title: Muscle pathology, limb strength, walking gait, respiratory function and neurological impairment establish disease progression in the p.N155K canine model of X-linked myotubular myopathy.
abstract: BACKGROUND
  Loss-of-function mutations in the myotubularin (MTM1) gene cause X-linked myotubular myopathy (XLMTM), a fatal, inherited pediatric disease that affects the entire skeletal musculature. Labrador retriever dogs carrying an MTM1 missense mutation exhibit strongly reduced synthesis of myotubularin, the founder member of a lipid phosphatase required for normal skeletal muscle function. The resulting canine phenotype resembles that of human patients with comparably severe mutations, and survival does not normally exceed 4 months.
  
  
  METHODS
  We studied MTM1 mutant dogs (n=7) and their age-matched control littermates (n=6) between the ages of 10 and 25 weeks. Investigators blinded to the animal identities sequentially measured limb muscle pathology, fore- and hind limb strength, walking gait, respiratory function and neurological impairment.
  
  
  RESULTS
  MTM1-mutant puppies display centrally-nucleated myofibers of reduced size and disrupted sarcotubular architecture progressing until the end of life, an average of 17 weeks. In-life measures of fore- and hind limb strength establish the rate at which XLMTM muscles weaken, and their corresponding decrease in gait velocity and stride length. Pulmonary function tests in affected dogs reveal a right-shifted relationship between peak inspiratory flow (PIF) and inspiratory time (TI); neurological assessments indicate that affected puppies as young as 10 weeks show early signs of neurological impairment (neurological severity score, NSS =8.6±0.9) with progressive decline (NSS =5.6±1.7 at 17 weeks-of-age).
  
  
  CONCLUSIONS
  Our findings document the rate of disease progression in a large animal model of XLMTM and lay a foundation for preclinical studies.
authors.affiliation: 1 Institute for Stem Cell and Regenerative Medicine, 2 Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA ; 3 Department of Comparative Medicine, University of Washington, Seattle, Washington, USA ; 4 Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic and State University, Blacksburg, Virginia, USA ; 5 Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA ; 6 Department of Physical Therapy, University of Florida, Gainesville, FL, USA ; 7 The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Goddard
authors.affiliation: 1 Institute for Stem Cell and Regenerative Medicine, 2 Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA ; 3 Department of Comparative Medicine, University of Washington, Seattle, Washington, USA ; 4 Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic and State University, Blacksburg, Virginia, USA ; 5 Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA ; 6 Department of Physical Therapy, University of Florida, Gainesville, FL, USA ; 7 The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Mack
authors.affiliation: 1 Institute for Stem Cell and Regenerative Medicine, 2 Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA ; 3 Department of Comparative Medicine, University of Washington, Seattle, Washington, USA ; 4 Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic and State University, Blacksburg, Virginia, USA ; 5 Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA ; 6 Department of Physical Therapy, University of Florida, Gainesville, FL, USA ; 7 The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Czerniecki
authors.affiliation: 1 Institute for Stem Cell and Regenerative Medicine, 2 Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA ; 3 Department of Comparative Medicine, University of Washington, Seattle, Washington, USA ; 4 Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic and State University, Blacksburg, Virginia, USA ; 5 Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA ; 6 Department of Physical Therapy, University of Florida, Gainesville, FL, USA ; 7 The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Valerie E
authors.initials: VE
authors.lastname: Kelly
authors.affiliation: 1 Institute for Stem Cell and Regenerative Medicine, 2 Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA ; 3 Department of Comparative Medicine, University of Washington, Seattle, Washington, USA ; 4 Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic and State University, Blacksburg, Virginia, USA ; 5 Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA ; 6 Department of Physical Therapy, University of Florida, Gainesville, FL, USA ; 7 The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Snyder
authors.affiliation: 1 Institute for Stem Cell and Regenerative Medicine, 2 Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA ; 3 Department of Comparative Medicine, University of Washington, Seattle, Washington, USA ; 4 Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic and State University, Blacksburg, Virginia, USA ; 5 Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA ; 6 Department of Physical Therapy, University of Florida, Gainesville, FL, USA ; 7 The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Grange
authors.affiliation: 1 Institute for Stem Cell and Regenerative Medicine, 2 Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA ; 3 Department of Comparative Medicine, University of Washington, Seattle, Washington, USA ; 4 Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic and State University, Blacksburg, Virginia, USA ; 5 Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA ; 6 Department of Physical Therapy, University of Florida, Gainesville, FL, USA ; 7 The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lawlor
authors.affiliation: 1 Institute for Stem Cell and Regenerative Medicine, 2 Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA ; 3 Department of Comparative Medicine, University of Washington, Seattle, Washington, USA ; 4 Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic and State University, Blacksburg, Virginia, USA ; 5 Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA ; 6 Department of Physical Therapy, University of Florida, Gainesville, FL, USA ; 7 The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Smith
authors.affiliation: 1 Institute for Stem Cell and Regenerative Medicine, 2 Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA ; 3 Department of Comparative Medicine, University of Washington, Seattle, Washington, USA ; 4 Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic and State University, Blacksburg, Virginia, USA ; 5 Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA ; 6 Department of Physical Therapy, University of Florida, Gainesville, FL, USA ; 7 The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Beggs
authors.affiliation: 1 Institute for Stem Cell and Regenerative Medicine, 2 Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA ; 3 Department of Comparative Medicine, University of Washington, Seattle, Washington, USA ; 4 Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic and State University, Blacksburg, Virginia, USA ; 5 Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA ; 6 Department of Physical Therapy, University of Florida, Gainesville, FL, USA ; 7 The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Martin K
authors.initials: MK
authors.lastname: Childers
keywords: Animal models; dog; muscle disease; muscular dystrophy; myopathy; myotubular myopathy