Evaluation of the dystrophin-glycoprotein complex, alpha-actinin, dysferlin and calpain 3 in an autosomal recessive muscular dystrophy in Labrador retrievers.
ABSTRACT Labrador retrievers suffer from an autosomal recessive muscular dystrophy of unknown aetiology. Dogs affected with this disease develop generalized weakness associated with severe, generalized skeletal muscle atrophy and mild elevations in creatine kinase in the first few months of life. The severity of signs tends to progress over the first year of life but can vary from mild exercise intolerance to non-ambulatory tetraparesis. Beyond 1 year of age, the signs usually stabilize and although muscle mass does not increase, affected dogs' strength may improve slightly. The pathological changes present on muscle biopsy include marked variation in muscle fibre size with hypertrophied and round atrophied fibres present. There is an increased number of fibres with central nuclei and split fibres can be seen. It has been suggested that the disorder is a model for limb-girdle muscular dystrophy. In recent years, mutations in genes encoding the proteolytic enzyme, calpain 3, a novel protein named dysferlin, and components of the dystrophin-glycoprotein complex have been identified as causes of autosomal recessive limb-girdle muscular dystrophy. We have evaluated these proteins in normal dogs and in three Labrador retrievers with autosomal recessive muscular dystrophy using immunohistochemistry and Western blot analysis on frozen skeletal muscle. The results demonstrate that dystrophin, the sarcoglycans, alpha-actinin, dysferlin and calpain 3 are present in the normal and affected dogs. We conclude that this autosomal recessive muscular dystrophy is not due to a deficiency of alpha-actinin, or any of the known autosomal recessive limb-girdle muscular dystrophy proteins, although we cannot rule out a malfunction of any of these proteins.
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ABSTRACT: A 5-month-old, male, Labrador retriever was evaluated for progressive weakness and muscle atrophy. Histologic evaluation of fresh frozen muscle revealed distinct cytoarchitectural changes and central mitochondrial accumulations indistinguishable from those found in the inherited myopathy described in Great Danes. Multiple male littermates and half-siblings were similarly affected.The Canadian veterinary journal. La revue veterinaire canadienne 05/2008; 49(4):393-7. · 1.06 Impact Factor
Article: Centronuclear Myopathy in Labrador Retrievers: A Recent Founder Mutation in the PTPLA Gene Has Rapidly Disseminated Worldwide.[show abstract] [hide abstract]
ABSTRACT: Centronuclear myopathies (CNM) are inherited congenital disorders characterized by an excessive number of internalized nuclei. In humans, CNM results from ∼70 mutations in three major genes from the myotubularin, dynamin and amphiphysin families. Analysis of animal models with altered expression of these genes revealed common defects in all forms of CNM, paving the way for unified pathogenic and therapeutic mechanisms. Despite these efforts, some CNM cases remain genetically unresolved. We previously identified an autosomal recessive form of CNM in French Labrador retrievers from an experimental pedigree, and showed that a loss-of-function mutation in the protein tyrosine phosphatase-like A (PTPLA) gene segregated with CNM. Around the world, client-owned Labrador retrievers with a similar clinical presentation and histopathological changes in muscle biopsies have been described. We hypothesized that these Labradors share the same PTPLA(cnm) mutation. Genotyping of an international panel of 7,426 Labradors led to the identification of PTPLA(cnm) carriers in 13 countries. Haplotype analysis demonstrated that the PTPLA(cnm) allele resulted from a single and recent mutational event that may have rapidly disseminated through the extensive use of popular sires. PTPLA-deficient Labradors will help define the integrated role of PTPLA in the existing CNM gene network. They will be valuable complementary large animal models to test innovative therapies in CNM.PLoS ONE 01/2012; 7(10):e46408. · 4.09 Impact Factor
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ABSTRACT: Animal models are of immense importance for studying mechanisms of disease and testing new therapies, and rodents have been used extensively in the field of neuromuscular disorders. Mice and rats can be genetically manipulated to over-express or not express genes that are important to muscle function, and these animals can be available in large numbers for analysis. Other species, such as cats and dogs, cannot be manipulated in the same ways or be used in large numbers, but they have spontaneously occurring muscle diseases with clinical presentations more closely resembling those of the human disorders. Therefore, cats and dogs may become valuable as intermediate disease models. This review focuses on canine and feline models of human inherited muscle diseases with comparisons to rodent models and an emphasis on the muscular dystrophies.Neuromuscular Disorders 03/2005; 15(2):127-38. · 2.80 Impact Factor