{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T13:43:38Z","timestamp":1790516618889,"version":"4.1.0"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"22","license":[{"start":{"date-parts":[[2022,6,4]],"date-time":"2022-06-04T00:00:00Z","timestamp":1654300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"FRM prix Pomaret de Lalande"},{"name":"FP7 Sybil program"},{"DOI":"10.13039\/501100001665","name":"ANR","doi-asserted-by":"publisher","award":["R09183KS"],"award-info":[{"award-number":["R09183KS"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,11,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Mutations in the fibrillin-1 (FBN1) gene are responsible for the autosomal dominant form of geleophysic dysplasia (GD), which is characterized by short stature and extremities, thick skin and cardiovascular disease. All known FBN1 mutations in patients with GD are localized within the region encoding the transforming growth factor-\u03b2 binding protein-like 5 (TB5) domain of this protein. Herein, we generated a knock-in mouse model, Fbn1Y1698C by introducing the p.Tyr1696Cys mutation from a patient with GD into the TB5 domain of murine Fbn1 to elucidate the specific role of this domain in endochondral ossification. We found that both Fbn1Y1698C\/+ and Fbn1Y1698C\/Y1698C mice exhibited a reduced stature reminiscent of the human GD phenotype. The Fbn1 point mutation introduced in these mice affected the growth plate formation owing to abnormal chondrocyte differentiation such that mutant chondrocytes failed to establish a dense microfibrillar network composed of FBN1. This original Fbn1 mutant mouse model offers new insight into the pathogenic events underlying GD. Our findings suggest that the etiology of GD involves the dysregulation of the extracellular matrix composed of an abnormal FBN1 microfibril network impacting the differentiation of the chondrocytes.<\/jats:p>","DOI":"10.1093\/hmg\/ddac131","type":"journal-article","created":{"date-parts":[[2022,6,5]],"date-time":"2022-06-05T21:20:22Z","timestamp":1654464022000},"page":"3777-3788","source":"Crossref","is-referenced-by-count":12,"title":["The critical role of the TB5 domain of fibrillin-1 in endochondral ossification"],"prefix":"10.1093","volume":"31","author":[{"given":"Laure","family":"Delhon","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9 , INSERM UMR1163, Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, Imagine Institute, Paris, F-75015 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zakaria","family":"Mougin","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9 and Universit\u00e9 Sorbonne Paris Nord , INSERM U1148, Laboratory of Vascular Translational Science, Bichat Hospital, Paris, F-75018 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9r\u00e9mie","family":"Jonquet","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9 and Universit\u00e9 Sorbonne Paris Nord , INSERM U1148, Laboratory of Vascular Translational Science, Bichat Hospital, Paris, F-75018 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ang\u00e9lique","family":"Bibimbou","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9 and Universit\u00e9 Sorbonne Paris Nord , INSERM U1148, Laboratory of Vascular Translational Science, Bichat Hospital, Paris, F-75018 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanne","family":"Dubail","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9 , INSERM UMR1163, Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, Imagine Institute, Paris, F-75015 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Bou-Chaaya","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9 , INSERM UMR1163, Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, Imagine Institute, Paris, F-75015 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Goudin","sequence":"additional","affiliation":[{"name":"SFR Necker , Imaging Platform, Necker-Enfants Malades Hospital, Paris, F-75015 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilfried","family":"Le Goff","sequence":"additional","affiliation":[{"name":"Sorbonne University , Inserm UMR_S1166, Institute of Cardiometabolism and Nutrition (ICAN), H\u00f4pital de la Piti\u00e9, Paris F-75013 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Boileau","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9 and Universit\u00e9 Sorbonne Paris Nord , INSERM U1148, Laboratory of Vascular Translational Science, Bichat Hospital, Paris, F-75018 , France"},{"name":"Departement of Genetics , AP-HP, Bichat Hospital, Paris, F-75018 