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In zebrafish, loss of function of ddrgk1 leads to defects in early cartilage development. Ddrgk1\u2212\/\u2212 mice show delayed mesenchymal condensation in the limb buds and early embryonic lethality. Mechanistically, Ddrgk1 interacts with Sox9 and reduces ubiquitin-mediated proteasomal degradation of Sox9 protein. To investigate the cartilage-specific role of DDRGK1, conditional knockout mice were generated by intercrossing Prx1-Cre transgenic mice with Ddrgkfl\/fl mice to delete its expression in limb mesenchymal cells. Mutant mice showed progressive severe shortening of the limbs and joint abnormalities. The growth plate showed disorganization with shortened proliferative zone and enlarged hypertrophic zone. In correlation with these findings, Sox9 and Col2a1 protein levels were decreased, while Col10a1 expression was expanded. These data demonstrate the importance of Ddrgk1 during growth plate development. In contrast, deletion of Ddrgk1 with the osteoblast-specific Osteocalcin-Cre and Leptin receptor-Cre lines did not show bone phenotypes, suggesting that the effect on limb development is cartilage-specific. To evaluate the role of DDRGK1 in cartilage postnatal homeostasis, inducible Agc1-CreERT2; Ddrgklfl\/fl mice were generated. Mice in which Ddrgk1 was deleted at 3\u00a0months of age showed disorganized growth plate, with significant reduction in proteoglycan deposition. These data demonstrate a postnatal requirement for Ddrgk1 in maintaining normal growth plate morphology. Together, these findings highlight the physiological role of Ddrgk1 in the development and maintenance of the growth plate cartilage. Furthermore, these genetic mouse models recapitulate the clinical phenotype of short stature and joint abnormalities observed in patients with Shohat type SEMD.<\/jats:p>","DOI":"10.1093\/hmg\/ddac078","type":"journal-article","created":{"date-parts":[[2022,4,4]],"date-time":"2022-04-04T13:32:27Z","timestamp":1649079147000},"page":"2820-2830","source":"Crossref","is-referenced-by-count":16,"title":["DDRGK1 is required for the proper development and maintenance of the growth plate cartilage"],"prefix":"10.1093","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6826-8535","authenticated-orcid":false,"given":"Monika","family":"Weisz-Hubshman","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adetutu T","family":"Egunsula","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Dawson","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Castellon","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Ming","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqing","family":"Chen-Evenson","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhiyin","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangjin","family":"Bae","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,4,4]]},"reference":[{"key":"2022082420172851100_ref1","doi-asserted-by":"crossref","first-page":"R160","DOI":"10.1530\/EC-21-0083","article-title":"New gene discoveries in skeletal diseases with short stature","volume":"10","author":"Costantini","year":"2021","journal-title":"Endocr. Connect."},{"key":"2022082420172851100_ref2","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.berh.2007.12.009","article-title":"Spondylo-epi-metaphyseal dysplasia","volume":"22","author":"Cormier-Daire","year":"2008","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"2022082420172851100_ref3","doi-asserted-by":"crossref","first-page":"2393","DOI":"10.1002\/ajmg.a.61366","article-title":"Nosology and classification of genetic skeletal disorders: 2019 revision","volume":"179","author":"Mortier","year":"2019","journal-title":"Am. J. Med. Genet. A"},{"key":"2022082420172851100_ref4","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.1038\/sj.emboj.7600205","article-title":"A novel protein-conjugating system for Ufm1, a ubiquitin-fold modifier","volume":"23","author":"Komatsu","year":"2004","journal-title":"EMBO J."},{"key":"2022082420172851100_ref5","doi-asserted-by":"crossref","first-page":"5417","DOI":"10.1074\/jbc.M109.036814","article-title":"A novel type of E3 ligase for the Ufm1 conjugation system","volume":"285","author":"Tatsumi","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2022082420172851100_ref6","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1007\/s11926-021-01022-w","article-title":"Enzymatic machinery of ubiquitin and ubiquitin-like modification systems in chondrocyte homeostasis and osteoarthritis","volume":"23","author":"Liu","year":"2021","journal-title":"Curr. Rheumatol. Rep."