title: X-linked myotubular myopathy in Rottweiler dogs is caused by a missense mutation in Exon 11 of the MTM1 gene.
abstract: BACKGROUND
  Congenital 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.
  
  
  RESULTS
  Histopathology, 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.
  
  
  CONCLUSIONS
  Here 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.
authors: Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA USA.
authors: G Diane
authors: GD
authors: Shelton
authors: Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave., Boston, MA 02115 USA.
authors: Branden E
authors: BE
authors: Rider
authors: Small Animal Specialist Hospital, North Ryde, NSW Australia.
authors: Georgina
authors: G
authors: Child
authors: Small Animal Specialist Hospital, North Ryde, NSW Australia.
authors: Sophia
authors: S
authors: Tzannes
authors: Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA USA.
authors: Ling T
authors: LT
authors: Guo
authors: Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave., Boston, MA 02115 USA.
authors: Behzad
authors: B
authors: Moghadaszadeh
authors: Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave., Boston, MA 02115 USA.
authors: Emily C
authors: EC
authors: Troiano
authors: Faculty of Veterinary Science, The University of Sydney, Sydney, NSW 2006 Australia.
authors: Bianca
authors: B
authors: Haase
authors: Faculty of Veterinary Science, The University of Sydney, Sydney, NSW 2006 Australia.
authors: Claire M
authors: CM
authors: Wade
authors: Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave., Boston, MA 02115 USA.
authors: Alan H
authors: AH
authors: Beggs
keywords: Animal model; Canine myopathy; Congenital myopathy; Myotubularin