ArticleAmerican journal of human genetics2016
Variants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization.
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Article in American journal of human genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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34 citing papers in PubMed, 105 citations in OpenAlex.
- Structural framework for the assembly of the human tRNA ligase complex.Nature communications · 2026Article
- Enzymology of the metazoan tRNA ligase complex: a lifetime in cycles.Cellular and molecular life sciences : CMLS · 2026Review
- Pyroxd1 is essential for murine viability with the homozygous N155S recurrent variant linked to myopathy, muscle hypotrophy and osteopenia.Acta neuropathologica communications · 2026Article
- Myofibrillar myopathy type 8 mimicking a Limb-Girdle Muscle Dystrophy: the first Tunisian case report.Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology · 2026Article
- Mechanistic basis for PYROXD1-mediated protection of the human tRNA ligase complex against oxidative inactivation.Nature structural & molecular biology · 2025Article
- A rare case of myopathy with fatigability due toJournal of neuromuscular diseases · 2025Article
- Mutational and clinical spectrum of myofibrillar myopathy in one center from China.Journal of neuromuscular diseases · 2024Article
- Congenital myopathies: pathophysiological mechanisms and promising therapies.Journal of translational medicine · 2024Review
- Exome sequencing in undiagnosed congenital myopathy reveals new genes and refines genes-phenotypes correlations.Genome medicine · 2024Article
- Genetic legacy and adaptive signatures: investigating the history, diversity, and selection signatures in Rendena cattle resilient to eighteenth century rinderpest epidemics.Genetics, selection, evolution : GSE · 2024Article
- Genome and RNA sequencing boost neuromuscular diagnoses to 62% from 34% with exome sequencing alone.Annals of clinical and translational neurology · 2024Article
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- Prdm16 mutation determines sex-specific cardiac metabolism and identifies two novel cardiac metabolic regulators.Cardiovascular research · 2024Article
- A 53-year-old man with a 16-year history of asymmetrical proximal muscle weakness, facial muscle weakness, and scapular winging.Brain pathology (Zurich, Switzerland) · 2023Article
- Connective tissue presentation in two families expands the phenotypic spectrum of PYROXD1 disorders.Human molecular genetics · 2023Article
- Protein Aggregates and Aggrephagy in Myopathies.International journal of molecular sciences · 2023Review
- Bi-AllelicInternational journal of molecular sciences · 2022Article
- Rare clinical phenotype of filaminopathy presenting as restrictive cardiomyopathy and myopathy in childhood.Orphanet journal of rare diseases · 2022Article
- Effects of stressful life-events on DNA methylation in panic disorder and major depressive disorder.Clinical epigenetics · 2022Article
- Yeast as a Tool to Understand the Significance of Human Disease-Associated Gene Variants.Genes · 2021Review
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Authors and funding
42 authors at 14 institutions in 5 countries.
Gina L O'GradyInstitute 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.
Heather A BestInstitute 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.
Tamar E SztalSchool of Biological Sciences, Monash University, Melbourne, VIC 3800, Australia.
Vanessa SchartnerInstitut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67400 Illkirch, France.
Myriam Sanjuan-VazquezDepartment of Molecular and Cellular Genetics, UMR7156, Université de Strasbourg, CNRS, Strasbourg 67081, France.
Sandra DonkervoortNational Institute of Neurological Disorders and Stroke Neurogenetics Branch, Neuromuscular and Neurogenetic Disorders of Childhood Section, NIH, Bethesda, MD 20892-1477, USA.
Osorio Abath NetoInstitut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67400 Illkirch, France.
Roger Bryan SuttonDepartment of Cell Physiology and Molecular Biophysics, and Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
Biljana IlkovskiInstitute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, NSW 2145, Australia.
Norma Beatriz RomeroSorbonne 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.
Tanya StojkovicCentre de Référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU La Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 7503 Paris, France.
Jahannaz DastgirNational Institute of Neurological Disorders and Stroke Neurogenetics Branch, Neuromuscular and Neurogenetic Disorders of Childhood Section, NIH, Bethesda, MD 20892-1477, USA.
Leigh B WaddellInstitute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, NSW 2145, Australia.
Anne BolandCentre National de Génotypage, Institut de Génomique, CEA, CP5721, 91057 Evry, France.
Ying HuNational Institute of Neurological Disorders and Stroke Neurogenetics Branch, Neuromuscular and Neurogenetic Disorders of Childhood Section, NIH, Bethesda, MD 20892-1477, USA.
Caitlin WilliamsSchool of Biological Sciences, Monash University, Melbourne, VIC 3800, Australia.
Avnika A RupareliaSchool of Biological Sciences, Monash University, Melbourne, VIC 3800, Australia.
Thierry MaisonobeCentre de Référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU La Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 7503 Paris, France.
