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Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors.

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The thyroid gland secretes primarily tetraiodothyronine (T), and some triiodothyronine (T). Under normal physiological circumstances, only one-fifth of circulating T is directly released by the thyroid, but in states of hyperactivation of thyroid-stimulating hormone receptors (TSHRs), patients develop a syndrome of relative T toxicosis. Thyroidal T production results from iodination of thyroglobulin (TG) at residues Tyr and Tyr, whereas thyroidal T production may originate in several different ways. In this study, the data demonstrate that within the carboxyl-terminal portion of mouse TG, T is formed independently of deiodination from T We found that upon iodination , T formation in TG was decreased in mice lacking TSHRs. Conversely, T that can be formed upon iodination of TG secreted from PCCL3 (rat thyrocyte) cells was augmented from cells previously exposed to increased TSH, a TSHR agonist, a cAMP analog, or a TSHR-stimulating antibody. We present data suggesting that TSH-stimulated TG phosphorylation contributes to enhanced T formation. These effects were reversed within a few days after removal of the hyperstimulating conditions. Indeed, direct exposure of PCCL3 cells to human serum from two patients with Graves' disease, but not control sera, led to secretion of TG with an increased intrinsic ability to form T upon iodination. Furthermore, TG secreted from human thyrocyte cultures hyperstimulated with TSH also showed an increased intrinsic ability to form T Our data support the hypothesis that TG processing in the secretory pathway of TSHR-hyperstimulated thyrocytes alters the structure of the iodination substrate in a way that enhances T formation, contributing to the relative T toxicosis of Graves' disease.

Human thyroglobulin (TG) gene is a single copy gene, 270 kb long, that maps on chromosome 8q24.2–8q24.3 and contains an 8.5-kb coding sequence divided into 48 exons. TG is exclusively synthesized in the thyroid gland and represents a highly specialized homodimeric glycoprotein for thyroid hormone biosynthesis. Mutations in the TG gene lead to permanent congenital hypothyroidism. The presence of low TG level and also normal perchlorate discharge test in a goitrous individual suggest a TG gene defect. Until now, 52 mutations have been identified and characterized in the human TG gene with functional impact such as structural changes in the protein that alter the normal protein folding, assembly and biosynthesis of thyroid hormones. 11 of the mutations affect splicing sites, 11 produce premature stop codons, 23 lead to amino acid changes, 6 deletions (5 single and 1 involving a large number of nucleotides) and 1 single nucleotide insertion. TG mutations are inherited in an autosomal recessive manner and affected individuals are either homozygous or compound heterozygous. The p.R277X, p.C1058R, p.C1977S, p.R1511X, p.A2215D and p.R2223H mutations are the most frequently identified TG mutations. This mini-review focuses on genetic and clinical aspects of TG gene defects.

Thyroxine synthesis from dead cellsComplete 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 bi-allelic 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.We demonstrate that TG W2346R/ W2346R humans, TG cog/cog mice, and TG rdw/rdw rats exhibit no detectable ER export of thyroglobulin, accompanied by severe thyroidal ER stress and thyroid cell death.Nevertheless, thyroxine is synthesized and brief treatment of TG rdw/rdw rats with anti-thyroid drug is lethal to the animals. When untreated, remarkably, thyroxine is synthesized on the mutant thyroglobulin protein, delivered via dead thyrocytes that decompose within the follicle lumen, where they are iodinated and cannabilized by surrounding live thyrocytes. As the animals continue to grow a goiter, circulating thyroxine increases. However, when TG rdw/rdw rats age, they cannot sustain goiter growth that provides 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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