Thyroid Hormone Synthesis Continues Despite Biallelic Thyroglobulin Mutation with Cell Death

Authors

Xiaohan Zhang, University of Michigan, Ann Arbor
Aaron P. Kellogg, University of Michigan, Ann Arbor
Cintia E. Citterio, Chapman UniversityFollow
Hao Zhang, University of Michigan, Ann Arbor
Dennis Larkin, University of Michigan, Ann Arbor
Yoshiaki Morishita, University of Michigan, Ann Arbor
Héctor M. Targovnik, Universidad de Buenos Aires
Viviana A. Balbi, Hospital de Niños Sor María Ludovica
Peter Arvan, University of Michigan, Ann Arbor

Document Type

Article

Publication Date

4-26-2021

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.

Comments

This article was originally published in JCI Insight, volume 6, issue 11, in 2021. https://doi.org/10.1172/jci.insight.148496

Recommended Citation

X. Zhang, A. P. Kellogg, C. E. Citterio, H. Zhang, D. Larkin, Y. Morishita, H. M. Targovnik, V. Balbi, and P. Arvan. Thyroid hormone synthesis continues despite biallelic thyroglobulin mutation with cell death. JCI Insight. 2021;26(11):e148496. https://doi.org/10.1172/jci.insight.148496

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