ArticleHuman molecular genetics2023
Connective tissue presentation in two families expands the phenotypic spectrum of PYROXD1 disorders.
Article in Human molecular genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 4 citations in OpenAlex.
- A severe neurodevelopmental syndrome linked to a South Asian founder variant in the UFMylation adaptor CDK5RAP3.Acta neuropathologica · 2026Article
- Enzymology of the metazoan tRNA ligase complex: a lifetime in cycles.Cellular and molecular life sciences : CMLS · 2026Review
- Pyroxd1 is essential for murine viability with the homozygous N155S recurrent variant linked to myopathy, muscle hypotrophy and osteopenia.Acta neuropathologica communications · 2026Article
- Myofibrillar myopathy type 8 mimicking a Limb-Girdle Muscle Dystrophy: the first Tunisian case report.Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology · 2026Article
- Mechanistic basis for PYROXD1-mediated protection of the human tRNA ligase complex against oxidative inactivation.Nature structural & molecular biology · 2025Article
- A rare case of myopathy with fatigability due toJournal of neuromuscular diseases · 2025Article
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Authors and funding
15 authors at 4 institutions in 2 countries.
Funding
Abstract
Recessive variants in the oxidoreductase PYROXD1 are reported to cause a myopathy in 22 affected individuals from 15 families. Here, we describe two female probands from unrelated families presenting with features of a congenital connective tissue disorder including osteopenia, blue sclera, soft skin, joint hypermobility and neuromuscular junction dysfunction in addition to known features of PYROXD1 myopathy including respiratory difficulties, weakness, hypotonia and oromotor dysfunction. Proband AII:1 is compound heterozygous for the recurrent PYROXD1 variant Chr12(GRCh38):g.21452130A>G;NM_024854.5:c.464A>G;p.(N155S) and Chr12(GRCh38):g.21462019_21462022del;NM_024854.5:c.892_895del;p.(V298Mfs*4) and proband BII:1 is compound heterozygous for Chr12(GRCh38):g.21468739-21468741del;NM_024854.5:c.1488_1490del;p.(E496del) and Chr12(GRCh38):g.21467619del;NM_024854.5:c.1254+1del. RNA studies demonstrate c.892_895del;p.(V298Mfs*4) is targeted by nonsense mediated decay and c.1254+1delG elicits in-frame skipping of exon-11. Western blot from cultured fibroblasts shows reduced PYROXD1 protein levels in both probands. Testing urine from BII:1 and six individuals with PYROXD1 myopathy showed elevated levels of deoxypyridinoline, a mature collagen crosslink, correlating with PYROXD1-disorder severity. Urine and serum amino acid testing of the same individuals revealed no reportable changes. In contrast to PYROXD1 knock-out, we find no evidence for disrupted tRNA ligase activity, as measured via XBP1 splicing, in fibroblasts expressing PYROXD1 variants. In summary, we expand the clinical spectrum of PYROXD1-related disorders to include an overlapping connective tissue and myopathy presentation, identify three novel, pathogenic PYROXD1 variants, and provide preliminary evidence that elevated urine DPD crosslinks may provide a clinical biomarker for PYROXD1 disorders. Our results advocate consideration of PYROXD1 variants in the differential diagnosis for undiagnosed individuals presenting with a connective tissue disorder and myopathy.
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