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2839-9856","authenticated-orcid":false,"given":"Val\u00e9rie","family":"Cormier-Daire","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9 , INSERM UMR1163, Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, Imagine Institute, Paris, F-75015 , France"},{"name":"Department of Medical Genetics , Reference Center for Skeletal dysplasia AP-HP, Necker-Enfants Malades Hospital, Paris, F-75015 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7788-708X","authenticated-orcid":false,"given":"Carine","family":"Le Goff","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9 and Universit\u00e9 Sorbonne Paris Nord , INSERM U1148, Laboratory of Vascular Translational Science, Bichat Hospital, Paris, F-75018 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,6,4]]},"reference":[{"key":"2022111201004811900_ref1","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1002\/ajmg.c.31337","article-title":"From tall to short: the role of TGF\u03b2 signaling in growth and its disorders","volume":"160C","author":"Le Goff","year":"2012","journal-title":"Am. J. Med. Genet."},{"key":"2022111201004811900_ref2","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1038\/bonekey.2015.9","article-title":"Chondrodysplasias and TGF\u03b2 signaling","volume":"4","author":"Le Goff","year":"2015","journal-title":"BoneKEy Rep."},{"key":"2022111201004811900_ref3","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1038\/ng.199","article-title":"ADAMTSL2 mutations in geleophysic dysplasia demonstrate a role for ADAMTS-like proteins in TGF-\u03b2 bioavailability regulation","volume":"40","author":"Le Goff","year":"2008","journal-title":"Nat. Genet."},{"key":"2022111201004811900_ref4","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.ajhg.2011.05.012","article-title":"Mutations in the TGF\u03b2 binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias","volume":"89","author":"Le Goff","year":"2011","journal-title":"Am. J. Hum. Genet.s"},{"key":"2022111201004811900_ref5","doi-asserted-by":"crossref","first-page":"2707","DOI":"10.1096\/fj.201800753RR","article-title":"Impairment of chondrogenesis and microfibrillar network in Adamtsl2 deficiency","volume":"33","author":"Delhon","year":"2019","journal-title":"FASEB J."},{"key":"2022111201004811900_ref6","first-page":"219","article-title":"Genetics of thoracic aortic aneurysms. Cur.R Atheroscler","volume":"14","author":"Jondeau","year":"2012","journal-title":"Rep."},{"key":"2022111201004811900_ref7","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.1038\/s41436-019-0444-y","article-title":"Genetic diversity and pathogenic variants as possible predictors of severity in a French sample of nonsyndromic heritable thoracic aortic aneurysms and dissections (nshTAAD)","volume":"21","author":"Arnaud","year":"2019","journal-title":"Genet. Med"},{"key":"2022111201004811900_ref8","doi-asserted-by":"crossref","first-page":"23ra20","DOI":"10.1126\/scitranslmed.3000488","article-title":"Mutations in Fibrillin-1 cause congenital scleroderma: stiff skin syndrome","volume":"2","author":"Loeys","year":"2010","journal-title":"Sci. Transl. Med."},{"key":"2022111201004811900_ref9","doi-asserted-by":"crossref","first-page":"S34","DOI":"10.1097\/IJG.0000000000000114","article-title":"Microfibril-associated disorders: fibrillinopathies","volume":"23","author":"Reinhardt","year":"2014","journal-title":"J. Glaucoma"},{"key":"2022111201004811900_ref10","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.matbio.2015.05.002","article-title":"The fibrillin microfibril scaffold: a niche for growth factors and mechanosensation?","volume":"47","author":"Sengle","year":"2015","journal-title":"Matrix Biol."},{"key":"2022111201004811900_ref11","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.matbio.2015.05.004","article-title":"ADAMTS proteins as modulators of microfibril formation and function","volume":"47","author":"Hubmacher","year":"2015","journal-title":"Matrix Biol."},{"key":"2022111201004811900_ref12","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.matbio.2017.11.014","article-title":"LTBPs in biology and medicine: LTBP diseases","volume":"71\u201372","author":"Rifkin","year":"2018","journal-title":"Matrix Biol."},{"key":"2022111201004811900_ref13","doi-asserted-by":"crossref","first-page":"e1002425","DOI":"10.1371\/journal.pgen.1002425","article-title":"Microenvironmental regulation by Fibrillin-1","volume":"8","author":"Sengle","year":"2012","journal-title":"PLoS Genet."