TSH Receptor Mutations and Diseases

The thyroid-stimulating hormone (TSH) receptor (TSHR) is a member of the glycoprotein hormone receptors (GPHRs), a sub-group of class A G protein-coupled receptors (GPCRs). TSHR and its ligand thyrotropin are of essential importance for growth and function of the thyroid gland. The TSHR activates different G-protein subtypes and signaling pathways, of which Gs and Gq induced signaling are of highest importance in the thyroid gland. A proper interplay between TSH and TSHR is pivotal for thyroid growth and regulated production and release of thyroid hormones (TH). Autoimmune (antibody binding) or non-autoimmune (occurrence of mutants) TSHR dysfunctions are the underlying cause of several pathologies, including rare cancer-development. The sequential processes of TSHR binding, signal transduction across the cell-membrane and activation of intracellular effectors involve elaborate specific structural properties of the receptor and several interacting proteins. In consequence, different pathogenic mutations at TSHR or TSH may have diverse impact on particular molecular functions, but finally result in either hypo- or hyperthyroid states accompanied or not by various growth anomalies. We here summarize current knowledge regarding naturally occurring TSHR mutations, associated diseases and related molecular pathogenic mechanisms at the level of TSHR structure and function. For complete coverage of this and related areas in Endocrinology, visit our free web-books, www.endotext.org and www.thyroidmanager.org