Recessive variants in the oxidoreductase enzyme PYROXD1 are associated with both a congenital myopathy and an adult onset limb girdle muscular dystrophy, but with only 25 patients currently known world-wide, it is likely many individuals are yet to be genetically diagnosed.
PYROXD1 is ubiquitously expressed and has a cell essential function for which no other enzyme can compensate. However, the exact role of PYROXD1 and why variants cause a myopathy remains unknown; a published role in regulation of the tRNA ligase complex does not completely explain the pathology of PYROXD1 disease. Our group is focused on defining the pathobiology of PYROXD1 myopathy using cell and mouse models. We have created a mouse model of the recurrent patient variant, p.N155S found on at least one allele in 80% of individuals with PYROXD1 myopathy. Pyroxd1N155S mice accurately phenocopy the human myopathy with skeletal muscle atrophy and significant skeletal muscle pathology on light and electron microscopy. Unexpectedly, we have also identified a significant bone phenotype where Pyroxd1N155S mice have reduced cortical thickness and bone density. Concurrently, our group has identified a subset of individuals with atypical PYROXD1 myopathy who have connective tissue features including osteopenia and blue sclera in addition to their skeletal muscle involvement, thus expanding the known phenotype associated with PYROXD1 variants.
Our collective findings support that PYROXD1 has role(s) in multiple important cellular pathways. We are now using functional studies and multi-omics to try to tease out the function of PYROXD1 in addition to pursuing therapeutic options including the effect of voluntary exercise on disease progression in Pyroxd1N155S mice.