is a promising therapeutic approach. The major DMD deletion "hot spot" is found between exons 45 and 53, and skipping exon 51 in particular is predicted to ameliorate the dystrophic phenotype in the greatest number of patients. Currently the mdx mouse is the most widely used animal model of DMD, although its mild phenotype limits its suitability in clinical trials. The Golden Retriever muscular dystrophy (GRMD) model has a severe phenotype, but due to its large size, is expensive to use. Both these models have mutations in regions of the dystrophin gene distant from the commonly mutated DMD "hot spot".Methodology/Principal Findings: Here we describe the severe phenotype, histopathological findings, and molecular analysis of Cavalier King Charles Spaniels with dystrophin-deficient muscular dystrophy (CKCS-MD). The dogs harbour a missense mutation in the 59 donor splice site of exon 50 that results in deletion of exon 50 in mRNA transcripts and a predicted premature truncation of the translated protein. Antisense oligonucleotide-mediated skipping of exon 51 in cultured myoblasts from an affected dog restored the reading frame and protein expression.Conclusions/Significance: Given the small size of the breed, the amiable temperament and the nature of the mutation, we propose that CKCS-MD is a valuable new model for clinical trials of antisense oligonucleotide-induced exon skipping and other therapeutic approaches for DMD.

Type: Article
Title: A Duchenne Muscular Dystrophy Gene Hot Spot Mutation in Dystrophin-Deficient Cavalier King Charles Spaniels Is Amenable to Exon 51 Skipping
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0008647
Publisher version: http://dx.doi.org/10.1371/journal.pone.0008647
Language: English
Additional information: © 2010 Walmsley et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The Muscular Dystrophy Association (USA) funds canine studies in the laboratory of one of the authors (GDS). Prof. Muntoni acknowledges the financial support from the Medical Research Coucil (Award G0502130) for antisense oligonucleotide studies and for funding the Biobank of the University College London Medical Research Council Neuromuscular translational research centre. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords: DMD GENE, SKELETAL-MUSCLE, CANINE MODEL, DELETION, EXPRESSION, MICE, DOG, CARDIOMYOPATHY, ORGANIZATION, THERAPY
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept
URI: https://discovery.ucl.ac.uk/id/eprint/141350
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