MUTATIONS OF THYROTROPIN RECEPTOR GENE

Thyrotropin is the primary pituitary hormone which stimulates the grow th and differentiation of thyroid cells. TSH binds a specific receptor present in the plasma membrane of thyroid cells and signals the G pro tein transducers, which activate different effectors, mainly adenyl cy clase and phospholipase C. The TSH receptor belongs to a broad class o f receptors known as seven-loop receptors because they contain a long stretch of amino acids which cross the plasma membrane seven times. Mu tations in the TSH receptor gene have been found in hyperfunctioning t hyroid adenomas. These mutations are: (a) somatic (present only in the tumor), (b) dominant (only one copy of the gene is affected), and (c) lead to the constitutive activation of the cAMP signaling cascade. Mo st mutations,which have been identified occur in the intracellular loo p III and in the transmembrane domain VI. Germline mutations in the sa me regions of the receptor have been found in congenital nonautoimmune hyperthyroidism. In addition, germ line mutations have been described in the extracellular domain of the receptor leading to increased TSH levels. The clinical implications of these findings are discussed.