{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T19:13:05Z","timestamp":1787166785544,"version":"build-2736575974"},"reference-count":79,"publisher":"American Society for Clinical Investigation","issue":"11","license":[{"start":{"date-parts":[[2021,6,8]],"date-time":"2021-06-08T00:00:00Z","timestamp":1623110400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["R01 DK40344"],"award-info":[{"award-number":["R01 DK40344"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100002608","name":"American Thyroid Association","doi-asserted-by":"crossref","award":["2018-012.R1"],"award-info":[{"award-number":["2018-012.R1"]}],"id":[{"id":"10.13039\/100002608","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute for Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["R01 DK48280"],"award-info":[{"award-number":["R01 DK48280"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,6,8]]},"abstract":"<jats:p>\n                    Complete absence of thyroid hormone is incompatible with life in vertebrates. Thyroxine is synthesized within thyroid follicles upon iodination of thyroglobulin conveyed from the endoplasmic reticulum (ER), via the Golgi complex, to the extracellular follicular lumen. In congenital hypothyroidism from biallelic thyroglobulin mutation, thyroglobulin is misfolded and cannot advance from the ER, eliminating its secretion and triggering ER stress. Nevertheless, untreated patients somehow continue to synthesize sufficient thyroxine to yield measurable serum levels that sustain life. Here, we demonstrate that\n                    <jats:italic>\n                      TG\n                      <jats:sup>W2346R\/W2346R<\/jats:sup>\n                    <\/jats:italic>\n                    humans,\n                    <jats:italic>\n                      TG\n                      <jats:sup>cog\/cog<\/jats:sup>\n                    <\/jats:italic>\n                    mice, and\n                    <jats:italic>\n                      TG\n                      <jats:sup>rdw\/rdw<\/jats:sup>\n                    <\/jats:italic>\n                    rats exhibited no detectable ER export of thyroglobulin, accompanied by severe thyroidal ER stress and thyroid cell death. Nevertheless, thyroxine was synthesized, and brief treatment of\n                    <jats:italic>\n                      TG\n                      <jats:sup>rdw\/rdw<\/jats:sup>\n                    <\/jats:italic>\n                    rats with antithyroid drug was lethal to the animals. When untreated, remarkably, thyroxine was synthesized on the mutant thyroglobulin protein, delivered via dead thyrocytes that decompose within the follicle lumen, where they were iodinated and cannibalized by surrounding live thyrocytes. As the animals continued to grow goiters, circulating thyroxine increased. However, when\n                    <jats:italic>\n                      TG\n                      <jats:sup>rdw\/rdw<\/jats:sup>\n                    <\/jats:italic>\n                    rats age, they cannot sustain goiter growth that provided the dying cells needed for ongoing thyroxine synthesis, resulting in profound hypothyroidism. These results establish a disease mechanism wherein dead thyrocytes support organismal survival.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.148496","type":"journal-article","created":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T12:00:50Z","timestamp":1619697650000},"source":"Crossref","is-referenced-by-count":8,"title":["Thyroid hormone synthesis continues despite biallelic thyroglobulin mutation with cell death"],"prefix":"10.1172","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8263-6904","authenticated-orcid":true,"given":"Xiaohan","family":"Zhang","sequence":"first","affiliation":[{"name":"Division of Metabolism, Endocrinology and 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 and Diabetes, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3547-5458","authenticated-orcid":true,"given":"Cintia E.","family":"Citterio","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan, USA."},{"name":"Universidad de Buenos Aires, Facultad de Farmacia y Bioqu\u00edmica, Departamento de Microbiolog\u00eda, Inmunolog\u00eda, Biotecnolog\u00eda y Gen\u00e9tica\/C\u00e1tedra de Gen\u00e9tica, Buenos Aires, Argentina."},{"name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas, Universidad de Buenos Aires, Instituto de Inmunolog\u00eda, Gen\u00e9tica y Metabolismo, Buenos Aires, Argentina."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Larkin","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4733-7981","authenticated-orcid":true,"given":"Yoshiaki","family":"Morishita","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan, USA."},{"name":"Division of Diabetes, Department of Internal Medicine, Aichi Medical University, Nagakute, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9ctor M.","family":"Targovnik","sequence":"additional","affiliation":[{"name":"Universidad de Buenos Aires, Facultad de Farmacia y Bioqu\u00edmica, Departamento de Microbiolog\u00eda, Inmunolog\u00eda, Biotecnolog\u00eda y Gen\u00e9tica\/C\u00e1tedra de Gen\u00e9tica, Buenos Aires, Argentina."},{"name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas, Universidad de Buenos Aires, Instituto de Inmunolog\u00eda, Gen\u00e9tica y Metabolismo, Buenos Aires, Argentina."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviana A.","family":"Balbi","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Growth, Hospital de Ni\u00f1os Sor Mar\u00eda Ludovica, La Plata, Argentina."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4007-8799","authenticated-orcid":true,"given":"Peter","family":"Arvan","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2021,6,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.719047"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1210\/er.2015-1090"},{"key":"B3","doi-asserted-by":"crossref","first-page":"S0303","DOI":"10.1016\/j.mce.2017.01.038","article-title":"Thyroid hormone biosynthesis and release","volume":"458","author":"Carvalho","year":"2017","journal-title":"Mol Cell Endocrinol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S0300-9084(99)80102-3"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1210\/endo-90-6-1417"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1210\/endo-100-4-1129"},{"key":"B7"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-1995-4"},{"key":"B9","doi-asserted-by":"crossref","DOI":"10.1016\/j.mce.2020.111124","article-title":"A novel mutation in intron 11 donor splice site, responsible of a rare genotype in thyroglobulin gene by altering the pre-mRNA splicing process. Cell expression and bioinformatic analysis","volume":"522","author":"Pio","year":"2021","journal-title":"Mol Cell Endocrinol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-019-0184-8"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.111641"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M806898200"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1172\/JCI35164"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.001786"},{"key":"B15","doi-asserted-by":"crossref","first-page":"S0303","DOI":"10.1016\/j.mce.2017.12.009","article-title":"Molecular