{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T11:29:48Z","timestamp":1788866988573,"version":"build-2803163510"},"reference-count":37,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2018,9,3]],"date-time":"2018-09-03T00:00:00Z","timestamp":1535932800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["NIH R01 CA160611"],"award-info":[{"award-number":["NIH R01 CA160611"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2018,11]]},"abstract":"<jats:p>Spondylometaphyseal dysplasia (SMD) is characterized by developmental changes in long bones and vertebrae. It has large phenotypic diversity and multiple genetic causes, including a recent link to novel variants in the extracellular matrix (ECM) protein fibronectin (FN), a regulator of ECM assembly and key link between the ECM and proper cell function. We identified a patient with a unique SMD, similar to SMD with corner fractures. The patient has been followed over 19 years and presents with short stature, genu varum, kyphoscoliosis, and pectus carinatum. Radiography shows metaphyseal changes that resolved over time, vertebral changes, and capitular avascular necrosis. Whole exome sequencing identified a novel heterozygous <jats:italic>FN1<\/jats:italic> variant (p.Cys97Trp). Using mass spectroscopy, mutant FN was detected in plasma and in culture medium of primary dermal fibroblasts isolated from the patient, but mutant protein was much less abundant than wild\u2010type FN. Immunofluorescence and immunoblotting analyses show that mutant fibroblasts assemble significantly lower amounts of FN matrix than wild\u2010type cells, and mutant FN was preferentially retained within the endoplasmic reticulum. This work highlights the importance of FN in skeletal development, and its potential role in the pathogenesis of a subtype of SMD.<\/jats:p>","DOI":"10.1111\/cge.13424","type":"journal-article","created":{"date-parts":[[2018,7,27]],"date-time":"2018-07-27T06:19:19Z","timestamp":1532672359000},"page":"429-437","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Mechanistic insights into the cellular effects of a novel <i>FN1<\/i> variant associated with a spondylometaphyseal dysplasia"],"prefix":"10.1111","volume":"94","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0974-7368","authenticated-orcid":false,"given":"E.B.","family":"Cadoff","sequence":"first","affiliation":[{"name":"Department of Molecular Biology Princeton University  Princeton New Jersey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Sheffer","sequence":"additional","affiliation":[{"name":"Department of Genetics and Metabolic Disorders Hadassah\u2010Hebrew University Medical Center  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Wientroub","sequence":"additional","affiliation":[{"name":"Department of Pediatric Orthopedics Dana\u2010Dwek Children's Hospital  Tel Aviv Israel"},{"name":"Sackler Faculty of Medicine Tel Aviv University  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.","family":"Ovadia","sequence":"additional","affiliation":[{"name":"Department of Pediatric Orthopedics Dana\u2010Dwek Children's Hospital  Tel Aviv Israel"},{"name":"Sackler Faculty of Medicine Tel Aviv University  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V.","family":"Meiner","sequence":"additional","affiliation":[{"name":"Department of Genetics and Metabolic Disorders Hadassah\u2010Hebrew University Medical Center  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.E.","family":"Schwarzbauer","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology Princeton University  Princeton New Jersey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,9,3]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/dgd.12203"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01657"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdrc.20167"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.095786"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37365"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/GIM.0b013e3181daae9b"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38059"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1086\/302158"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2013.05.017"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.09.019"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-cellbio-100109-104020"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a005041"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M206286200"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E14-03-0800"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M410762200"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e02-01-0048"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.119.4.1079"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0177(199610)207:2<145::AID-AJA3>3.0.CO;2-H"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.2910200102"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2006.468"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/pr500202e"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/1044-0305(94)80016-2"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471250953.bi1320s40"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/pr801109k"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq054"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M112.017707"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.102.5.1558"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.02566"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi990202b"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.87.3.663"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002470050005"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.113.6.1463"},{"issue":"20","key":"e_1_2_6_35_1","doi-asserted-by":"crossref","first-page":"12840","DOI":"10.1016\/S0021-9258(18)98769-7","article-title":"Five type I modules of fibronectin form a functional unit that binds to fibroblasts and Staphylococcus aureus","volume":"266","author":"Sottile J","year":"1991","journal-title":"J Biol Chem"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2007.04.016"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200707150"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.150276"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcge.13424","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.13424","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,16]],"date-time":"2023-09-16T16:08:55Z","timestamp":1694880535000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cge.13424"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,3]]},"references-count":37,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2018,11]]}},"alternative-id":["10.1111\/cge.13424"],"URL":"https:\/\/doi.org\/10.1111\/cge.13424","archive":["Portico"],"relation":{},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"value":"0009-9163","type":"print"},{"value":"1399-0004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,3]]},"assertion":[{"value":"2018-05-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-07-24","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-09-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}