Dataset Information

A duchenne muscular dystrophy gene hot spot mutation in dystrophin-deficient cavalier king charles spaniels is amenable to exon 51 skipping.

ABSTRACT: 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".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.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.

SUBMITTER: Walmsley GL

PROVIDER: S-EPMC2800183 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A duchenne muscular dystrophy gene hot spot mutation in dystrophin-deficient cavalier king charles spaniels is amenable to exon 51 skipping.

Walmsley Gemma L GL Arechavala-Gomeza Virginia V Fernandez-Fuente Marta M Burke Margaret M MM Nagel Nicole N Holder Angela A Stanley Rachael R Chandler Kate K Marks Stanley L SL Muntoni Francesco F Shelton G Diane GD Piercy Richard J RJ

PloS one 20100113 1

<h4>Background</h4>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 e ...[more]

PMID: 20072625

Similar Datasets

Project description:BACKGROUND:Syringomyelia (SM) is a debilitating condition in the cavalier King Charles spaniel (CKCS) that results in neuropathic pain and diminished quality of life. Von Frey aesthesiometry (VFA) is a method of mechanical quantitative sensory testing that provides an objective sensory threshold (ST) value and can be used to quantify neuropathic pain (NP) and monitor response to therapy. The utility of VFA has been previously established in client-owned dogs with acute spinal cord injury but the technique has not been evaluated in dogs with SM. The goal of this study was to evaluate ST, as determined by VFA, in dogs with and without SM, to assess the utility of VFA in quantifying NP in SM-affected dogs. We hypothesized the SM-affected CKCS would have lower ST values, consistent with hyperesthesia, when compared to control CKCS. Additionally, we hypothesized that ST values in SM-affected dogs would be inversely correlated with syrinx size on MRI and with owner-derived clinical sign scores. RESULTS:ST values for the thoracic and pelvic limbs differed significantly between the SM-affected and control CKCS (p?=?0.027; p?=?0.0396 respectively). Median ST value (range) for the thoracic limbs was 184.1?g (120.9-552) for control dogs, and 139.9?g (52.6-250.9) for SM-affected dogs. The median ST value (range) for the pelvic limbs was 164.9?g (100.8-260.3) in control dogs and 129.8?g (57.95-168.4) in SM-affected dogs. The ST values in SM-affected dogs did not correlate with syrinx height on MRI (r?=?0.314; p?=?0.137). Owner-reported clinical sign scores showed an inverse correlation with pelvic limb ST values, where dogs with lower ST values (hyperesthesia) were reported by their owners to display more frequent and severe clinical signs (r?=?-?0.657; p?=?0.022). CONCLUSION:ST values were lower in SM-affected CKCS compared to control dogs, suggesting the presence of neuropathic pain. Dogs with lower ST pelvic limb values were perceived by their owners to have more severe clinical signs classically associated with SM. Our results suggest that VFA might offer quantitative assessment of neuropathic pain in SM-affected dogs and could be useful for monitoring response to therapy in future clinical studies.

Project description:There is a growing interest in developing new molecular markers of heart disease in young dogs affected by myxomatous mitral valve disease. The study aimed to measure 3 circulating microRNAs and their application as potential biomarkers in the plasma of Cavalier King Charles Spaniels with early asymptomatic myxomatous mitral valve disease. The hypothesis is that healthy Cavalier King Charles Spaniels have different microRNA expression profiles than affected dogs in American College of Veterinary Internal Medicine (ACVIM) stage B1. The profiles can differ within the same class among subjects of different ages. This is a prospective cross-sectional study. Thirty-three Cavalier King Charles Spaniels in ACVIM stage B1 were divided into three groups (11 younger than 3 years, 11 older than 3 years and younger than 7 years, and 11 older than 7 years), and 11 healthy (ACVIM stage A) dogs of the same breed were included as the control group. Three circulating microRNAs (miR-1-3p, miR30b-5p, and miR-128-3p) were measured by quantitative real-time PCR using TaqMan® probes. Diagnostic performance was evaluated by calculating the area under the receiver operating curve (AUC). MiR-30b-5p was significantly higher in ACVIM B1 dogs than in ACVIM A subjects, and the area under the receiver operating curve was 0.79. According to the age of dogs, the amount of miR-30b-5p was statistically significantly higher in group B1<3y (2.3 folds, P = 0.034), B1 3-7y (2.2 folds, P = 0.028), and B1>7y (2.7 folds, P = 0.018) than in group A. The area under the receiver operating curves were fair in discriminating between group B1<3y and group A (AUC 0.780), between B1 3-7y and A (AUC 0.78), and good in discriminating between group B1>7y and A (AUC 0.822). Identifying dogs with early asymptomatic myxomatous mitral valve disease through the evaluation of miR-30b-5p represents an intriguing possibility that certainly merits further research. Studies enrolling a larger number of dogs with preclinical stages of myxomatous mitral valve disease are needed to expand further and validate conclusively the preliminary findings from this report.

Project description:Our knowledge about the underlying pathomechanisms of craniocervical junction abnormalities (CCJA) in dogs mostly derives from measurements based on tomographic imaging. These images are static and the positioning of the dogs’ head does not reflect the physiological in vivo position of the craniocervical junction (CCJ). Aberrant motion patterns and ranges of motion (ROM) in sound individuals of CCJA predisposed breeds may be a pathogenetic trigger. To further extend our limited knowledge of physiological motion of the CCJ, this prospective, comparative study investigates the in vivo motion patterns and ROM of the CCJ in walk and trot in sound Cavalier King Charles Spaniels and Chihuahuas. The Labrador retriever is used as a reference breed without predisposition for CCJA. This is the first detailed description of CCJ movement of trotting dogs. Biplanar fluoroscopy images, recorded in walking and trotting dogs, were matched to a virtual reconstruction of the skull and cranial cervical spine utilising Scientific Rotoscoping. Kinematic data reveal the same motion patterns among all breeds and gaits with individual temporal and spatial differences in each dog. A stride cycle-dependent lateral rotation of the cranial cervical spine and axial rotation of the atlantoaxial joint in trot in dogs is described for the first time. The ROM of the atlantoaxial and atlantooccipital joints in walk and trot were not statistically significantly greater in the CCJA-predisposed breeds CKCS and Chihuahua. ROM values of all translational and rotational degrees of freedom were larger in walk than trot, although this is only statistically significant for the atlantoaxial joint. Until proven otherwise, a more species-specific than breed-specific general motion pattern of the CCJ in walking and trotting, clinically sound dogs must be assumed. Species-specific anatomic properties of the CCJ seem to supersede breed-specific anatomical differences in clinically sound dogs.

Dataset Information

A duchenne muscular dystrophy gene hot spot mutation in dystrophin-deficient cavalier king charles spaniels is amenable to exon 51 skipping.

Publications

A duchenne muscular dystrophy gene hot spot mutation in dystrophin-deficient cavalier king charles spaniels is amenable to exon 51 skipping.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets