title: Progressive Structural Defects in Canine Centronuclear Myopathy Indicate a Role for HACD1 in Maintaining Skeletal Muscle Membrane Systems.
abstract: Mutations in HACD1/PTPLA cause recessive congenital myopathies in humans and dogs. Hydroxyacyl-coA dehydratases are required for elongation of very long chain fatty acids, and HACD1 has a role in early myogenesis, but the functions of this striated muscle-specific enzyme in more differentiated skeletal muscle remain unknown. Canine HACD1 deficiency is histopathologically classified as a centronuclear myopathy (CNM). We investigated the hypothesis that muscle from HACD1-deficient dogs has membrane abnormalities in common with CNMs with different genetic causes. We found progressive changes in tubuloreticular and sarcolemmal membranes and mislocalized triads and mitochondria in skeletal muscle from animals deficient in HACD1. Furthermore, comparable membranous abnormalities in cultured HACD1-deficient myotubes provide additional evidence that these defects are a primary consequence of altered HACD1 expression. Our novel findings, including T-tubule dilatation and disorganization, associated with defects in this additional CNM-associated gene provide a definitive pathophysiologic link with these disorders, confirm that dogs deficient in HACD1 are relevant models, and strengthen the evidence for a unifying pathogenesis in CNMs via defective membrane trafficking and excitation-contraction coupling in muscle. These results build on previous work by determining further functional roles of HACD1 in muscle and provide new insight into the pathology and pathogenetic mechanisms of HACD1 CNM. Consequently, alterations in membrane properties associated with HACD1 mutations should be investigated in humans with related phenotypes.
authors.affiliation: Comparative Neuromuscular Diseases Laboratory, Department of Clinical Sciences and Services, Royal Veterinary College, London, United Kingdom. Electronic address: glw22@liv.ac.uk.
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Walmsley
authors.affiliation: French National Institute of Health and Medical Research (Inserm), Mondor Institute of Biomedical Research (IMRB) U955-E10 Biology of the Neuromuscular System, Créteil, France; University of Paris East, Alfort School of Veterinary Medicine (EnvA), Maisons-Alfort, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blot
authors.affiliation: Electron Microscopy Unit, Institute of Neurology, London, United Kingdom.
authors.forename: Kerrie
authors.initials: K
authors.lastname: Venner
authors.affiliation: Dubowitz Neuromuscular Centre, University College London Institute of Child Health and Great Ormond Street Hospital, London, United Kingdom.
authors.forename: Caroline
authors.initials: C
authors.lastname: Sewry
authors.affiliation: Department of Translational Medicine and Neurogenetics, Institute of Genetics and Cellular and Molecular Biology (IGBMC), Inserm U964, CNRS UMR7104, Strasbourg University, Illkirch, France.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Laporte
authors.affiliation: French National Institute of Health and Medical Research (Inserm), Mondor Institute of Biomedical Research (IMRB) U955-E10 Biology of the Neuromuscular System, Créteil, France; University of Paris East, Alfort School of Veterinary Medicine (EnvA), Maisons-Alfort, France.
authors.forename: Jordan
authors.initials: J
authors.lastname: Blondelle
authors.affiliation: French National Institute of Health and Medical Research (Inserm), Mondor Institute of Biomedical Research (IMRB) U955-E10 Biology of the Neuromuscular System, Créteil, France; University of Paris East, Alfort School of Veterinary Medicine (EnvA), Maisons-Alfort, France.
authors.forename: Inès
authors.initials: I
authors.lastname: Barthélémy
authors.affiliation: French National Institute of Health and Medical Research (Inserm), Mondor Institute of Biomedical Research (IMRB) U955-E10 Biology of the Neuromuscular System, Créteil, France; University of Paris East, Alfort School of Veterinary Medicine (EnvA), Maisons-Alfort, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Maurer
authors.affiliation: French National Institute of Health and Medical Research (Inserm), Mondor Institute of Biomedical Research (IMRB) U955-E10 Biology of the Neuromuscular System, Créteil, France; University of Paris East, Alfort School of Veterinary Medicine (EnvA), Maisons-Alfort, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Blanchard-Gutton
authors.affiliation: French National Institute of Health and Medical Research (Inserm), Mondor Institute of Biomedical Research (IMRB) U955-E10 Biology of the Neuromuscular System, Créteil, France; University of Paris East, Alfort School of Veterinary Medicine (EnvA), Maisons-Alfort, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Pilot-Storck
authors.affiliation: French National Institute of Health and Medical Research (Inserm), Mondor Institute of Biomedical Research (IMRB) U955-E10 Biology of the Neuromuscular System, Créteil, France; University of Paris East, Alfort School of Veterinary Medicine (EnvA), Maisons-Alfort, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Tiret
authors.affiliation: Comparative Neuromuscular Diseases Laboratory, Department of Clinical Sciences and Services, Royal Veterinary College, London, United Kingdom.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Piercy
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000473:pathology; D004195:Disease Models, Animal; D004285:Dogs; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D018482:Muscle, Skeletal / Q000473:pathology*; D020914:Myopathies, Structural, Congenital / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*
chemical_list: D017027:Protein Tyrosine Phosphatases