A duchenne muscular dystrophy gene hot spot mutation in dystrophin-deficient Cavalier King Charles Spaniels is amenable to exon 51 skipping

Walmsley, Gemma L, Arechavala-Gomeza, Virginia, Fernandez-Fuente, Marta, Burke, Margaret M, Nagel, Nicole, Holder, Angela, Stanley, Rachael, Chandler, Kate, Marks, Stanley L, Muntoni, Francesco, Shelton, G Diane and Piercy, Richard J (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). e8647. ISSN 1932-6203

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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 5' 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.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Clinical and Laboratory Investigation
Subjects: R Medicine
R Medicine > RB Pathology > RB151 Theories of disease. Etiology. Pathogenesis
Related URLs:
Depositing User: Patricia Butler
Date Deposited: 05 Jul 2013 07:59
Last Modified: 06 Mar 2017 05:58
URI: http://sro.sussex.ac.uk/id/eprint/45578

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