X-linked myotubular myopathy in Rottweiler dogs is caused by a missense mutation in Exon 11 of the MTM1 gene

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.

Pten is necessary for the quiescence and maintenance of adult muscle stem cells

“…Sporadic fusion of SCs into myofibers occurs in resting skeletal muscles, with or without cell cycle entry5354. Consistently, we observed both EdU + MyoG + and EdU − MyoG + cells in resting muscles of WT mice.…”

A Homozygous RAB3GAP1:c.743delC Mutation in Rottweilers with Neuronal Vacuolation and Spinocerebellar Degeneration

“…A variety of progressive neurologic diseases occur in young Rottweilers and are presumed to be hereditary (Table ) . The clinical histories of the RAB3GAP1:c.743delC homozygotes in the current study most closely resemble those previously reported for dogs with NVSD.…”

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In vivo gene editing in dystrophic mouse muscle and muscle stem cells

“…Yet, limitations remain for the use of AONs, including variable efficiencies of tissue uptake, depending on AON chemistry, a requirement for repeated AON injection to maintain effective skipping, and the potential for AON-associated toxicities ((9, 10) and Supplementary Text). …”