{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T09:34:54Z","timestamp":1793266494350,"version":"4.5.0"},"reference-count":39,"publisher":"SAGE Publications","issue":"11","license":[{"start":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:00:00Z","timestamp":1789862400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"Institute of Genetics","award":["PJT-152870"],"award-info":[{"award-number":["PJT-152870"]}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Thyroid\u00ae"],"published-print":{"date-parts":[[2026,11,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      Resistance to thyroid hormone \u03b1 (RTH\u03b1) is a rare disorder caused by pathogenic\n                      <jats:italic toggle=\"yes\">THRA<\/jats:italic>\n                      variants. We investigated the molecular basis of RTH\u03b1 in a child with developmental delay, dysmorphic features, and a suggestive biochemical profile.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      Whole-exome sequencing identified a\n                      <jats:italic toggle=\"yes\">de novo THRA<\/jats:italic>\n                      variant. Cell-based transcriptional assays assessed thyroid hormone responsiveness, coactivator dependence, and dominant-negative activity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      A novel heterozygous frameshift variant, c.1125_1132dup (p.Gly378Alafs*2), truncating the ligand-binding domain, was identified. The mutant receptor showed markedly impaired responses to triiodothyronine (T3) and TRIAC. CBP\/p300 and PGC1\u03b1 failed to activate the variant, supporting loss of function. Co-expression studies demonstrated strong inhibition of wild-type\n                      <jats:italic toggle=\"yes\">THRA<\/jats:italic>\n                      activity that was not rescued by high T3 concentrations, indicating a potent dominant-negative effect. Disruption of DNA binding abolished this interference, showing that DNA occupancy is required.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      These findings expand the spectrum of pathogenic\n                      <jats:italic toggle=\"yes\">THRA<\/jats:italic>\n                      variants and provide new insight into transcriptional repression in RTH\u03b1.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/10507256261490862","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T05:27:46Z","timestamp":1789968466000},"page":"1267-1274","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional Characterization of a Novel Variant of the Thyroid Hormone Receptor Alpha in a Child with Developmental Delay and Abnormal Thyroid Function"],"prefix":"10.1177","volume":"36","author":[{"given":"V\u00e9ronique","family":"Caron","sequence":"first","affiliation":[{"name":"Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montr\u00e9al, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3393-5625","authenticated-orcid":false,"given":"Katherine","family":"Bonnycastle","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Genetics Service, Centre Hospitalier Universitaire Sainte-Justine, Montr\u00e9al, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2220-5849","authenticated-orcid":false,"given":"Agathe","family":"Rio","sequence":"additional","affiliation":[{"name":"Endocrinology Service, Centre Hospitalier Universitaire Sainte-Justine, Montr\u00e9al, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyne","family":"Chiniara","sequence":"additional","affiliation":[{"name":"Endocrinology Service, Centre Hospitalier Universitaire Sainte-Justine, Montr\u00e9al, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e9lanie","family":"Henderson","sequence":"additional","affiliation":[{"name":"Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montr\u00e9al, Quebec, Canada."},{"name":"Department of Pediatrics, Universit\u00e9 de Montr\u00e9al, Montreal, Quebec, Canada."},{"name":"Department of Social and Preventive Medicine, School of Public Health, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy","family":"Van Vliet","sequence":"additional","affiliation":[{"name":"Endocrinology Service, Centre Hospitalier Universitaire Sainte-Justine, Montr\u00e9al, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9","family":"Tremblay","sequence":"additional","affiliation":[{"name":"Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montr\u00e9al, Quebec, Canada."},{"name":"Department of Obstetrics and Gynecology, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Quebec, Canada."},{"name":"Department of Biochemistry and Molecular Medicine, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1317-8267","authenticated-orcid":false,"given":"Fabien","family":"Magne","sequence":"additional","affiliation":[{"name":"Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montr\u00e9al, Quebec, Canada."},{"name":"Department of Clinical Biochemistry, Centre Hospitalier Universitaire Sainte-Justine, Montr\u00e9al, Quebec, 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