Variants in PYROXD1 cause early-onset myopathy with distinctive histopathology

AJHG Nov16PYROXD1 is a nuclear-cytoplasmic pyridine nucleotide-disulphide reductase (PNDR). 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 pryroxD1 knock-down recapitulate features of PYROXD1 myopathy with sarcomeric disorganization, myofibrillar aggregates, and marked swimming defect. 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.

O’Grady GL, Best HA, Sztal TE, et al. Variants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar disorganization. Am J Hum Genet. 2016 Nov 3;99(5):1086-1105.