{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T06:29:41Z","timestamp":1784874581894,"version":"3.55.0"},"reference-count":17,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2017,12,26]],"date-time":"2017-12-26T00:00:00Z","timestamp":1514246400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000912","name":"March of Dimes Foundation","doi-asserted-by":"publisher","award":["#6\u2010FY14\u2010366"],"award-info":[{"award-number":["#6\u2010FY14\u2010366"]}],"id":[{"id":"10.13039\/100000912","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2018,2]]},"abstract":"<jats:p>Filamin B (FLNB) functions as a switch that can affect chrondrocyte development and endochondral bone formation through a series of signaling molecules and transcription factors that also affect Sertoli cell development. Here, we report a subject with a novel skeletal dysplasia and co\u2010existing 46,XY gonadal dysgenesis and biallelic mutations in <jats:italic>FLNB.<\/jats:italic> Whole exome sequencing was performed to identify mutations. Quantitative polymerase chain reaction (qPCR) and flow variant assays were performed to quantify RNA, proteins and phosphorylated proteins. The TOPFLASH reporter was performed to quantify \u03b2\u2010catenin activity. Mutations were identified in the <jats:italic>FLNB<\/jats:italic> gene (<jats:italic>FLNB<\/jats:italic>:p.F964L, <jats:italic>FLNB<\/jats:italic>:p.A1577V). These mutations increased binding of FLNB protein to the MAP3K1 and RAC1 signal transduction complex and activated \u03b2\u2010catenin and had different effects on phosphorylation of MAP kinase pathway intermediates and SOX9 expression. Direct activation of \u03b2\u2010catenin through the FLNB\u2010MAP3K1\u2010RAC1 complex by <jats:italic>FLNB<\/jats:italic> mutations is a novel mechanism for causing 46,XY gonadal dysgenesis. The mechanism of action varies from those reported previously for loss of function mutations in <jats:italic>SOX9<\/jats:italic> and gain\u2010of\u2010function mutations in <jats:italic>MAP3K1.<\/jats:italic><\/jats:p>","DOI":"10.1111\/cge.13165","type":"journal-article","created":{"date-parts":[[2017,11,2]],"date-time":"2017-11-02T16:36:38Z","timestamp":1509640598000},"page":"412-416","source":"Crossref","is-referenced-by-count":11,"title":["Biallelic mutations in <i>FLNB<\/i> cause a skeletal dysplasia with 46,XY gonadal dysgenesis by activating \u03b2\u2010catenin"],"prefix":"10.1111","volume":"93","author":[{"given":"K.","family":"Upadhyay","sequence":"first","affiliation":[{"name":"Departments of Pathology and Radiology Albert Einstein College of Medicine and Montefiore Medical Center  New York City New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Loke","sequence":"additional","affiliation":[{"name":"Departments of Pathology and Radiology Albert Einstein College of Medicine and Montefiore Medical Center  New York City New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V.","family":"O","sequence":"additional","affiliation":[{"name":"Departments of Pathology and Radiology Albert Einstein College of Medicine and Montefiore Medical Center  New York City New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Taragin","sequence":"additional","affiliation":[{"name":"Departments of Pathology and Radiology Albert Einstein College of Medicine and Montefiore Medical Center  New York City New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2209-5376","authenticated-orcid":false,"given":"H.","family":"Ostrer","sequence":"additional","affiliation":[{"name":"Departments of Pathology and Radiology Albert Einstein College of Medicine and Montefiore Medical Center  New York City New York"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,12,26]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-4889(01)00072-6"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2009.12.001"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2005.038695"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1319"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20348"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22012"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2009.06.009"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1171104"},{"key":"e_1_2_6_10_1","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1093\/hmg\/ddt502","article-title":"Mutations in MAP3K1 tilt the balance from SOX9\/FGF9 to WNT\/\u03b2\u2010catenin signaling","volume":"23","author":"Loke J","year":"2013","journal-title":"Hum Mol Genet"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.3.1113"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M409158200"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M604322200"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2011.01834.x"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e08-06-0576"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/372525a0"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90041-8"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2012.09.016"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcge.13165","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.13165","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,28]],"date-time":"2023-09-28T07:25:51Z","timestamp":1695885951000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cge.13165"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,12,26]]},"references-count":17,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2018,2]]}},"alternative-id":["10.1111\/cge.13165"],"URL":"https:\/\/doi.org\/10.1111\/cge.13165","archive":["Portico"],"relation":{},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"value":"0009-9163","type":"print"},{"value":"1399-0004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,12,26]]}}}