Clinical Expression of Mutations in the TSH Receptor: TSH-R Disorders

Thyroid growth and function are mainly controlled by Thyroid-Stimulating Hormone (TSH), secreted by the pituitary gland. TSH acts via a membrane receptor (TSHR) (Fig. 1) that belongs to the large superfamily of G-protein coupled receptors (GPCRs). Differently from other GPCRs, TSH-R and the highly homologuous follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) are characterized by a large extracellular domain, responsible for ligand binding. In the human thyroid, intracellular TSH signaling is mediated through cAMP and, to a lesser extent, by phospholipase C. After the molecular cloning of TSH-R by several groups in 19891-4, an expanding number of TSH-R germline or somatic mutations have been reported in patients with thyroid disorders. TSH-R mutations are now known to be responsible for a variety of clinical phenotypes, about which knowledge is mandatory for good clinical practice. In addition, the study of naturally occurring TSH-R mutations represents an excellent tool to unravel the molecular mechanisms of receptor functioning. Eight different phenotypes are associated with TSH-R mutations (Fig.2). Somatic activating TSH-R mutations are found in autonomous thyroid adenomas (ATA), toxic multinodular goiter (TMNG) and rarely in differentiated thyroid cancers (DTC). Germline activating mutations are responsible for sporadic and familial congenital hyperthyroidism. Inactivating germline mutations are associated with inherited TSH resistance. A comprehensive and up-to-date database of human TSH-R mutations can be found on the web (www.uni-leipzig.de/innere/TSH/).