},{"key":"2022082420172851100_ref7","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.ceb.2019.07.008","article-title":"SOX9 in cartilage development and disease","volume":"61","author":"Lefebvre","year":"2019","journal-title":"Curr. Opin. Cell Biol."},{"key":"2022082420172851100_ref8","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1016\/j.bbrc.2020.06.095","article-title":"Ubiquitin conjugating enzyme E2 M promotes apoptosis in osteoarthritis chondrocytes via Wnt\/beta-catenin signaling","volume":"529","author":"Ba","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2022082420172851100_ref9","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1172\/JCI90193","article-title":"Loss of DDRGK1 modulates SOX9 ubiquitination in spondyloepimetaphyseal dysplasia","volume":"127","author":"Egunsola","year":"2017","journal-title":"J. Clin. Invest."},{"key":"2022082420172851100_ref10","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.matbio.2004.10.002","article-title":"The transcription factor Sox9 is degraded by the ubiquitin-proteasome system and stabilized by a mutation in a ubiquitin-target site","volume":"23","author":"Akiyama","year":"2005","journal-title":"Matrix Biol."},{"key":"2022082420172851100_ref11","doi-asserted-by":"crossref","first-page":"4149","DOI":"10.1128\/MCB.20.11.4149-4158.2000","article-title":"Phosphorylation of SOX9 by cyclic AMP-dependent protein kinase A enhances SOX9's ability to transactivate a Col2a1 chondrocyte-specific enhancer","volume":"20","author":"Huang","year":"2000","journal-title":"Mol. Cell. Biol."},{"key":"2022082420172851100_ref12","doi-asserted-by":"crossref","first-page":"13640","DOI":"10.1074\/jbc.RA119.011164","article-title":"Progranulin modulates cartilage-specific gene expression via sirtuin 1-mediated deacetylation of the transcription factors SOX9 and P65","volume":"295","author":"Feng","year":"2020","journal-title":"J. Biol. Chem."},{"key":"2022082420172851100_ref13","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1111\/acel.12456","article-title":"Acetylation reduces SOX9 nuclear entry and ACAN gene transactivation in human chondrocytes","volume":"15","author":"Bar Oz","year":"2016","journal-title":"Aging Cell"},{"key":"2022082420172851100_ref14","doi-asserted-by":"crossref","DOI":"10.3390\/ijms21041274","article-title":"Generation of a quantitative luciferase reporter for Sox9 SUMOylation","volume":"21","author":"Saotome","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"2022082420172851100_ref15","doi-asserted-by":"crossref","first-page":"14417","DOI":"10.1074\/jbc.M511330200","article-title":"Interactions between PIAS proteins and SOX9 result in an increase in the cellular concentrations of SOX9","volume":"281","author":"Hattori","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2022082420172851100_ref16","doi-asserted-by":"crossref","first-page":"558","DOI":"10.7196\/SAMJnew.7917","article-title":"Identification of a mutation in the ubiquitin-fold modifier 1-specific peptidase 2 gene, UFSP2, in an extended South African family with Beukes hip dysplasia","volume":"105","author":"Watson","year":"2015","journal-title":"S. Afr. Med. J."},{"key":"2022082420172851100_ref17","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1111\/cge.13134","article-title":"Novel spondyloepimetaphyseal dysplasia due to UFSP2 gene mutation","volume":"93","author":"Di Rocco","year":"2018","journal-title":"Clin. Genet."},{"key":"2022082420172851100_ref18","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmg.2020.104021","article-title":"UFSP2-related spondyloepimetaphyseal dysplasia: a confirmatory report","volume":"63","author":"Zhang","year":"2020","journal-title":"Eur. J. Med. Genet."},{"key":"2022082420172851100_ref19","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1002\/ajmg.1320460403","article-title":"New form of spondyloepimetaphyseal dysplasia (SEMD) in Jewish family of Iraqi origin","volume":"46","author":"Shohat","year":"1993","journal-title":"Am. J. Med. Genet."},{"key":"2022082420172851100_ref20","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1002\/1873-3468.12518","article-title":"A novel approach to assess the ubiquitin-fold modifier 1-system in cells","volume":"591","author":"Ishimura","year":"2017","journal-title":"FEBS Lett."},{"key":"2022082420172851100_ref21","doi-asserted-by":"crossref","first-page":"10248","DOI":"10.1074\/jbc.M110.172171","article-title":"Structure of ubiquitin-fold modifier 1-specific protease UfSP2","volume":"286","author":"Ha","year":"2011","journal-title":"J. Biol. Chem."