By Michaela Yuen


Hum Mol Genet 2023 Mar 15;ddad035. doi: 10.1093/hmg/ddad035

Expanding the phenotype: Individuals with variants in the oxidoreductase PYROXD1 present with a myopathy and connective tissue disorder.

Expanding the phenotype


PYROXD1 encodes Pyridine Nucleotide-Disulphide Oxidoreductase Domain 1 (PYROXD1), a ubiquitously expressed oxidoreductase enzyme essential to cell survival. Recessive variants in PYROXD1 were initially associated with an early onset myopathy in 2016 and later shown to also cause adult-onset limb-girdle muscular dystrophy (2019). The present study further expands the clinical phenotype of PYROXD1-disease to include features of a congenital connective tissue disorder.

The authors report two female probands with compound heterozygous variants in PYROXD1 (3 novel variants and 1 recurrent variant) associated with reduced protein levels in cultured fibroblasts. Both probands exhibit respiratory difficulties, weakness, hypotonia, and oromotor dysfunction, which are typical features of PYROXD1 myopathy. However, they also presented with features of a congenital connective tissue disorder including osteopenia, blue sclera, soft skin and joint hypermobility.

Due to the discovery of a connective tissue dysfunction in these two probands, the authors investigated whether urinary excreted collagen crosslinks (urine deoxypyridinoline [DPD]), which are clinically used for the diagnosis of primary connective tissue disorders, are a useful biomarker for PYROXD1-related disorders. They found all six PYROXD1-disorder patients available for this study displayed elevated DPD levels compared to age-appropriate reference ranges. While this work remains to be confirmed in a larger group of patients, it appears that DPD levels correlates with the severity of the disorder, suggesting they could represent a valuable biomarker to assess PYROXD1 function for clinical management of patients or interpretation of novel PYROXD1 variants.

Despite being critical for cell survival PYROXD1’s functions and enzymatic substrates are currently poorly understood. A small number of studies investigating PYROXD1 function have highlighted that it is essential for the regulation of reactive oxygen species (ROS) levels, mitochondrial function, and maintenance of the t-RNA ligase complex. The present study suggests PYROXD1 may also be involved in collagen biosynthesis resulting in predominant bone and muscle dysfunction.

Supported by their findings, the authors recommend that PYROXD1 should be considered as a possible genetic cause for undiagnosed patients with a myopathy and features of a connective tissue disorder and inclusion of PYROXD1 on connective tissue disorder gene panels may be diagnostically useful.

About the Author

Image of Fran Evesson. Fran is smiling at the camera. The subject has dark hair and an orange top with cats on.

Dr Fran Evesson leads the Disease Mechanisms and Therapies team in Kids Neuroscience Centre, located between Kids Research and Children’s Medical Research Institute in Sydney, Australia. Dr Evesson attained her PhD in 2012, focused on the defining the cell biology of dysferlin and then extended this work during her postdoctoral training in Boston, USA. In 2016 Dr Evesson returned to Australia to take up her current position and her research interests are now centred around causes and consequences of inherited neuromuscular disorders, from improving patient diagnoses to using cell and animal models to perform deep mechanistic studies and pre-clinical therapy development.

This article is presented by the

Publication Highlights Committee.

Published on 20 June 2023.


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