{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:25:14Z","timestamp":1790727914984,"version":"4.1.0"},"reference-count":28,"publisher":"National Academy of Sciences","issue":"24","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2000,11,21]]},"abstract":"<jats:p>\n                    Patients with mutations in the thyroid hormone receptor \u03b2\n (\n                    <jats:italic>TR\u03b2<\/jats:italic>\n                    ) gene manifest resistance to thyroid hormone\n (RTH), resulting in a constellation of variable phenotypic\n abnormalities. To understand the molecular basis underlying the action\n of mutant TR\u03b2\n                    <jats:italic>in vivo<\/jats:italic>\n                    , we generated mice with a\n targeted mutation in the\n                    <jats:italic>TR\u03b2<\/jats:italic>\n                    gene (\n                    <jats:italic>TR\u03b2<\/jats:italic>\n                    <jats:italic>PV<\/jats:italic>\n                    ;\n PV, mutant thyroid hormone receptor kindred PV) by using homologous\n recombination and the\n                    <jats:italic>Cre<\/jats:italic>\n                    \/\n                    <jats:italic>lox<\/jats:italic>\n                    P system.\n Mice expressing a single\n                    <jats:italic>PV<\/jats:italic>\n                    allele showed the typical\n abnormalities of thyroid function found in heterozygous humans with\n RTH. Homozygous\n                    <jats:italic>PV<\/jats:italic>\n                    mice exhibit severe dysfunction of the\n pituitary\u2013thyroid axis, impaired weight gains, and abnormal bone\n development. This phenotype is distinct from that seen in mice with a\n null mutation in the\n                    <jats:italic>TR\u03b2<\/jats:italic>\n                    gene. Importantly, we\n identified abnormal expression patterns of several genes in tissues of\n                    <jats:italic>TR\u03b2<\/jats:italic>\n                    <jats:italic>PV<\/jats:italic>\n                    mice, demonstrating the interference of the mutant\n TR with the gene regulatory functions of the wild-type TR\n                    <jats:italic>in\n vivo<\/jats:italic>\n                    . These results show that the actions of mutant and\n wild-type TR\u03b2\n                    <jats:italic>in vivo<\/jats:italic>\n                    are distinct. This model allows\n further study of the molecular action of mutant TR\n                    <jats:italic>in\n vivo<\/jats:italic>\n                    , which could lead to better treatment for RTH patients.\n                  <\/jats:p>","DOI":"10.1073\/pnas.230285997","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:40:52Z","timestamp":1027680052000},"page":"13209-13214","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":216,"title":["Mice with a targeted mutation in the thyroid hormone \u03b2 receptor gene exhibit impaired growth and resistance to thyroid hormone"],"prefix":"10.1073","volume":"97","author":[{"given":"Masahiro","family":"Kaneshige","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Biology, National Cancer Institute, and\r Genetic Disease Research Branch, National Human Genome\r Research Institute, National Institutes of Health, Bethesda, MD\r 20892; Laboratory of Genetics, The Salk Institute for\r Biological Studies, La Jolla, CA 92037; Laboratory of\r Molecular Endocrinology, Institute of Human Virology, Baltimore, MD\r 21201; Department of Medicine and Pediatrics, The\r University of Chicago, Chicago, IL 60637; and\r Department of Pathology, Wake Forest..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kumiko","family":"Kaneshige","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, National Cancer Institute, and\r Genetic Disease Research Branch, National Human Genome\r Research Institute, National Institutes of Health, Bethesda, MD\r 20892; Laboratory of Genetics, The Salk Institute for\r Biological Studies, La Jolla, CA 92037; Laboratory of\r Molecular Endocrinology, Institute of Human Virology, Baltimore, MD\r 21201; Department of Medicine and Pediatrics, The\r University of Chicago, Chicago, IL 60637; and\r Department of Pathology, Wake Forest..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu-guang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, National Cancer Institute, and\r Genetic Disease Research Branch, National Human Genome\r Research Institute, National Institutes of Health, Bethesda, MD\r 20892; Laboratory of Genetics, The Salk Institute for\r Biological Studies, La Jolla, CA 92037; Laboratory of\r Molecular Endocrinology, Institute of Human Virology, Baltimore, MD\r 21201; Department of Medicine and Pediatrics, The\r University of Chicago, Chicago, IL 60637; and\r Department of Pathology, Wake Forest..