Congenital human thyroglobulin defect due to low expression of the thyroid-specific transcription factor TTF-1.

TTF-1 and Pax-8 are thyroid-specific transcription factors, from homeo and paired box genes, respectively, that are responsible for thyroid development and for thyroglobulin and thyroperoxidase gene expression. However, TTF-1 and Pax-8 preferentially bind to the thyroglobulin and thyroperoxidase promoters, respectively. Here, we have studied a patient with defective thyroglobulin synthesis. Thyroglobulin mRNA was found at very low levels while the mRNA for thyroperoxidase was found to be more abundant compared with control tissue. The low levels of thyroglobulin mRNA are caused by a transcriptional defect due to the virtual absence of TTF-1 expression as determined by Northern blot analysis, reverse transcriptase-PCR, and electrophoretic mobility shift assays. The level of Pax-8 mRNA was the same in the goiter and in the control thyroid. These results are the first reported evidence of a congenital goiter with a thyroglobulin synthesis defect due to the low expression of the thyroid-specific transcription factor TTF-1. Moreover, these data suggest that TTF-1 and Pax-8 would be differentially regulating thyroglobulin and thyroperoxidase gene transcription.