{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T06:24:57Z","timestamp":1777875897056,"version":"3.51.4"},"reference-count":31,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T00:00:00Z","timestamp":1675209600000},"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":[[2023,2]]},"abstract":"\n Background:<\/jats:title>\n \n Mutations of thyroid hormone receptor \u03b1 (TR\u03b11) result in resistance to thyroid hormone (RTH\u03b1), exhibiting symptoms of retarded growth, delayed bone maturation, anemia, and severe constipation. Using a mouse model of RTH\u03b1 (\n \n Thra1\n PV\/+<\/jats:sup>\n <\/jats:italic>\n mouse), we aimed at understanding the molecular basis underlying the severe constipation observed in patients.\n <\/jats:p>\n <\/jats:sec>\n \n Methods:<\/jats:title>\n \n The\n \n Thra1\n PV\/+<\/jats:sup>\n <\/jats:italic>\n mouse expresses a strong dominant negative mutant, PV, which has lost T3 binding and transcription activity.\n \n Thra1\n PV\/+<\/jats:sup>\n <\/jats:italic>\n mouse faithfully reproduces growth abnormalities and anemia as shown in RTH\u03b1 patients and therefore is a valid model to examine causes of severe constipation in patients. We used histopathological analysis, confocal fluorescence imaging, transmission electron microscopy (TEM), and gene expression profiles to comprehensively analyze the colonic abnormalities of\n \n Thra1\n PV\/+<\/jats:sup>\n <\/jats:italic>\n mouse.\n <\/jats:p>\n <\/jats:sec>\n \n Results:<\/jats:title>\n \n We found a significant increase in colonic transit time and decrease stool water content in\n \n Thra1\n PV\/+<\/jats:sup>\n <\/jats:italic>\n mouse, mimicking constipation as found in patients. Histopathological analysis showed expanded lamina propria filled with interstitium fluid between crypt columns, enlarged muscularis mucosa, and increased content of collagen in expanded submucosa. The TEM analysis revealed shorter muscle fibers with wider gap junctions between muscle cells, fewer caveolae, and hypoplastic interstitial cells of Cajal (ICC) in the rectal smooth muscles of\n \n Thra1\n PV\/+<\/jats:sup>\n <\/jats:italic>\n mice. These abnormal histological manifestations suggested defective intercellular transfer of small molecules, electrolytes, and signals for communication among muscles cells, validated by Lucifer Yellow transferring assays. Expression of key smooth muscle contractility regulators, such as calmodulin, myosin light-chain kinase, and phosphorylated myosin light chain, was markedly lower, and c-KIT signaling in ICC was attenuated, resulting in decreased contractility of the rectal smooth muscles of\n \n Thra1\n PV\/+<\/jats:sup>\n <\/jats:italic>\n mice. Collectively, these abnormal histopathological alterations and diminished contractility regulators led to the constipation exhibited in patients.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions:<\/jats:title>\n This is the first demonstration that TR\u03b11 mutants could act to cause abnormal rectum smooth muscle organization, defects in intercellular exchange of small molecules, and decreased expression of contractility regulators to weaken the contractility of rectal smooth muscles. These findings provide new insights into the molecular basis underlying constipation found in RTH\u03b1 patients.<\/jats:p>\n <\/jats:sec>","DOI":"10.1089\/thy.2022.0336","type":"journal-article","created":{"date-parts":[[2022,9,14]],"date-time":"2022-09-14T13:13:27Z","timestamp":1663161207000},"page":"239-250","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":6,"title":["Morphological and Functional Colonic Defects Caused by a Mutated Thyroid Hormone Receptor \u03b1"],"prefix":"10.1177","volume":"33","author":[{"given":"Minjun","family":"Kim","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Kruhlak","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoria","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Office of Research Services, Diagnostic and Research Services Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia","family":"Zerfas","sequence":"additional","affiliation":[{"name":"Office of Research Services, Diagnostic and Research Services Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"Bishop","sequence":"additional","affiliation":[{"name":"Translational and Functional Genomics Branch, National Human Genome Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6737-3173","authenticated-orcid":false,"given":"Woo Kyung Lee","family":"Doolittle","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elijah F.","family":"Edmondson","sequence":"additional","affiliation":[{"name":"Molecular Histopathology Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuelin Jack","family":"Zhu","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheue-yann","family":"Cheng","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 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