{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T03:18:51Z","timestamp":1777000731855,"version":"3.51.4"},"reference-count":17,"publisher":"Cold Spring Harbor Laboratory","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cold Spring Harb Mol Case Stud"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:p>Osteogenesis imperfecta (OI) is a heritable disorder of bone metabolism characterized by multiple fractures with minimal trauma. Autosomal recessive OI type VIII is associated with biallelic pathogenic variants in<jats:italic>P3H1<\/jats:italic>and classically characterized by skeletal anomalies in addition to significant bone fragility, sometimes presenting with in utero fractures and\/or neonatal lethality.<jats:italic>P3H1<\/jats:italic>encodes a collagen prolyl hydroxylase that critically 3-hydroxylates proline residue 986 on the \u03b1 chain of collagen types I and II to achieve proper folding and assembly of mature collagen and is present in a complex with CRTAP and CypB. Most individuals with OI type VIII have had biallelic predicted loss-of-function variants leading to reduced or absent levels of<jats:italic>P3H1<\/jats:italic>mRNA. The reported missense variants have all fallen in the catalytic domain of the protein and are thought to be associated with a milder phenotype. Here, we describe an infant presenting with five long bone fractures in the first year of life found to have a novel missense variant in<jats:italic>trans<\/jats:italic>with a nonsense variant in<jats:italic>P3H1<\/jats:italic>without any other bony anomalies on imaging. We hypothesize that missense variants in the catalytic domain of P3H1 lead to decreased but not absent hydroxylation of Pro986, with preserved KDEL retention signal and complex stability, causing an attenuated phenotype.<\/jats:p>","DOI":"10.1101\/mcs.a006260","type":"journal-article","created":{"date-parts":[[2023,3,24]],"date-time":"2023-03-24T15:55:25Z","timestamp":1679673325000},"page":"a006260","source":"Crossref","is-referenced-by-count":4,"title":["Milder presentation of osteogenesis imperfecta type VIII due to compound heterozygosity for a predicted loss-of-function variant and novel missense variant in<i>P3H1<\/i>\u2014further expansion of the phenotypic spectrum"],"prefix":"10.1101","volume":"9","author":[{"given":"Kristen A.","family":"Mikhail","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"VanSickle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda Z.","family":"Rossetti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"246","published-online":{"date-parts":[[2023,3,24]]},"reference":[{"key":"2023032408550857000_9.1.a006260.1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.28.7.433"},{"key":"2023032408550857000_9.1.a006260.2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1968"},{"key":"2023032408550857000_9.1.a006260.3","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2011.44"},{"key":"2023032408550857000_9.1.a006260.4","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp481"},{"key":"2023032408550857000_9.1.a006260.5","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-021-02302-2"},{"key":"2023032408550857000_9.1.a006260.6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004121"},{"key":"2023032408550857000_9.1.a006260.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2016.11.019"},{"key":"2023032408550857000_9.1.a006260.8","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.007070"},{"key":"2023032408550857000_9.1.a006260.9","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-009-0872-0"},{"key":"2023032408550857000_9.1.a006260.10","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.464156"},{"key":"2023032408550857000_9.1.a006260.11","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"2023032408550857000_9.1.a006260.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.bonr.2018.09.002"},{"key":"2023032408550857000_9.1.a006260.13","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0036809"},{"key":"2023032408550857000_9.1.a006260.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2020.03.004"},{"key":"2023032408550857000_9.1.a006260.15","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M312807200"},{"key":"2023032408550857000_9.1.a006260.16","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.102228"},{"key":"2023032408550857000_9.1.a006260.17","doi-asserted-by":"publisher","DOI":"10.1007\/s00774-011-0284-6"}],"container-title":["Molecular Case Studies"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/mcs.a006260","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,24]],"date-time":"2023-03-24T15:55:31Z","timestamp":1679673331000},"score":1,"resource":{"primary":{"URL":"http:\/\/molecularcasestudies.cshlp.org\/lookup\/doi\/10.1101\/mcs.a006260"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2]]},"references-count":17,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,3,24]]},"published-print":{"date-parts":[[2023,2]]}},"alternative-id":["10.1101\/mcs.a006260"],"URL":"https:\/\/doi.org\/10.1101\/mcs.a006260","relation":{},"ISSN":["2373-2865","2373-2873"],"issn-type":[{"value":"2373-2865","type":"print"},{"value":"2373-2873","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2]]}}}