{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,5]],"date-time":"2025-10-05T19:55:46Z","timestamp":1759694146202,"version":"3.37.3"},"reference-count":14,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2017,9,8]],"date-time":"2017-09-08T00:00:00Z","timestamp":1504828800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 GM113100"],"award-info":[{"award-number":["R01 GM113100"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2017,12]]},"abstract":"<jats:sec><jats:label\/><jats:p>Mutations in <jats:italic>GLI3<\/jats:italic>, which encodes a transcription factor of the Hedgehog signaling pathway, cause several developmental anomalies linked to inappropriate tissue patterning. Here, we report a novel missense variant in the fifth zinc finger domain of <jats:italic>GLI3<\/jats:italic> (c.1826G&gt;A; p.(Cys609Tyr)) initially identified in a proband with preaxial polydactyly type IV, developmental delay, sensorineural hearing loss, skeletal, and genitourinary anomalies. Additional family members exhibited various digital anomalies such as preaxial polydactyly, syndactyly, and postaxial polydactyly either in isolation or combined. Functional studies of Cys609Tyr GLI3 in cultured cells showed abnormal GLI3 processing leading to decreased GLI3 repressor production, increased basal transcriptional activity, and submaximal GLI reporter activity with Hedgehog pathway activation, thus demonstrating an intriguing molecular mechanism for this GLI3\u2010related phenotype. Given the complexity of GLI3 post\u2010translational processing and opposing biological functions as a transcriptional activator and repressor, our findings highlight the importance of performing functional studies of presumed <jats:italic>GLI3<\/jats:italic> variants. This family also demonstrates how <jats:italic>GLI3<\/jats:italic> variants are variably expressed.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ajmg.a.38415","type":"journal-article","created":{"date-parts":[[2017,9,8]],"date-time":"2017-09-08T10:55:49Z","timestamp":1504868149000},"page":"3221-3225","source":"Crossref","is-referenced-by-count":8,"title":["A novel missense variant in the GLI3 zinc finger domain in a family with digital anomalies"],"prefix":"10.1002","volume":"173","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8185-8401","authenticated-orcid":false,"given":"J. Aaron","family":"Crapster","sequence":"first","affiliation":[{"name":"Department of Chemical and Systems Biology Stanford University School of Medicine Stanford California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Louanne","family":"Hudgins","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics Stanford University School of Medicine Stanford California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James K.","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Chemical and Systems Biology Stanford University School of Medicine Stanford California"},{"name":"Department of Developmental Biology Stanford University School of Medicine Stanford California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia","family":"Gomez\u2010Ospina","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics Stanford University School of Medicine Stanford California"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,9,8]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.32167"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2004.029181"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2014.62"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/med\/9780199935710.001.0001"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320070110"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-cellbio-092910-154048"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13353-012-0109-x"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21328"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/8.9.1769"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33720"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1322362111"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_7_14_1","first-page":"565","article-title":"Correlated mutation analysis of c2h2 zinc finger domains","volume":"14","author":"Takafumi N.","year":"2003","journal-title":"Genome Informatics"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-014-0110-9"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fajmg.a.38415","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.38415","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,6]],"date-time":"2023-10-06T16:42:14Z","timestamp":1696610534000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.38415"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9,8]]},"references-count":14,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2017,12]]}},"alternative-id":["10.1002\/ajmg.a.38415"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.38415","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"type":"print","value":"1552-4825"},{"type":"electronic","value":"1552-4833"}],"subject":[],"published":{"date-parts":[[2017,9,8]]}}}