ArticleJCI insight2021
Thyroid hormone synthesis continues despite biallelic thyroglobulin mutation with cell death.
Article in JCI insight, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 18 citations in OpenAlex.
- Article
- Substrate for Thyroid Hormone Synthesis: Biochemistry, Evolution, and Physiology.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Review
- Thyroid Hormone Synthesis Without Thyroglobulin.Thyroid : official journal of the American Thyroid Association · 2026Article
- Thyroidal expression of ER molecular chaperone GRP170 is required for efficient TSH-mediated thyroid hormone synthesis.JCI insight · 2025Article
- A Genetically-Engineered Thyroid Gland Built for Selective Triiodothyronine Secretion.International journal of molecular sciences · 2025Article
- CRABP1 Signalosomes in Non-Canonical Actions of Retinoic Acid-Maintaining Health and Preventing Thyroid Dysfunction in Aging.Endocrines · 2025Article
- Genetics of primary congenital hypothyroidism: three decades of discoveries and persisting etiological challenges.European thyroid journal · 2025Review
- Lactoferrin alleviates oxidative stress and endoplasmic reticulum stress induced by autoimmune thyroiditis by modulating the mTOR pathway in the thyroid.Journal of endocrinological investigation · 2025Article
- Molecular detection of a novel mutation in theJournal of advanced veterinary and animal research · 2024Article
- Towards translating in vitro measures of thyroid hormone system disruption to in vivo responses in the pregnant rat via a biologically based dose response (BBDR) model.Toxicology and applied pharmacology · 2023Article
- Perturbation of endoplasmic reticulum proteostasis triggers tissue injury in the thyroid gland.JCI insight · 2023Article
- The p.Pro2232Leu variant in the ChEL domain of thyroglobulin gene causes intracellular transport disorder and congenital hypothyroidism.Endocrine · 2023Article
- Defective Thyroglobulin: Cell Biology of Disease.International journal of molecular sciences · 2022Review
- Article
- Editorial: Hydrogen sulfide: Physiology, Pharmacology and Toxicology, Volume II.Frontiers in pharmacology · 2022Article
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 3 countries.
Funding
Abstract
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 TGW2346R/W2346R humans, TGcog/cog mice, and TGrdw/rdw 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 TGrdw/rdw 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 TGrdw/rdw 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.