Variants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization
| Autor: | Tanya Stojkovic, Haluk Topaloglu, Robert J. Bryson-Richardson, Thierry Maisonobe, Ying Hu, Gina L. O'Grady, Roger Bryan Sutton, Myriam Sanjuan-Vazquez, D. Ardicli, Avnika A. Ruparelia, Sandra T. Cooper, Nigel F. Clarke, Monkol Lek, Beryl B. Cummings, Vanessa Schartner, Himanshu Joshi, Georg Ramm, Osorio Abath Neto, Taru Tukiainen, Sandra Donkervoort, Anthony Peduto, Juliette Nectoux, Norma B. Romero, Jean-François Deleuze, Viola Oorschot Ing, Beril Talim, Biljana Ilkovski, Stephen W. Reddel, Sylvie Friant, Carsten G. Bönnemann, Susan Brammah, Daniel G. MacArthur, Heather A. Best, Jahannaz Dastgir, Kristen J. Nowak, Tamar E. Sztal, Kathryn N. North, Anne Boland, Nigel G. Laing, Leigh B. Waddell, Jocelyn Laporte, Caitlin Williams |
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| Přispěvatelé: | Çocuk Sağlığı ve Hastalıkları, The University of Sydney, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique moléculaire, génomique, microbiologie (GMGM), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Cytoplasm Protein Conformation ELAV-Like Protein 4 Reductase Cohort Studies 0302 clinical medicine Nemaline myopathy Chlorocebus aethiops Zebrafish Creatine Kinase Genetics (clinical) Genetics & Heredity 3. Good health Cell biology Pedigree medicine.anatomical_structure Glutathione Reductase Biochemistry COS Cells Distal Myopathies Female medicine.symptom Oxidoreductases Myopathies Structural Congenital Saccharomyces cerevisiae Proteins Mutation Missense Biology Article 03 medical and health sciences Genetics medicine Animals Humans Amino Acid Sequence Myopathy Muscle Skeletal Cell Nucleus [SDV.GEN]Life Sciences [q-bio]/Genetics Flavoproteins Skeletal muscle Genetic Variation medicine.disease biology.organism_classification Cell nucleus 030104 developmental biology HEK293 Cells Myofibril 030217 neurology & neurosurgery Gene Deletion Genome-Wide Association Study |
| Zdroj: | American Journal of Human Genetics American Journal of Human Genetics, Elsevier (Cell Press), 2016, 99 (5), pp.1086-1105. ⟨10.1016/j.ajhg.2016.09.005⟩ American Journal of Human Genetics, 2016, 99 (5), pp.1086-1105. ⟨10.1016/j.ajhg.2016.09.005⟩ |
| ISSN: | 1537-6605 0002-9297 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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