{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T11:46:18Z","timestamp":1785757578498,"version":"3.56.0"},"reference-count":28,"publisher":"National Academy of Sciences","issue":"19","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2013,5,7]]},"abstract":"<jats:p>\n                    Genetic evidence from patients with mutations of the thyroid hormone receptor \u03b1 gene (\n                    <jats:italic>THRA<\/jats:italic>\n                    ) indicates that the dominant negative activity of mutants underlies the pathological manifestations. However, the molecular mechanisms by which TR\u03b11 mutants exert dominant negative activity in vivo are not clear. We tested the hypothesis that the severe hypothyroidism in patients with\n                    <jats:italic>THRA<\/jats:italic>\n                    mutations is due to an inability of TR\u03b11 mutants to properly release the nuclear corepressors (NCORs), thereby inhibiting thyroid hormone-mediated transcription activity. We crossed\n                    <jats:italic>Thra1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>PV<\/jats:italic>\n                    <\/jats:sup>\n                    mice, expressing a dominant negative TR\u03b11 mutant (TR\u03b11PV), with mice expressing a mutant\n                    <jats:italic>Ncor1<\/jats:italic>\n                    allele (\n                    <jats:italic>Ncor1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u0394ID<\/jats:italic>\n                    <\/jats:sup>\n                    mice) that cannot recruit the TR or PV mutant. TR\u03b11PV shares the same C-terminal mutated sequences as those of patients with frameshift mutations of the\n                    <jats:italic>THRA<\/jats:italic>\n                    gene. Remarkably, NCOR1\u0394ID ameliorated abnormalities in the thyroid-pituitary axis of\n                    <jats:italic>Thra1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>PV\/+<\/jats:italic>\n                    <\/jats:sup>\n                    mice. The severe retarded growth, infertility, and delayed bone development were partially reverted in\n                    <jats:italic>Thra1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>PV\/+<\/jats:italic>\n                    <\/jats:sup>\n                    mice expressing NCOR1\u0394ID. The impaired adipogenesis was partially corrected by de-repression of peroxisome-proliferator activated receptor \u03b3 and CCAAT\/enhancer-binding protein \u03b1 gene, due to the inability of TR\u03b11PV to recruit NCOR1\u0394ID to form a repressor complex. Thus, the aberrant recruitment of NCOR1 by TR\u03b11 mutants could lead to clinical hypothyroidism in humans. Therefore, therapies aimed at the TR\u03b11\u2013NCOR1 interaction or its downstream actions could be tested as potential targets in treating TR\u03b11 mutant-mediated hypothyroidism in patients.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1222334110","type":"journal-article","created":{"date-parts":[[2013,4,23]],"date-time":"2013-04-23T03:10:22Z","timestamp":1366686622000},"page":"7850-7855","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":42,"title":["Nuclear receptor corepressor (NCOR1) regulates in vivo actions of a mutated thyroid hormone receptor \u03b1"],"prefix":"10.1073","volume":"110","author":[{"given":"Laura","family":"Fozzatti","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong Wook","family":"Kim","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong Won","family":"Park","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark C.","family":"Willingham","sequence":"additional","affiliation":[{"name":"Department of Pathology, Wake Forest University, Winston-Salem, NC 27157; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony N.","family":"Hollenberg","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism and Diabetes, Beth Israel Medical Center, Harvard Medical School, Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheue-Yann","family":"Cheng","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2013,4,22]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1010052101214"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2011.04.021"},{"key":"e_1_3_3_3_2","first-page":"348","article-title":"The syndromes of resistance to thyroid hormone","volume":"14","author":"Refetoff S","year":"1993","unstructured":"S Refetoff, RE Weiss, SJ Usala, The syndromes of resistance to thyroid hormone. 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