Thyroid Hormone Synthesis Without Thyroglobulin

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 TG 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.

We recently engineered mice with homozygous Tg-KO, 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.

We found that, concomitant with goiter growth, animals completely lacking TG (like patients or animals with biallelic TG defect) are able to eventually normalize circulating T4 levels when their goiter has sufficiently enlarged, while maintaining serum T3 at ∼two-thirds normal levels throughout life. Very little T3-containing protein is synthesized in the thyroid glands of Tg-KO 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.

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.