analysis of thyroglobulin mutations found in patients with goiter and hypothyroidism","volume":"473","author":"Siffo","year":"2018","journal-title":"Mol Cell Endocrinol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-018-0588-7"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2013-1891"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1097\/00005792-192411000-00002"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1007\/s00405-018-4915-6"},{"key":"B20","unstructured":"Maenhaut C, et al. Ontogeny, anatomy, metabolism and physiology of the thyroid. In: Feingold KR, et al. eds. Endotext. South Dartmouth (MA): MDText.com, Inc; 2000. https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK285554\/ Accessed May 5, 2021"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1079\/BJN20051581"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1210\/endo-87-2-339"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-002-0680-z"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1507\/endocrj.45.315"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.2009.03621.x"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1007\/s00431-013-1976-9"},{"key":"B27","unstructured":"Medeiros-Neto G. Thyroxine poisoning. In: Feingold KR, et al. eds. Endotext. South Dartmouth (MA): MDText.com, Inc; 2000. https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK279036\/ Accessed May 5, 2021"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.1995.tb01886.x"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/ncb0311-184"},{"key":"B30","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms11422","article-title":"miR-216b regulation of c-Jun mediates GADD153\/CHOP-dependent apoptosis","volume":"7","author":"Xu","year":"2016","journal-title":"Nat Commun"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/nature17041"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/febs.13755"},{"issue":"pt b","key":"B33","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1016\/j.brainres.2016.04.042","article-title":"ER stress and Parkinson\u2019s disease: Pathological inputs that converge into the secretory pathway","volume":"1648","author":"Mercado","year":"2016","journal-title":"Brain Res"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-012513-104649"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1677\/jme.0.0320903"},{"issue":"5","key":"B36","first-page":"496","article-title":"Evaluation and characterization of congenital hypothyroidism in rdw dwarf rats","volume":"48","author":"Umezu","year":"1998","journal-title":"Lab Anim Sci"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.17.9909"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.133.3.517"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119112"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M608863200"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1677\/joe.0.1260051"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.jhered.a110492"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1006\/abbi.1993.1038"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1006\/abbi.1996.0093"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)98913-1"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0854.2009.00948.x"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.02.016"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.281337"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00194.2018"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201802366RR"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA120.012656"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.24923"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M212074200"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2738"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1250704"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3253"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1038\/nature11714"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0086057"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/0303-7207(91)90214-D"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0185(20000501)259:1<60::AID-AR7>3.0.CO;2-F"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1262\/jrd.50.675"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-169x.2004.00748.x"},{"issue":"2","key":"B63","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/BF00219074","article-title":"Immunocytochemical localization of aminopeptidase N on the cell surface of isolated porcine thyroid follicles","volume":"250","author":"Nilsson","year":"1987","journal-title":"Cell Tissue Res"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.6.2478"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1210\/endo.141.11.7794"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.07.002"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2015.0523"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1016\/S0034-5288(18)34558-2"},{"issue":"1","key":"B69","first-page":"24","article-title":"Congenital hypothyroid Pax8(-\/-) mutant mice can be rescued by inactivating the TRalpha gene","volume":"16","author":"Flamant","year":"2002","journal-title":"Mol Endocrinol"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1507\/endocrj.EJ16-0005"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.84.7.5862"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2003-030587"},{"issue":"1-2","key":"B73","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1515\/jpem-2012-0287","article-title":"A clinically euthyroid child with a large goiter due to a thyroglobulin gene defect: clinical features and genetic studies","volume":"26","author":"Hermanns","year":"2013","journal-title":"J Pediatr Endocrinol Metab"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1677\/joe.0.0940131"},{"issue":"4","key":"B75","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1530\/eje.0.1490247","article-title":"Primary congenital hypothyroidism: defects in iodine pathways","volume":"149","author":"de Vijlder","year":"2003","journal-title":"Eur J Endocrinol"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.97.3.607"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1089\/thy.1997.7.89"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1002\/art.38878"},{"key":"B79"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/148496\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:32:17Z","timestamp":1779150737000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/148496"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,8]]},"references-count":79,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,6,8]]},"published-print":{"date-parts":[[2021,6,8]]}},"alternative-id":["10.1172\/jci.insight.148496"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.148496","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,8]]},"article-number":"e148496"}}