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

TitleVariants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization.
Publication TypeJournal Article
Year of Publication2016
AuthorsO'Grady, GL, Best, HA, Sztal, TE, Schartner, V, Sanjuan-Vazquez, M, Donkervoort, S, Neto, OAbath, Sutton, RBryan, Ilkovski, B, Romero, NBeatriz, Stojkovic, T, Dastgir, J, Waddell, LB, Boland, A, Hu, Y, Williams, C, Ruparelia, AA, Maisonobe, T, Peduto, AJ, Reddel, SW, Lek, M, Tukiainen, T, Cummings, BB, Joshi, H, Nectoux, J, Brammah, S, Deleuze, J-F, Ing, VOorschot, Ramm, G, Ardicli, D, Nowak, KJ, Talim, B, Topaloglu, H, Laing, NG, North, KN, MacArthur, DG, Friant, S, Clarke, NF, Bryson-Richardson, RJ, Bönnemann, CG, Laporte, J, Cooper, ST
JournalAm J Hum Genet
Date Published2016 Nov 03
KeywordsAmino Acid Sequence, Animals, Cell Nucleus, Cercopithecus aethiops, Cohort Studies, COS Cells, Creatine Kinase, Cytoplasm, Distal Myopathies, ELAV-Like Protein 4, Female, Flavoproteins, Gene Deletion, Genetic Variation, Genome-Wide Association Study, Glutathione Reductase, HEK293 Cells, Humans, Male, Muscle, Skeletal, Mutation, Missense, Myopathies, Structural, Congenital, Oxidoreductases, Pedigree, Protein Conformation, Saccharomyces cerevisiae Proteins, Zebrafish

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.

Alternate JournalAm. J. Hum. Genet.
PubMed ID27745833
PubMed Central IDPMC5097943
Grant ListR01 AR063634 / AR / NIAMS NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
UM1 HG008900 / HG / NHGRI NIH HHS / United States