{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T11:54:55Z","timestamp":1791114895664,"version":"4.1.0"},"reference-count":22,"publisher":"National Academy of Sciences","issue":"6","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1999,3,16]]},"abstract":"\n Truncation mutations of the\n GLI3<\/jats:italic>\n zinc finger transcription factor can cause Greig cephalopolysyndactyly syndrome (GCPS), Pallister\u2013Hall syndrome (PHS), and postaxial polydactyly type A (PAP-A). GLI3 is homologous to\n Drosophila<\/jats:italic>\n Cubitus interruptus (Ci), which regulates the\n patched<\/jats:italic>\n (\n ptc<\/jats:italic>\n ),\n gooseberry<\/jats:italic>\n (\n gsb<\/jats:italic>\n ), and\n decapentaplegic<\/jats:italic>\n (\n dpp<\/jats:italic>\n ) genes. Ci is sequestered in the cytoplasm and is subject to posttranslational processing whereby the full-length transcriptional activator form (Ci\n 155<\/jats:sup>\n ) can be cleaved to a repressor form (Ci\n 75<\/jats:sup>\n ). Under hedgehog signaling, the Ci\n 155<\/jats:sup>\n form translocates to the nucleus whereas in the absence of hedgehog, the Ci\n 75<\/jats:sup>\n form translocates to the nucleus. Based on the correlation of GLI3 truncation mutations and the human phenotypes, we hypothesized that GLI3 shows transcriptional activation or repression activity and subcellular localization similar to Ci. Here we show that full-length GLI3 localizes to the cytoplasm and activates\n PTCH1<\/jats:italic>\n expression, which is similar to full-length Ci\n 155<\/jats:sup>\n . PHS mutant protein (GLI3-PHS) localizes to the nucleus and represses GLI3-activated\n PTCH1<\/jats:italic>\n expression, which is similar to Ci\n 75<\/jats:sup>\n . The GCPS mutant protein has no effect on GLI3-activated\n PTCH1<\/jats:italic>\n transcription, consistent with the role of haploinsufficiency in this disorder. The PAP-A mutant protein (GLI3-PAP-A) showed less specific subcellular localization but still inhibited GLI3-activated\n PTCH1<\/jats:italic>\n transcription, suggesting it may be a weaker allele than the GLI3-PHS mutation. These data show that\n GLI3<\/jats:italic>\n mutations in humans mimic functional effects of the\n Drosophila ci<\/jats:italic>\n gene and correlate with the distinct effects of these mutations on human development.\n <\/jats:p>","DOI":"10.1073\/pnas.96.6.2880","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:42:40Z","timestamp":1027680160000},"page":"2880-2884","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":154,"title":["GLI<\/i>\n 3<\/i>\n mutations in human disorders mimic\n Drosophila<\/i>\n Cubitus interruptus protein functions and localization"],"prefix":"10.1073","volume":"96","author":[{"given":"Sang Hoon","family":"Shin","sequence":"first","affiliation":[{"name":"National Institutes of Health, National Human Genome Research Institute, Genetic Disease Research Branch, Bethesda, MD 20892; and Karolinska Institute, Department of Bioscience, Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priit","family":"Kogerman","sequence":"additional","affiliation":[{"name":"National Institutes of Health, National Human Genome Research Institute, Genetic Disease Research Branch, Bethesda, MD 20892; and Karolinska Institute, Department of Bioscience, Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Lindstr\u00f6m","sequence":"additional","affiliation":[{"name":"National Institutes of Health, National Human Genome Research Institute, Genetic Disease Research Branch, Bethesda, MD 20892; and Karolinska Institute, Department of Bioscience, Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rune","family":"Toftg\u00e1rd","sequence":"additional","affiliation":[{"name":"National Institutes of Health, National Human Genome Research Institute, Genetic Disease Research Branch, Bethesda, MD 20892; and Karolinska Institute, Department of Bioscience, Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie G.","family":"Biesecker","sequence":"additional","affiliation":[{"name":"National Institutes of Health, National Human Genome Research Institute, Genetic Disease Research Branch, Bethesda, MD 20892; and Karolinska Institute, Department of Bioscience, Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[1999,3,16]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/352539a0"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0397-266"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1197-269"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1197-259"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.10.10.5408-5415.1990"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80292-5"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80331-1"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(98)70227-1"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80325-6"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.33.7.585"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320400403"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/6.11.1979"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81268-4"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.124.13.2537"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4773(97)00656-4"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.124.7.1313"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1089\/dna.1995.14.629"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.6.3496"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/3793"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1996.8457"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/16.13.3955"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.124.22.4523"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.96.6.2880","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T17:50:58Z","timestamp":1649872258000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.96.6.2880"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1999,3,16]]},"references-count":22,"journal-issue":{"issue":"6","published-print":{"date-parts":[[1999,3,16]]}},"alternative-id":["10.1073\/pnas.96.6.2880"],"URL":"https:\/\/doi.org\/10.1073\/pnas.96.6.2880","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[1999,3,16]]},"assertion":[{"value":"1998-12-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"1998-12-31","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"1999-03-16","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}