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Dace","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, National Cancer Institute, and\r Genetic Disease Research Branch, National Human Genome\r Research Institute, National Institutes of Health, Bethesda, MD\r 20892; Laboratory of Genetics, The Salk Institute for\r Biological Studies, La Jolla, CA 92037; Laboratory of\r Molecular Endocrinology, Institute of Human Virology, Baltimore, MD\r 21201; Department of Medicine and Pediatrics, The\r University of Chicago, Chicago, IL 60637; and\r Department of Pathology, Wake Forest..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Garrett","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, National Cancer Institute, and\r Genetic Disease Research Branch, National Human Genome\r Research Institute, National Institutes of Health, Bethesda, MD\r 20892; Laboratory of Genetics, The Salk Institute for\r Biological Studies, La Jolla, CA 92037; Laboratory of\r Molecular Endocrinology, Institute of Human Virology, Baltimore, MD\r 21201; Department of Medicine and Pediatrics, The\r University of Chicago, Chicago, IL 60637; and\r Department of Pathology, Wake Forest..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd A.","family":"Carter","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, National Cancer Institute, and\r Genetic Disease Research Branch, National Human Genome\r Research Institute, National Institutes of Health, Bethesda, MD\r 20892; Laboratory of Genetics, The Salk Institute for\r Biological Studies, La Jolla, CA 92037; Laboratory of\r Molecular Endocrinology, Institute of Human Virology, Baltimore, MD\r 21201; Department of Medicine and Pediatrics, The\r University of Chicago, Chicago, IL 60637; and\r Department of Pathology, Wake Forest..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rasa","family":"Kazlauskaite","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, National Cancer Institute, and\r Genetic Disease Research Branch, National Human Genome\r Research Institute, National Institutes of Health, Bethesda, MD\r 20892; Laboratory of Genetics, The Salk Institute for\r Biological Studies, La Jolla, CA 92037; Laboratory of\r Molecular Endocrinology, Institute of Human Virology, Baltimore, MD\r 21201; Department of Medicine and Pediatrics, The\r University of Chicago, Chicago, IL 60637; and\r Department of Pathology, Wake Forest..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel G.","family":"Pankratz","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, National Cancer Institute, and\r Genetic Disease Research Branch, National Human Genome\r Research Institute, National Institutes of Health, Bethesda, MD\r 20892; Laboratory of Genetics, The Salk Institute for\r Biological Studies, La Jolla, CA 92037; Laboratory of\r Molecular Endocrinology, Institute of Human Virology, Baltimore, MD\r 21201; Department of Medicine and Pediatrics, The\r University of Chicago, Chicago, IL 60637; and\r Department of Pathology, Wake Forest..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Wynshaw-Boris","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, National Cancer Institute, and\r Genetic Disease Research Branch, National Human Genome\r Research Institute, National Institutes of Health, Bethesda, MD\r 20892; Laboratory of Genetics, The Salk Institute for\r Biological Studies, La Jolla, CA 92037; Laboratory of\r Molecular Endocrinology, Institute of Human Virology, Baltimore, MD\r 21201; Department of Medicine and Pediatrics, The\r University of Chicago, Chicago, IL 60637; and\r Department of Pathology, Wake Forest..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Refetoff","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, National Cancer Institute, and\r Genetic Disease Research Branch, National Human Genome\r Research Institute, National Institutes of Health, Bethesda, MD\r 20892; Laboratory of Genetics, The Salk Institute for\r Biological Studies, La Jolla, CA 92037; Laboratory of\r Molecular Endocrinology, Institute of Human Virology, Baltimore, MD\r 21201; Department of Medicine and Pediatrics, The\r University of Chicago, Chicago, IL 60637; and\r Department of Pathology, Wake Forest..