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


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.

DOI: 10.1016/j.ajhg.2016.09.005

Cite this paper

@article{OGrady2016VariantsIT, title={Variants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization.}, author={Gina L. O'Grady and Heather A Best and Tamar E. Sztal and Vanessa Schartner and Myriam Sanjuan-Vazquez and Sandra C. Donkervoort and Os{\'o}rio Abath Neto and Roger Bryan Sutton and Biljana Ilkovski and Norma Beatriz Romero and Tanya Stojkovic and Jahannaz Dastgir and Leigh B. Waddell and Anne Boland and Ying Hu and Caitlin L. Williams and Avnika A. Ruparelia and Thierry Maisonobe and Anthony J. Peduto and Stephen W R Reddel and Monkol Lek and Taru Tukiainen and Beryl B. Cummings and Himanshu Joshi and Juliette Nectoux and Susan Brammah and Jean-François Deleuze and Viola Oorschot Ing and Georg Ramm and Didem Ardicli and Kristen Jean Nowak and Beril Talim and Haluk Topaloğlu and Nigel G Laing and Kathryn N North and Daniel G. MacArthur and Sylvie Friant and Nigel F. Clarke and Robert J. Bryson-Richardson and Carsten G B{\"{o}nnemann and Jocelyn Laporte and Sandra T Cooper}, journal={American journal of human genetics}, year={2016}, volume={99 5}, pages={1086-1105} }