{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T09:30:34Z","timestamp":1790847034335,"version":"4.1.0"},"reference-count":41,"publisher":"SAGE Publications","issue":"6","license":[{"start":{"date-parts":[[2013,6,1]],"date-time":"2013-06-01T00:00:00Z","timestamp":1370044800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Thyroid\u00ae"],"published-print":{"date-parts":[[2013,6]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">NKX2-1<\/jats:italic>\n                      mutations have been described in several patients with primary congenital hypothyroidism, respiratory distress, and benign hereditary chorea, which are classical manifestations of the brain\u2013thyroid\u2013lung syndrome (BTLS).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic toggle=\"yes\">NKX2-1<\/jats:italic>\n                      gene was sequenced in the members of a Brazilian family with clinical features of BTLS, and a novel monoallelic mutation was identified in the affected patients. We introduced the mutation in an expression vector for the functional characterization by transfection experiments using both thyroidal and lung-specific promoters.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      The mutation is a deletion of a cytosine at position 834 (ref. sequence NM_003317) (c.493delC) that causes a frameshift with formation of an abnormal protein from amino acid 165 and a premature stop at position 196. The last amino acid of the nuclear localization signal, the whole homeodomain, and the carboxy-terminus of NKX2-1 are all missing in the mutant protein, which has a premature stop codon at position 196 (p.Arg165Glyfs*32). The p.Arg165Glyfs*32 mutant does not bind DNA, and it is unable to transactivate the thyroglobulin (Tg) and the surfactant protein-C (SP-C) promoters. Interestingly, a dose-dependent dominant negative effect of the p.Arg165Glyfs*32 was demonstrated only on the Tg promoter, but not on the SP-C promoter. This effect was also noticed when the mutation was tested in presence of PAX8 or cofactors that synergize with NKX2-1 (P300 and TAZ). The functional effect was also compared with the data present in the literature and demonstrated that, so far, it is very difficult to establish a specific correlation among\n                      <jats:italic toggle=\"yes\">NKX2-1<\/jats:italic>\n                      mutations, their functional consequence, and the clinical phenotype of affected patients, thus suggesting that the detailed mechanisms of transcriptional regulation still remain unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      We describe a novel\n                      <jats:italic toggle=\"yes\">NKX2-1<\/jats:italic>\n                      mutation and demonstrate that haploinsufficiency may not be the only explanation for BTLS. Our results indicate that NKX2-1 activity is also finely regulated in a tissue-specific manner, and additional studies are required to better understand the complexities of genotype\u2013phenotype correlations in the NKX2-1 deficiency syndrome.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1089\/thy.2012.0267","type":"journal-article","created":{"date-parts":[[2013,2,4]],"date-time":"2013-02-04T13:20:41Z","timestamp":1359984041000},"page":"675-682","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":34,"title":["Identification and Functional Characterization of a Novel Mutation in the\n                    <i>NKX2-1<\/i>\n                    Gene: Comparison with the Data in the Literature"],"prefix":"10.1177","volume":"23","author":[{"given":"Immacolata Cristina","family":"Nettore","sequence":"first","affiliation":[{"name":"University of Naples \u201cFederico II\u201d","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Mirra","sequence":"additional","affiliation":[{"name":"University of Naples \u201cFederico II\u201d","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfonso Massimiliano","family":"Ferrara","sequence":"additional","affiliation":[{"name":"University of Naples \u201cFederico II\u201d","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annarita","family":"Sibilio","sequence":"additional","affiliation":[{"name":"University of Naples \u201cFederico II\u201d","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Pagliara","sequence":"additional","affiliation":[{"name":"University of Naples \u201cFederico II\u201d","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia Suemi Kamoi","family":"Kay","sequence":"additional","affiliation":[{"name":"Parana Federal University","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulo Jos\u00e8","family":"Lorenzoni","sequence":"additional","affiliation":[{"name":"Parana Federal University","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lineu Cesar","family":"Werneck","sequence":"additional","affiliation":[{"name":"Parana Federal University","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isac","family":"Bruck","sequence":"additional","affiliation":[{"name":"Parana Federal University","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia Helena Coutinho","family":"dos Santos","sequence":"additional","affiliation":[{"name":"Parana Federal 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