* Interest of the canine models in hereditary myopathies 

* Characterization of hereditary  myopathies

* Research of therapeutic processes

* Development of tools of functional evaluations


CHaracterization of hereditary myopathies


To date, the UETM contributed to identify and characterize four hereditary animal myopathies, three canine myopathies and one feline myopathy.

The GRMD dog (Golden Retriever Muscular Dystrophy)

Animal model of the Duchenne muscular dystrophy, the GRMD dog was discovered in the United States in 1988. We have been hosting it in the UETM animal house since 1996. It carries a specific mutation in the intron 6 of the gene encoding the dystrophin. It displays early histological lesions (necroses, regeneration, fibrosis and adipose) and a progressive clinical evolution depending on individuals. 


Hemato-eosin staining (A) and immunolabelling anti-Dystrophin (B and C) on transverse sections of muscle biopsies removed from a healthy dog (B) or from GRMD dogs (A and C) showing necroses and muscular regeneration (A) and absence of dystrophin (C) in the GRMD dogs.

The LRMD dog (Labrador Retriever Muscular Dystrophy)

The LRMD dog, like the GRMD dog, is affected by a dystrophinopathy homologous to the Duchenne myopathy. The mutation responsible of the phenotype is an insertion in the intron 20 of the dystrophin gene. From the clinical point of view, the LRMD dogs are severely affected and, contrary to the GRMD dogs, few phenotype variations are observed from one individual to another.

The confrontation of both canine models, GRMD and LRMD, constitutes a methodological way to understand the phenotypic variations also observed in Duchenne patients.

The HFMD cat (Hypertrophic Feline Muscular Dystrophy)

Currently, the HFMD cat is the only feline model of dystrophic myopathy. The UETM animal house hosts the only existing colony (source: Dr. F. Gaschen, Switzerland). This model is in characterization, and this work is carried in collaboration with Valerie Chetboul’s team (Unit of Cardiology, UMR 841 -ENVA).

The CNM dog (Canine Centronuclear Myopathy)

The canine centronuclear myopathy affecting the Labradors Retrievers and identified in France in the nineties, represents the only spontaneous model of human autosomic centronuclear myopathy. The genetic anomaly responsible for the disease was characterized in collaboration with Laurent Tiret’s team (Unit for Molecular and Cell Genetics, UMR 955 - ENVA). It affects a gene encoding a protein called PTPLA (Protein Tyrosine Phosphatase-Like A). The function of this protein is still unknown; however, it presents strong functional similarities with the myotubularine (a deficient molecular substrate in human heterosomic centronuclear myopathy). The current objectives are to identify the PTPLA function and to understand how the gene mutation leads to the observed phenotypes.

 


Hemato-eosin staining on transverse sections of muscle biopsies removed from 5 months old dogs (left) and 7 years old dogs (right).

The mutation that we identified is currently responsible for the majority of cases in USA, UK and Switzerland, indicating a genetic homogeneity despite various phenotypes. Thereby, in order to purify the Labrador retriever breeding, the Unit for Molecular and Cell Genetics has created a website (http://www.labradorcnm.com) which aim is to collect and analyze a large number of biological samples.