Abstract
BackgroundCongenital and inherited myopathies in dogs are faithful models of human muscle diseases and are being recognized with increasing frequency. In fact, canine models of dystrophin deficient muscular dystrophy and X-linked myotubular myopathy are of tremendous value in the translation of new and promising therapies for the treatment of these diseases. We have recently identified a family of Australian Rottweilers in which male puppies were clinically affected with severe muscle weakness and atrophy that resulted in early euthanasia or death. X-linked myotubular myopathy was suspected based on the early and severe clinical presentation and histopathological changes within muscle biopsies. The aim of this study was to determine the genetic basis for myopathy in these dogs and compare and contrast the clinical presentation, histopathology, ultrastructure, and mutation in this family of Rottweiler dogs with the previously described myotubular myopathy in Labrador retrievers.ResultsHistopathology, histochemistry, and ultrastructural examination of muscle biopsies from affected Rottweiler puppies were consistent with an X-linked myotubular myopathy. An unusual finding that differed from the previously reported Labradors and similar human cases was the presence of excessive autophagy and prominent autophagic vacuoles. Molecular investigations confirmed a missense mutation in exon 11 of MTM1 that was predicted to result in a non-functional phosphatase activity. Although the clinical presentations and histopathology were similar, the MTM1 p.(Q384P) mutation is different from the p.(N155K) mutation in exon 7 affecting Labrador retrievers with X-linked myotubular myopathy.ConclusionsHere we describe a second pathogenic mutation in MTM1 causing X-linked myotubular myopathy in dogs. Our findings suggest a variety of MTM1 mutations in dogs as seen in human patients. The number of MTM1 mutations resulting in similar severe and progressive clinical myopathy and histopathological changes are likely to increase as canine myopathies are further characterized.
Highlights
Congenital and inherited myopathies in dogs are faithful models of human muscle diseases and are being recognized with increasing frequency
The centronuclear myopathies (CNMs) are a group of pathologically defined disorders that characteristically have a high proportion of small myofibers with centrally placed nuclei [1,2,3]
Severe and progressive myopathy in related litters of Rottweiler puppies A 13-week-old male Rottweiler (III-2 from Figure 1) from a litter of 10 puppies (6 females and 4 males) was referred for progressive weakness. Two pups from this first litter were previously lost; the first was a female that died within a few weeks of birth, and the second a male pup (III-1) euthanized by the attending veterinarian at 9 weeks of age for an initial alteration in facial expression and exercise intolerance progressing to an inability to bear weight
Summary
Congenital and inherited myopathies in dogs are faithful models of human muscle diseases and are being recognized with increasing frequency. We have recently identified a family of Australian Rottweilers in which male puppies were clinically affected with severe muscle weakness and atrophy that resulted in early euthanasia or death. X-linked myotubular myopathy was suspected based on the early and severe clinical presentation and histopathological changes within muscle biopsies. The aim of this study was to determine the genetic basis for myopathy in these dogs and compare and contrast the clinical presentation, histopathology, ultrastructure, and mutation in this family of Rottweiler dogs with the previously described myotubular myopathy in Labrador retrievers. Abnormal membrane tubulation in myotubularin-deficient muscle leads to altered T-tubule and triad morphology and defective excitation contraction coupling, which is thought to play a major role in the initial pathophysiological events leading to weakness [10,11]. The condition is not dystrophic as myofibers remain largely intact and serum creatine kinase (CK) activities are within the reference range or only mildly elevated
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