2. Academic Validation
  3. Variants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization

Variants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization

  • Am J Hum Genet. 2016 Nov 3;99(5):1086-1105. doi: 10.1016/j.ajhg.2016.09.005.
Gina L O'Grady 1,  Heather A Best 2,  Tamar E Sztal 3,  Vanessa Schartner 4,  Myriam Sanjuan-Vazquez 5,  Sandra Donkervoort 6,  Osorio Abath Neto 4,  Roger Bryan Sutton 7,  Biljana Ilkovski 8,  Norma Beatriz Romero 9,  Tanya Stojkovic 10,  Jahannaz Dastgir 6,  Leigh B Waddell 8,  Anne Boland 11,  Ying Hu 6,  Caitlin Williams 3,  Avnika A Ruparelia 3,  Thierry Maisonobe 10,  Anthony J Peduto 12,  Stephen W Reddel 13,  Monkol Lek 14,  Taru Tukiainen 14,  Beryl B Cummings 14,  Himanshu Joshi 8,  Juliette Nectoux 15,  Susan Brammah 16,  Jean-François Deleuze 11,  Viola Oorschot Ing 17,  Georg Ramm 18,  Didem Ardicli 19,  Kristen J Nowak 20,  Beril Talim 19,  Haluk Topaloglu 19,  Nigel G Laing 20,  Kathryn N North 21,  Daniel G MacArthur 14,  Sylvie Friant 5,  Nigel F Clarke 2,  Robert J Bryson-Richardson 3,  Carsten G Bönnemann 6,  Jocelyn Laporte 22,  Sandra T Cooper 23
Affiliations

Affiliations

  • 1 Institute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, NSW 2145, Australia; Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, NSW 2006, Australia; Paediatric Neurology Service, Starship Children's Health, Auckland 1023, New Zealand.
  • 2 Institute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, NSW 2145, Australia; Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, NSW 2006, Australia.
  • 3 School of Biological Sciences, Monash University, Melbourne, VIC 3800, Australia.
  • 4 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67400 Illkirch, France.
  • 5 Department of Molecular and Cellular Genetics, UMR7156, Université de Strasbourg, CNRS, Strasbourg 67081, France.
  • 6 National Institute of Neurological Disorders and Stroke Neurogenetics Branch, Neuromuscular and Neurogenetic Disorders of Childhood Section, NIH, Bethesda, MD 20892-1477, USA.
  • 7 Department of Cell Physiology and Molecular Biophysics, and Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
  • 8 Institute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, NSW 2145, Australia.
  • 9 Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, GH Pitié-Salpêtrière, 47 Boulevard de l'hôpital, 75013 Paris, France; Centre de Référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU La Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 7503 Paris, France.
  • 10 Centre de Référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU La Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 7503 Paris, France.
  • 11 Centre National de Génotypage, Institut de Génomique, CEA, CP5721, 91057 Evry, France.
  • 12 Department of Radiology, Westmead Hospital, Western Clinical School, University of Sydney, Sydney, NSW 1024, Australia.
  • 13 Department of Neurology, Concord Clinical School, University of Sydney, Sydney, NSW 2139, Australia.
  • 14 Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • 15 Service de Biochimie et Génétique Moléculaire, HUPC Hôpital Cochin, Paris 75014, France; INSERM, U1016, Institut Cochin, CNRS UMR8104, Université Paris Descartes, Paris 75014, France.
  • 16 Electron Microscope Unit, Concord Repatriation General Hospital, Concord, NSW 2139, Australia.
  • 17 The Clive and Vera Ramaciotti Centre for Structural Cryo-Electron Microscopy, Monash University, Melbourne, VIC 3800, Australia.
  • 18 The Clive and Vera Ramaciotti Centre for Structural Cryo-Electron Microscopy, Monash University, Melbourne, VIC 3800, Australia; Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC 3800, Australia.
  • 19 Department of Pediatric Neurology, Hacettepe University Children's Hospital, 06100 Ankara, Turkey.
  • 20 Centre for Medical Research, The University of Western Australia & the Harry Perkins Institute of Medical Research, Perth, WA 6009, Australia.
  • 21 Institute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, NSW 2145, Australia; Murdoch Children's Research Institute, The Royal Children's Hospital, Flemington Road, Parkville, VIC 3052, Australia.
  • 22 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67400 Illkirch, France; Université de Strasbourg, 67081 Illkirch, France.
  • 23 Institute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, NSW 2145, Australia; Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, NSW 2006, Australia. Electronic address: sandra.cooper@sydney.edu.au.
PMID: 27745833 DOI: 10.1016/j.ajhg.2016.09.005
Abstract

This study establishes PYROXD1 variants as a cause of early-onset myopathy and uses biospecimens and cell lines, yeast, and zebrafish models to elucidate the fundamental role of PYROXD1 in skeletal muscle. Exome Sequencing identified recessive variants in PYROXD1 in nine probands from five families. Affected individuals presented in infancy or childhood with slowly progressive proximal and distal weakness, facial weakness, nasal speech, swallowing difficulties, and normal to moderately elevated creatine kinase. Distinctive histopathology showed abundant internalized nuclei, myofibrillar disorganization, desmin-positive inclusions, and thickened Z-bands. PYROXD1 is a nuclear-cytoplasmic pyridine nucleotide-disulphide reductase (PNDR). PNDRs are flavoproteins (FAD-binding) and catalyze pyridine-nucleotide-dependent (NAD/NADH) reduction of thiol residues in other proteins. Complementation experiments in yeast lacking Glutathione Reductase glr1 show that human PYROXD1 has reductase activity that is strongly impaired by the disease-associated missense mutations. Immunolocalization studies in human muscle and zebrafish myofibers demonstrate that PYROXD1 localizes to the nucleus and to striated sarcomeric compartments. Zebrafish with ryroxD1 knock-down recapitulate features of PYROXD1 myopathy with sarcomeric disorganization, myofibrillar aggregates, and marked swimming defect. We characterize variants in the oxidoreductase PYROXD1 as a cause of early-onset myopathy with distinctive histopathology and introduce altered redox regulation as a primary cause of congenital muscle disease.

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