{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T15:32:41Z","timestamp":1793287961315,"version":"4.5.0"},"reference-count":50,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"National Institute of Diabetes and Digestive and Kidney Diseases","award":["F30DK139717"],"award-info":[{"award-number":["F30DK139717"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute of Diabetes and Digestive and Kidney Diseases","award":["R01DK132017"],"award-info":[{"award-number":["R01DK132017"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute of Diabetes and Digestive and Kidney Diseases","award":["R01DK15070"],"award-info":[{"award-number":["R01DK15070"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Thyroid\u00ae"],"published-print":{"date-parts":[[2026,4,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      Heterozygosity of genetically encoded misfolded mutant thyroglobulin (TG, the thyroid hormone protein precursor) occurs with a frequency estimated at 1-in-217 people worldwide, resulting in subclinical hypothyroidism that largely escapes medical detection. However, patients carrying biallelic\n                      <jats:italic toggle=\"yes\">TG<\/jats:italic>\n                      mutation, when untreated, are frankly hypothyroid unless and until they develop a massive goiter. To date, TG is the only proven endogenous precursor protein for thyroid hormone synthesis in vertebrates. Our objective was to understand how homozygous expression of mutant TG protein that cannot undergo secretion to the iodination site in the thyroid follicle lumen can be compatible with patients or animal models ultimately achieving normal\/near-normal circulating T4 and T3 levels. Notably, in both monoallelic and biallelic disease, dead thyrocytes have been reported in the lumen of thyroid follicles.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      We recently engineered mice with homozygous\n                      <jats:italic toggle=\"yes\">Tg-KO<\/jats:italic>\n                      , making it possible to study circulating T4 and T3 in the complete absence of TG protein expression. We also employed immunoblotting methods to test for the presence of thyroidal T4-containing and T3-containing protein.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      We found that, concomitant with goiter growth, animals completely lacking TG (like patients or animals with biallelic\n                      <jats:italic toggle=\"yes\">TG<\/jats:italic>\n                      defect) are able to eventually normalize circulating T4 levels when their goiter has sufficiently enlarged, while maintaining serum T3 at \u223ctwo-thirds normal levels throughout life. Very little T3-containing protein is synthesized in the thyroid glands of\n                      <jats:italic toggle=\"yes\">Tg-KO<\/jats:italic>\n                      mice; however, T4-containing protein is synthesized on the ghosts of dead thyrocytes, with T3 generated from circulating T4 deiodination. Albeit inefficient, thyroidal T4-containing protein content is not appreciably different in the presence of homozygous mutant TG or in the complete absence of TG.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>Our data suggest that in biallelic TG mutation, thyroid stimulating hormone (TSH)-driven iodination underlies inefficient T4 formation derived from the iodoproteome of dead thyrocytes. In the presence of homozygous mutant TG or in the complete absence of TG, normalizing circulating T4 requires massive goiter growth to generate sufficient cells to sustain this inefficient hormonogenesis mechanism.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/10507256261429120","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T10:38:57Z","timestamp":1773225537000},"page":"441-450","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["Thyroid Hormone Synthesis Without Thyroglobulin"],"prefix":"10.1177","volume":"36","author":[{"given":"Crystal","family":"Young","sequence":"first","affiliation":[{"name":"Division of Metabolism, Endocrinology &amp; Diabetes, University of Michigan, Ann Arbor, Michigan, USA."},{"name":"Department of Molecular &amp; Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology &amp; Diabetes, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron P.","family":"Kellogg","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology &amp; Diabetes, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana L.","family":"Fonseca","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Pena","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology &amp; Diabetes, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alisa","family":"Beyzin","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology &amp; Diabetes, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Hui","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Chicago, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annunziata G.","family":"Cicatiello","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology &amp; Diabetes, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio C.","family":"Bianco","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Refetoff","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Chicago, Chicago, Illinois, USA."},{"name":"Department of Pediatrics and Committee on Genetics, The University of Chicago, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4007-8799","authenticated-orcid":false,"given":"Peter","family":"Arvan","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology &amp; Diabetes, University of Michigan, Ann Arbor, Michigan, USA."},{"name":"Department of Molecular &amp; Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,3,9]]},"reference":[{"key":"e_1_3_3_2_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.194445"},{"key":"e_1_3_3_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2016.174"},{"key":"e_1_3_3_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-024-00986-0"},{"key":"e_1_3_3_5_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2013-1813"},{"key":"e_1_3_3_6_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2009-0041"},{"key":"e_1_3_3_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-019-0184-8"},{"key":"e_1_3_3_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2024.108026"},{"key":"e_1_3_3_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.719047"},{"key":"e_1_3_3_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-1995-4"},{"key":"e_1_3_3_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27693-8"},{"key":"e_1_3_3_12_1","doi-asserted-by":"publisher","DOI":"10.1107\/S2059798321010056"},{"key":"e_1_3_3_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-30082-4"},{"key":"e_1_3_3_14_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2015-1090"},{"key":"e_1_3_3_15_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232113605"},{"key":"e_1_3_3_16_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.148496"},{"issue":"4","key":"e_1_3_3_17_1","first-page":"1438","article-title":"Two novel cysteine substitutions (C1263R and C1995S) of thyroglobulin cause a defect in intracellular transport of thyroglobulin in patients with congenital goiter and the variant type of adenomatous goiter","volume":"84","author":"Hishinuma A","year":"1999","unstructured":"16.Hishinuma A, , Takamatsu J, , Ohyama Y, et al. Two novel cysteine substitutions (C1263R and C1995S) of thyroglobulin cause a defect in intracellular transport of thyroglobulin in patients with congenital goiter and the variant type of adenomatous goiter. 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Thyroid albumin originates from blood. Endocrinology 1992;131(2):578\u2013584.","journal-title":"Endocrinology"},{"key":"e_1_3_3_48_1","doi-asserted-by":"publisher","DOI":"10.1210\/endo.137.2.8593798"},{"issue":"10","key":"e_1_3_3_49_1","first-page":"1097","article-title":"[Iodine metabolism in chronic thyroiditis. 2. Studies on the iodinated albumin-like proteins in the serum and the thyroid tissue in chronic thyroiditis]","volume":"46","author":"Morita R","year":"1971","unstructured":"48.Morita R. [Iodine metabolism in chronic thyroiditis. 2. Studies on the iodinated albumin-like proteins in the serum and the thyroid tissue in chronic thyroiditis]. 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