title: Variants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization.
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.
authors.affiliation: 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.
authors.forename: Gina L
authors.initials: GL
authors.lastname: O'Grady
authors.affiliation: 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.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Best
authors.affiliation: School of Biological Sciences, Monash University, Melbourne, VIC 3800, Australia.
authors.forename: Tamar E
authors.initials: TE
authors.lastname: Sztal
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67400 Illkirch, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Schartner
authors.affiliation: Department of Molecular and Cellular Genetics, UMR7156, Université de Strasbourg, CNRS, Strasbourg 67081, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Sanjuan-Vazquez
authors.affiliation: National Institute of Neurological Disorders and Stroke Neurogenetics Branch, Neuromuscular and Neurogenetic Disorders of Childhood Section, NIH, Bethesda, MD 20892-1477, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Donkervoort
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67400 Illkirch, France.
authors.forename: Osorio
authors.initials: O
authors.lastname: Abath Neto
authors.affiliation: Department of Cell Physiology and Molecular Biophysics, and Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
authors.forename: Roger Bryan
authors.initials: RB
authors.lastname: Sutton
authors.affiliation: Institute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, NSW 2145, Australia.
authors.forename: Biljana
authors.initials: B
authors.lastname: Ilkovski
authors.affiliation: 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.
authors.forename: Norma Beatriz
authors.initials: NB
authors.lastname: Romero
authors.affiliation: Centre de Référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU La Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 7503 Paris, France.
authors.forename: Tanya
authors.initials: T
authors.lastname: Stojkovic
authors.affiliation: National Institute of Neurological Disorders and Stroke Neurogenetics Branch, Neuromuscular and Neurogenetic Disorders of Childhood Section, NIH, Bethesda, MD 20892-1477, USA.
authors.forename: Jahannaz
authors.initials: J
authors.lastname: Dastgir
authors.affiliation: Institute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, NSW 2145, Australia.
authors.forename: Leigh B
authors.initials: LB
authors.lastname: Waddell
authors.affiliation: Centre National de Génotypage, Institut de Génomique, CEA, CP5721, 91057 Evry, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Boland
authors.affiliation: National Institute of Neurological Disorders and Stroke Neurogenetics Branch, Neuromuscular and Neurogenetic Disorders of Childhood Section, NIH, Bethesda, MD 20892-1477, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: School of Biological Sciences, Monash University, Melbourne, VIC 3800, Australia.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Williams
authors.affiliation: School of Biological Sciences, Monash University, Melbourne, VIC 3800, Australia.
authors.forename: Avnika A
authors.initials: AA
authors.lastname: Ruparelia
authors.affiliation: Centre de Référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU La Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 7503 Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Maisonobe
authors.affiliation: Department of Radiology, Westmead Hospital, Western Clinical School, University of Sydney, Sydney, NSW 1024, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Peduto
authors.affiliation: Department of Neurology, Concord Clinical School, University of Sydney, Sydney, NSW 2139, Australia.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Reddel
authors.affiliation: 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.
authors.forename: Monkol
authors.initials: M
authors.lastname: Lek
authors.affiliation: 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.
authors.forename: Taru
authors.initials: T
authors.lastname: Tukiainen
authors.affiliation: 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.
authors.forename: Beryl B
authors.initials: BB
authors.lastname: Cummings
authors.affiliation: Institute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, NSW 2145, Australia.
authors.forename: Himanshu
authors.initials: H
authors.lastname: Joshi
authors.affiliation: Service de Biochimie et Génétique Moléculaire, HUPC Hôpital Cochin, Paris 75014, France; INSERM, U1016, Institut Cochin, CNRS UMR8104, Université Paris Descartes, Paris 75014, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Nectoux
authors.affiliation: Electron Microscope Unit, Concord Repatriation General Hospital, Concord, NSW 2139, Australia.
authors.forename: Susan
authors.initials: S
authors.lastname: Brammah
authors.affiliation: Centre National de Génotypage, Institut de Génomique, CEA, CP5721, 91057 Evry, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Deleuze
authors.affiliation: The Clive and Vera Ramaciotti Centre for Structural Cryo-Electron Microscopy, Monash University, Melbourne, VIC 3800, Australia.
authors.forename: Viola Oorschot
authors.initials: VO
authors.lastname: Ing
authors.affiliation: 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.
authors.forename: Georg
authors.initials: G
authors.lastname: Ramm
authors.affiliation: Department of Pediatric Neurology, Hacettepe University Children's Hospital, 06100 Ankara, Turkey.
authors.forename: Didem
authors.initials: D
authors.lastname: Ardicli
authors.affiliation: Centre for Medical Research, The University of Western Australia & the Harry Perkins Institute of Medical Research, Perth, WA 6009, Australia.
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Nowak
authors.affiliation: Department of Pediatric Neurology, Hacettepe University Children's Hospital, 06100 Ankara, Turkey.
authors.forename: Beril
authors.initials: B
authors.lastname: Talim
authors.affiliation: Department of Pediatric Neurology, Hacettepe University Children's Hospital, 06100 Ankara, Turkey.
authors.forename: Haluk
authors.initials: H
authors.lastname: Topaloglu
authors.affiliation: Centre for Medical Research, The University of Western Australia & the Harry Perkins Institute of Medical Research, Perth, WA 6009, Australia.
authors.forename: Nigel G
authors.initials: NG
authors.lastname: Laing
authors.affiliation: 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.
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: North
authors.affiliation: 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.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: MacArthur
authors.affiliation: Department of Molecular and Cellular Genetics, UMR7156, Université de Strasbourg, CNRS, Strasbourg 67081, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Friant
authors.affiliation: 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.
authors.forename: Nigel F
authors.initials: NF
authors.lastname: Clarke
authors.affiliation: School of Biological Sciences, Monash University, Melbourne, VIC 3800, Australia.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bryson-Richardson
authors.affiliation: National Institute of Neurological Disorders and Stroke Neurogenetics Branch, Neuromuscular and Neurogenetic Disorders of Childhood Section, NIH, Bethesda, MD 20892-1477, USA.
authors.forename: Carsten G
authors.initials: CG
authors.lastname: Bönnemann
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67400 Illkirch, France; Université de Strasbourg, 67081 Illkirch, France.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Laporte
authors.affiliation: 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.
authors.forename: Sandra T
authors.initials: ST
authors.lastname: Cooper
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000235:genetics* / Q000378:metabolism; D002522:Chlorocebus aethiops; D015331:Cohort Studies; D003402:Creatine Kinase / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D049310:Distal Myopathies / Q000235:genetics* / Q000473:pathology; D000067779:ELAV-Like Protein 4 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005420:Flavoproteins / Q000378:metabolism; D017353:Gene Deletion; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005980:Glutathione Reductase / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal / Q000473:pathology; D020125:Mutation, Missense; D020914:Myopathies, Structural, Congenital / Q000235:genetics* / Q000473:pathology; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D011487:Protein Conformation; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics
chemical_list: D000067779:ELAV-Like Protein 4; C498010:ELAVL4 protein, human; D005420:Flavoproteins; C508746:GLR1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D010088:Oxidoreductases; D005980:Glutathione Reductase; D003402:Creatine Kinase