{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T12:39:17Z","timestamp":1793104757507,"version":"4.5.0"},"reference-count":21,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2023,3,15]],"date-time":"2023-03-15T00:00:00Z","timestamp":1678838400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"National Health and Medical Research Council of Australia","award":["APP1048816"],"award-info":[{"award-number":["APP1048816"]}],"id":[{"id":"https:\/\/ror.org\/011kf5r70","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Health and Medical Research Council of Australia","award":["APP1136197"],"award-info":[{"award-number":["APP1136197"]}],"id":[{"id":"https:\/\/ror.org\/011kf5r70","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Health and Medical Research Council of Australia","award":["APP1080587"],"award-info":[{"award-number":["APP1080587"]}],"id":[{"id":"https:\/\/ror.org\/011kf5r70","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Muscular Dystrophy Association of the USA","id":[{"id":"https:\/\/ror.org\/01frxsf98","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung and Blood Institute","doi-asserted-by":"crossref","award":["UM1 HG008900"],"award-info":[{"award-number":["UM1 HG008900"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["R01 HG009141"],"award-info":[{"award-number":["R01 HG009141"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,6,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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&amp;gt;G;NM_024854.5:c.464A&amp;gt;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.<\/jats:p>","DOI":"10.1093\/hmg\/ddad035","type":"journal-article","created":{"date-parts":[[2023,3,1]],"date-time":"2023-03-01T10:09:09Z","timestamp":1677665349000},"page":"2084-2092","source":"Crossref","is-referenced-by-count":9,"title":["Connective tissue presentation in two families expands the phenotypic spectrum of\n                    <i>PYROXD1<\/i>\n                    disorders"],"prefix":"10.1093","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2418-3230","authenticated-orcid":false,"given":"Frances J","family":"Evesson","sequence":"first","affiliation":[{"name":"Kids Neuroscience Centre, Kids Research Institute, The Children\u2019s Hospital at Westmead , Westmead, NSW , Australia"},{"name":"Functional Neuromics , Children's Medical Research Institute, , Westmead, NSW , Australia"},{"name":"The University of Sydney , Children's Medical Research Institute, , Westmead, NSW , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Dziaduch","sequence":"additional","affiliation":[{"name":"Kids Neuroscience Centre, Kids Research Institute, The Children\u2019s Hospital at Westmead , Westmead, NSW , Australia"},{"name":"Functional Neuromics , Children's Medical Research Institute, , Westmead, NSW , Australia"},{"name":"The University of Sydney , Children's Medical Research Institute, , Westmead, NSW , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha J","family":"Bryen","sequence":"additional","affiliation":[{"name":"Kids Neuroscience Centre, Kids Research Institute, The Children\u2019s Hospital at Westmead , Westmead, NSW , Australia"},{"name":"Discipline of Child and Adolescent Health , Faculty of Medicine and Health, , Westmead, NSW , Australia"},{"name":"The University of Sydney , Faculty of Medicine and Health, , Westmead, NSW , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Moore","sequence":"additional","affiliation":[{"name":"NSW Biochemical Genetics Service, The Children\u2019s Hospital at Westmead , Westmead, NSW , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Pittman","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine , Saint Louis, MO , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beena","family":"Devanapalli","sequence":"additional","affiliation":[{"name":"NSW Biochemical Genetics Service, The Children\u2019s Hospital at Westmead , Westmead, NSW , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leigh B","family":"Waddell","sequence":"additional","affiliation":[{"name":"Kids Neuroscience Centre, Kids Research Institute, The Children\u2019s Hospital at Westmead , Westmead, NSW , Australia"},{"name":"Discipline of Child and Adolescent Health , Faculty of Medicine and Health, , Westmead, NSW , Australia"},{"name":"The University of Sydney , Faculty of Medicine and Health, , Westmead, NSW , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique M","family":"Ryan","sequence":"additional","affiliation":[{"name":"Royal Children\u2019s Hospital, Murdoch Children\u2019s Research Institute and University of Melbourne , Melbourne , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoj P","family":"Menezes","sequence":"additional","affiliation":[{"name":"Discipline of Child and Adolescent Health , Faculty of Medicine and Health, , Westmead, NSW , Australia"},{"name":"The University of Sydney , Faculty of Medicine and Health, , Westmead, NSW , Australia"},{"name":"Department of Neurology, Children's Hospital at Westmead , Westmead, NSW , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conrad C","family":"Weihl","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine , Saint Louis, MO , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adviye Ayper","family":"Tolun","sequence":"additional","affiliation":[{"name":"Discipline of Child and Adolescent Health , Faculty of Medicine and Health, , Westmead, NSW , Australia"},{"name":"The University of Sydney , Faculty of Medicine and Health, , Westmead, NSW , Australia"},{"name":"NSW Biochemical Genetics Service, The Children\u2019s Hospital at Westmead , Westmead, NSW , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"Zaidman","sequence":"additional","affiliation":[{"name":"Department of Neurology , Divisions of Child Neurology and Neuromuscle, , St. Louis, MO , USA"},{"name":"Washington University in St. Louis School of Medicine , Divisions of Child Neurology and Neuromuscle, , St. Louis, MO , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, The Children\u2019s Hospital at Westmead , Sydney , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lesley C","family":"Ad\u00e8s","sequence":"additional","affiliation":[{"name":"Discipline of Child and Adolescent Health , Faculty of Medicine and Health, , Westmead, NSW , Australia"},{"name":"The University of Sydney , Faculty of Medicine and Health, , Westmead, NSW , Australia"},{"name":"Department of Clinical Genetics, The Children\u2019s Hospital at Westmead , Sydney , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra T","family":"Cooper","sequence":"additional","affiliation":[{"name":"Kids Neuroscience Centre, Kids Research Institute, The Children\u2019s Hospital at Westmead , Westmead, NSW 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