{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T11:28:40Z","timestamp":1784633320524,"version":"3.55.0"},"reference-count":44,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2021,4,1]],"date-time":"2021-04-01T00:00:00Z","timestamp":1617235200000},"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":[[2021,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      In humans, resistance to thyroid hormone (RTH) caused by mutations in the thyroid hormone receptor alpha (\n                      <jats:italic toggle=\"yes\">THRA<\/jats:italic>\n                      ) gene, RTH\u03b1, manifests as tissue-specific hypothyroidism and circulating thyroid hormone levels exhibit hypothyroid-like clinical features. Before the identification of patients with RTH\u03b1, several Thr\u03b11 knock-in mouse models were generated to clarify the function of TR\u03b11. However, the phenotypes of these mice were not consistent with the clinical presentation of RTH\u03b1 in humans. For the present study, we generated an RTH\u03b1 mouse model that carries the\n                      <jats:italic toggle=\"yes\">Thra1<\/jats:italic>\n                      <jats:sup>E403X<\/jats:sup>\n                      mutation found in human RTH\u03b1 patients. Here, we report the gross phenotypes of this mouse RTH\u03b1 model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      Traditional homologous recombination gene targeting techniques were used to introduce a mutation (\n                      <jats:italic toggle=\"yes\">Thra1<\/jats:italic>\n                      <jats:sup>E403X)<\/jats:sup>\n                      in the mouse\n                      <jats:italic toggle=\"yes\">Thra<\/jats:italic>\n                      gene. The phenotypes of the resulting mice were studied and compared with clinical features observed for RTH\u03b1 with\n                      <jats:italic toggle=\"yes\">\n                        THRA\n                        <jats:sup>E403X<\/jats:sup>\n                      <\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Thr\u03b11\n                      <jats:sup>E403X\/E403X<\/jats:sup>\n                      homozygous mice exhibited severe neurological phenotypes, such as spasticity and motor ataxia, which were similar to those observed in endemic cretinism. Thr\u03b11\n                      <jats:sup>E403X\/+<\/jats:sup>\n                      heterozygous mice reproduced most clinical manifestations of patient with RTH\u03b1, such as a normal survival rate and male fertility, as well as delayed postnatal growth and development, neurological and motor coordination deficits, and anemia. The mice had typical thyroid function with a modest increase in serum triiodothyronine (T3) levels, a low thyroxine (T4)\/T3 ratio, and low reverse T3 (rT3) levels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      The Thr\u03b11\n                      <jats:sup>E403X\/+<\/jats:sup>\n                      mice faithfully recapitulate the clinical features of human RTH\u03b1 and thus can provide a useful tool to dissect the role of TR\u03b11 in development and to determine the pathological mechanisms of RTH\u03b1.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1089\/thy.2019.0733","type":"journal-article","created":{"date-parts":[[2020,9,14]],"date-time":"2020-09-14T02:17:10Z","timestamp":1600049830000},"page":"678-691","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":5,"title":["Generation and Characterization of a New Resistance to Thyroid Hormone Mouse Model with Thyroid Hormone Receptor Alpha Gene Mutation"],"prefix":"10.1177","volume":"31","author":[{"given":"Yue","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism, Endocrine Institute, and Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Defa","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Endocrine Institute, and Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranran","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Endocrine Institute, and Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pingping","family":"Dang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Endocrine Institute, and Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Xi","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Endocrine Institute, and Liaoning Provincial Key Laboratory of 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