Anthony J PedutoDepartment of Radiology, Westmead Hospital, Western Clinical School, University of Sydney, Sydney, NSW 1024, Australia.
Stephen W ReddelDepartment of Neurology, Concord Clinical School, University of Sydney, Sydney, NSW 2139, Australia.
Monkol LekAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Taru TukiainenAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Beryl B CummingsAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Himanshu JoshiInstitute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, NSW 2145, Australia.
Juliette NectouxService de Biochimie et Génétique Moléculaire, HUPC Hôpital Cochin, Paris 75014, France; INSERM, U1016, Institut Cochin, CNRS UMR8104, Université Paris Descartes, Paris 75014, France.
Susan BrammahElectron Microscope Unit, Concord Repatriation General Hospital, Concord, NSW 2139, Australia.
Jean-François DeleuzeCentre National de Génotypage, Institut de Génomique, CEA, CP5721, 91057 Evry, France.
Viola Oorschot IngThe Clive and Vera Ramaciotti Centre for Structural Cryo-Electron Microscopy, Monash University, Melbourne, VIC 3800, Australia.
Georg RammThe 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.
Didem ArdicliDepartment of Pediatric Neurology, Hacettepe University Children's Hospital, 06100 Ankara, Turkey.
Kristen J NowakCentre for Medical Research, The University of Western Australia & the Harry Perkins Institute of Medical Research, Perth, WA 6009, Australia.
Beril TalimDepartment of Pediatric Neurology, Hacettepe University Children's Hospital, 06100 Ankara, Turkey.
Haluk TopalogluDepartment of Pediatric Neurology, Hacettepe University Children's Hospital, 06100 Ankara, Turkey.
Nigel G LaingCentre for Medical Research, The University of Western Australia & the Harry Perkins Institute of Medical Research, Perth, WA 6009, Australia.
Kathryn N NorthInstitute 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.
Daniel G MacArthurAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Sylvie FriantDepartment of Molecular and Cellular Genetics, UMR7156, Université de Strasbourg, CNRS, Strasbourg 67081, France.
Nigel F ClarkeInstitute 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.
Robert J Bryson-RichardsonSchool of Biological Sciences, Monash University, Melbourne, VIC 3800, Australia.
Carsten G BönnemannNational Institute of Neurological Disorders and Stroke Neurogenetics Branch, Neuromuscular and Neurogenetic Disorders of Childhood Section, NIH, Bethesda, MD 20892-1477, USA.
Jocelyn LaporteInstitut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67400 Illkirch, France; Université de Strasbourg, 67081 Illkirch, France.
Sandra T CooperInstitute 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.
Monash University · AUThe University of Sydney · AUBroad Institute · USCentre National de la Recherche Scientifique · FRNational Institute of Neurological Disorders and Stroke · USChildren's Hospital at Westmead · AUHacettepe University Hospital · TRInstitut de génétique et de biologie moléculaire et cellulaire · FRAssistance Publique – Hôpitaux de Paris · FRCommissariat à l'Énergie Atomique et aux Énergies Alternatives · FRThe University of Western Australia · AUConcord Repatriation General Hospital · AURoyal Children's Hospital · AUTexas Tech University · US
Funding
Large Scale Sequencing and Analysis of GenomesU54HG003067 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI GABRIEL, STACEY, LANDER, ERIC S · 2004 to 2015
$568.6MMolecular and Clinical Manifestations of Matrix and Aggregate MyopathiesZIANS003129 · NINDS · NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE · PI BÖNNEMANN, CARSTEN · 2011 to 2025
$52.8MJoint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5MA powerful web-based discovery platform for rare disease geneticsR01HG009141 · NHGRI · BROAD INSTITUTE, INC. · PI QUINLAN, AARON R, REHM, HEIDI L · 2017 to 2020
$2.9MHuman dysferlin and its implications in Limb-Girdle Muscular DystrophyR01AR063634 · NIAMS · TEXAS TECH UNIVERSITY HEALTH SCIS CENTER · PI SUTTON, ROGER BRYAN · 2014 to 2018
$1.8MNHGRI NIH HHS U54 HG003067NHGRI NIH HHS UM1 HG008900NIAMS NIH HHS R01 AR063634
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.
Indexed as
Genetic VariationAmino Acid SequenceAnimalsCell NucleusChlorocebus aethiopsCohort StudiesCOS CellsCreatine KinaseCytoplasmDistal MyopathiesELAV-Like Protein 4FemaleFlavoproteinsGene DeletionGenome-Wide Association StudyGlutathione ReductaseCreatine KinaseELAVL4 protein, humanELAV-Like Protein 4FlavoproteinsGLR1 protein, S cerevisiaeGlutathione ReductaseOxidoreductasesSaccharomyces cerevisiae Proteins
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