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce","family":"Weintraub","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, National Cancer Institute, and\r Genetic Disease Research Branch, National Human Genome\r Research Institute, National Institutes of Health, Bethesda, MD\r 20892; Laboratory of Genetics, The Salk Institute for\r Biological Studies, La Jolla, CA 92037; Laboratory of\r Molecular Endocrinology, Institute of Human Virology, Baltimore, MD\r 21201; Department of Medicine and Pediatrics, The\r University of Chicago, Chicago, IL 60637; and\r Department of Pathology, Wake Forest..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark C.","family":"Willingham","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, National Cancer Institute, and\r Genetic Disease Research Branch, National Human Genome\r Research Institute, National Institutes of Health, Bethesda, MD\r 20892; Laboratory of Genetics, The Salk Institute for\r Biological Studies, La Jolla, CA 92037; Laboratory of\r Molecular Endocrinology, Institute of Human Virology, Baltimore, MD\r 21201; Department of Medicine and Pediatrics, The\r University of Chicago, Chicago, IL 60637; and\r Department of Pathology, Wake Forest..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carrolee","family":"Barlow","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, National Cancer Institute, and\r Genetic Disease Research Branch, National Human Genome\r Research Institute, National Institutes of Health, Bethesda, MD\r 20892; Laboratory of Genetics, The Salk Institute for\r Biological Studies, La Jolla, CA 92037; Laboratory of\r Molecular Endocrinology, Institute of Human Virology, Baltimore, MD\r 21201; Department of Medicine and Pediatrics, The\r University of Chicago, Chicago, IL 60637; and\r Department of Pathology, Wake Forest..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheue-yann","family":"Cheng","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, National Cancer Institute, and\r Genetic Disease Research Branch, National Human Genome\r Research Institute, National Institutes of Health, Bethesda, MD\r 20892; Laboratory of Genetics, The Salk Institute for\r Biological Studies, La Jolla, CA 92037; Laboratory of\r Molecular Endocrinology, Institute of Human Virology, Baltimore, MD\r 21201; Department of Medicine and Pediatrics, The\r University of Chicago, Chicago, IL 60637; and\r Department of Pathology, Wake Forest..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2000,11,7]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1530\/eje.0.1300015"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02253060"},{"key":"e_1_3_3_3_2","first-page":"141","volume":"52","author":"Shibata H","year":"1997","unstructured":"H Shibata, T E Spencer, S A Onate, G Jenster, S Y Tsai, M J Tsai, B W O'Malley Recent Prog Horm Res 52, 141\u2013164 (1997).","journal-title":"Recent Prog Horm Res"},{"key":"e_1_3_3_4_2","first-page":"348","volume":"14","author":"Refetoff S","year":"1993","unstructured":"S Refetoff, R E Weiss, S J Usala Endocr Rev 14, 348\u2013399 (1993).","journal-title":"Endocr Rev"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1210\/jcem-73-5-990"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1210\/mend-4-12-1988"},{"key":"e_1_3_3_7_2","first-page":"1450","volume":"8","author":"Yen P M","year":"1994","unstructured":"P M Yen, W W Chin Mol Endocrinol 8, 1450\u20131454 (1994).","journal-title":"Mol Endocrinol"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1210\/mend.12.12.0201"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/17.16.4760"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF03401809"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1998.8396"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI5205"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo.140.2.6527"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1089\/thy.1999.9.1137"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115542"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00033a034"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80086-0"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.8.24.3045"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.12.5860"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1089\/thy.1999.9.1265"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1996.tb00664.x"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo.139.12.6412"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo-116-3-873"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1210\/mend.14.1.0404"},{"key":"e_1_3_3_25_2","first-page":"248","volume":"6","author":"Meier C A","year":"1992","unstructured":"C A Meier, B M Dickstein, K Ashizawa, J H McClaskey, P Muchmore, S C Ransom, J B Menke, E H Hao, S J Usala, B B Bercu, et al. 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