},{"key":"2022082420172851100_ref22","doi-asserted-by":"crossref","first-page":"44005","DOI":"10.1074\/jbc.M208265200","article-title":"Osteoblast-specific knockout of the insulin-like growth factor (IGF) receptor gene reveals an essential role of IGF signaling in bone matrix mineralization","volume":"277","author":"Zhang","year":"2002","journal-title":"J. Biol. Chem."},{"key":"2022082420172851100_ref23","doi-asserted-by":"crossref","first-page":"2608","DOI":"10.1126\/science.1056602","article-title":"Virus-assisted mapping of neural inputs to a feeding center in the hypothalamus","volume":"291","author":"DeFalco","year":"2001","journal-title":"Science"},{"key":"2022082420172851100_ref24","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1017\/S0007114500000398","article-title":"Ontogeny of the expression of leptin and its receptor in the murine fetus and placenta","volume":"83","author":"Hoggard","year":"2000","journal-title":"Br. J. Nutr."},{"key":"2022082420172851100_ref25","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.stem.2014.06.008","article-title":"Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow","volume":"15","author":"Zhou","year":"2014","journal-title":"Cell Stem Cell"},{"key":"2022082420172851100_ref26","doi-asserted-by":"crossref","first-page":"2813","DOI":"10.1101\/gad.1017802","article-title":"The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6","volume":"16","author":"Akiyama","year":"2002","journal-title":"Genes Dev."},{"key":"2022082420172851100_ref27","doi-asserted-by":"crossref","first-page":"2511","DOI":"10.1002\/jbmr.1696","article-title":"The postnatal role of Sox9 in cartilage","volume":"27","author":"Henry","year":"2012","journal-title":"J. Bone Miner. Res."},{"key":"2022082420172851100_ref28","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.gpb.2016.04.001","article-title":"UFMylation: a unique & fashionable modification for life","volume":"14","author":"Wei","year":"2016","journal-title":"Genomics Proteomics Bioinformatics"},{"key":"2022082420172851100_ref29","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.15252\/embr.201540891","article-title":"Expanding the ubiquitin code through post-translational modification","volume":"16","author":"Herhaus","year":"2015","journal-title":"EMBO Rep."},{"key":"2022082420172851100_ref30","doi-asserted-by":"crossref","first-page":"57R","DOI":"10.1093\/glycob\/12.4.57R","article-title":"Chondrodysplasias due to proteoglycan defects","volume":"12","author":"Schwartz","year":"2002","journal-title":"Glycobiology"},{"key":"2022082420172851100_ref31","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.ydbio.2009.02.024","article-title":"Aggrecan modulation of growth plate morphogenesis","volume":"329","author":"Domowicz","year":"2009","journal-title":"Dev. Biol."},{"key":"2022082420172851100_ref32","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.ydbio.2014.10.005","article-title":"Aggrecan is required for growth plate cytoarchitecture and differentiation","volume":"396","author":"Lauing","year":"2014","journal-title":"Dev. Biol."},{"key":"2022082420172851100_ref33","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1002\/gene.10092","article-title":"Expression of Cre recombinase in the developing mouse limb bud driven by a Prxl enhancer","volume":"33","author":"Logan","year":"2002","journal-title":"Genesis"},{"key":"2022082420172851100_ref34","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1002\/dvg.20564","article-title":"Generation of aggrecan-CreERT2 knockin mice for inducible Cre activity in adult cartilage","volume":"47","author":"Henry","year":"2009","journal-title":"Genesis"},{"key":"2022082420172851100_ref35","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1016\/j.stem.2019.11.003","article-title":"Identification of functionally distinct Mx1+alphaSMA+ periosteal skeletal stem cells","volume":"25","author":"Ortinau","year":"2019","journal-title":"Cell Stem Cell"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddac078\/43682429\/ddac078.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/31\/16\/2820\/45499298\/ddac078.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/31\/16\/2820\/45499298\/ddac078.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,19]],"date-time":"2023-11-19T16:27:06Z","timestamp":1700411226000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/31\/16\/2820\/6563112"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,4]]},"references-count":35,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2022,4,4]]},"published-print":{"date-parts":[[2022,8,23]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddac078","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,8,15]]},"published":{"date-parts":[[2022,4,4]]}}}