Grant: Operating Grant

In response to signals from the pituitary gland, the thyroid gland synthesizes and secretes thyroid hormones, which in turn control brain development and basal metabolic rate. 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 at the level of the thyroid gland itself; so-called primary hypothyroidism. However, defects in the brain or pituitary gland can also cause hypothyroidism of central origin. Recently, our laboratory, in association with a team of international collaborators, identified a new cause of central hypothyroidism. We identified several families with mutations in a gene called immunoglobulin superfamily, member 1 (IGSF1) in which males are hypothyroid and have enlarged testicles. We observed similar characteristics in mice in which the Igsf1 gene was genetically deleted. How the loss of IGSF1 causes hypothyroidism is unknown; however, our recent results suggest that IGSF1 may play an important role in thyroid hormone transport. That is, proteins at the surface (membrane) of cells of the thyroid gland form a channel or pore through which thyroid hormones enter into the circulation. In addition, these transporters are needed to direct thyroid hormones from circulation into the cells of the body where they have their effects. Our research will examine how IGSF1 controls the body's ability to take up and excrete thyroid hormones and their metabolites (i.e., breakdown products) and how mutations in the IGSF1 gene impair these functions. The results of our work will not only uncover heretofore unknown aspects of human physiology, but may highlight novel therapeutic targets.