Grant: Project Grant

In response to thyroid-stimulating hormone (TSH) from the pituitary gland, the thyroid secretes hormones, which in turn control brain development and basal metabolism. Thyroid hormone deficiency (or hypothyroidism) is a common disorder and is most often treated with hormone replacement. If untreated, especially in infancy, hypothyroidism can have significant health consequences, including developmental delay and cognitive impairments. The condition is most often caused by problems with the thyroid itself, so-called primary hypothyroidism. However, defects in the brain or pituitary gland can also cause hypothyroidism of central origin. Our laboratory discovered the most common congenital form of central hypothyroidism, which is caused by mutations in a gene called immunoglobulin superfamily, member 1 (IGSF1). IGSF1 is produced at high levels in thyrotrope cells of the pituitary. The brain secretes a hormone called thyrotropin-releasing hormone (TRH), which stimulates TSH release from thyrotropes. In the absence of IGSF1, thyrotropes secrete less TSH in response to TRH. How IGSF1 controls TSH synthesis and secretion is unknown, however, because the basic functions of IGSF1 in cells are unresolved. In the present application, we propose complementary strategies to address these fundamental gaps in knowledge. The results of our work will not only uncover heretofore unknown aspects of human physiology, but may highlight novel therapeutic targets for central hypothyroidism.