},{"key":"2022111201004811900_ref14","doi-asserted-by":"crossref","first-page":"3675","DOI":"10.1093\/hmg\/ddy276","article-title":"ADAMTS10-mediated tissue disruption in Weill\u2013Marchesani syndrome","volume":"27","author":"Mularczyk","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"2022111201004811900_ref15","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1093\/hmg\/4.suppl_1.1799","article-title":"Mutations in the human gene for fibrillin-1 (FBN1) in the Marfan syndrome and related disorders","volume":"4","author":"Dietz","year":"1995","journal-title":"Hum. Mol. 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Genet."},{"key":"2022111201004811900_ref20","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1002\/dvg.22022","article-title":"Generation of Fbn1 conditional null mice implicates the extracellular microfibrils in osteoprogenitor recruitment","volume":"50","author":"Cook","year":"2012","journal-title":"Genesis"},{"key":"2022111201004811900_ref21","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1002\/jbmr.2598","article-title":"Fibrillin-1 regulates skeletal stem cell differentiation by modulating TGF\u03b2 activity within the marrow niche: FIBRILLIN-1 regulation of marrow stem cells","volume":"31","author":"Smaldone","year":"2016","journal-title":"J. Bone Miner. Res."},{"key":"2022111201004811900_ref22","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.matbio.2015.09.004","article-title":"Fibrillin microfibrils in bone physiology","volume":"52\u201354","author":"Smaldone","year":"2016","journal-title":"Matrix Biol."},{"key":"2022111201004811900_ref23","doi-asserted-by":"crossref","first-page":"e1002356","DOI":"10.1371\/journal.pgen.1002356","article-title":"SOX9 governs differentiation stage-specific gene expression in growth plate chondrocytes via direct concomitant transactivation and repression","volume":"7","author":"Leung","year":"2011","journal-title":"PLoS Genet."},{"key":"2022111201004811900_ref24","doi-asserted-by":"crossref","first-page":"e48634","DOI":"10.1371\/journal.pone.0048634","article-title":"Fibrillin-1 mutations causing Weill-Marchesani syndrome and Acromicric and geleophysic dysplasias disrupt Heparan Sulfate interactions","volume":"7","author":"Cain","year":"2012","journal-title":"PLoS One"},{"key":"2022111201004811900_ref25","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1016\/j.str.2013.08.004","article-title":"Structure of the Fibrillin-1 N-terminal domains suggests that Heparan sulfate regulates the early stages of microfibril assembly","volume":"21","author":"Yadin","year":"2013","journal-title":"Structure"},{"key":"2022111201004811900_ref26","doi-asserted-by":"crossref","first-page":"2890","DOI":"10.1016\/j.febslet.2014.06.061","article-title":"Heparin\/heparan sulfate controls fibrillin-1, \u22122 and \u22123 self-interactions in microfibril assembly","volume":"588","author":"Sabatier","year":"2014","journal-title":"FEBS Lett."},{"key":"2022111201004811900_ref27","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.matbio.2019.02.001","article-title":"Limb- and tendon-specific Adamtsl2 deletion identifies a role for ADAMTSL2 in tendon growth in a mouse model for geleophysic dysplasia","volume":"82","author":"Hubmacher","year":"2019","journal-title":"Matrix Biol."},{"key":"2022111201004811900_ref28","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1242\/dmm.017046","article-title":"Adamtsl2 deletion results in bronchial fibrillin microfibril accumulation and bronchial epithelial dysplasia: a novel mouse model providing insights into geleophysic dysplasia","volume":"8","author":"Hubmacher","year":"2015","journal-title":"Dis. Model. Mech."},{"key":"2022111201004811900_ref29","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1136\/jmedgenet-2015-103647","article-title":"Mutations in LTBP3 cause acromicric dysplasia and geleophysic dysplasia","volume":"53","author":"McInerney-Leo","year":"2016","journal-title":"J. Med. Genet."}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddac131\/45054463\/ddac131.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/31\/22\/3777\/46937654\/ddac131.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/31\/22\/3777\/46937654\/ddac131.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,12]],"date-time":"2022-11-12T01:01:18Z","timestamp":1668214878000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/31\/22\/3777\/6601993"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,4]]},"references-count":29,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2022,6,4]]},"published-print":{"date-parts":[[2022,11,10]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddac131","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,11,15]]},"published":{"date-parts":[[2022,6,4]]}}}