SOMATIC MUTATIONS IN THE THYROTROPIN RECEPTOR GENE CAUSE HYPERFUNCTIONING THYROID ADENOMAS

THE pituitary hormone thyrotropin stimulates the function, expression of differentiation and growth of thyrocytes by cyclic AMP-dependent me chanisms1-3. Tissue hyperplasia and hyperthyroidism are therefore expe cted to result when activation of the adenylyl cyclase-cAMP cascade is unregulated. This is observed in several situations4,5, including whe n somatic mutations impair the GTPase activity of the G protein G(salp ha) (refs 6, 7). Such a mechanism is probably responsible for the deve lopment of a minority, of monoclonal hyperfunctioning thyroid adenomas 6,8,9. Here we identify somatic mutations in the carboxy-terminal port ion of the third cytoplasmic loop of the thyrotropin receptor in three out of eleven hyperfunctioning thyroid adenomas. These mutations are restricted to tumour tissue and involve two different residues (aspart ic acid at position 619 to glycine in two cases, and alanine at positi on 623 to isoleucine in one case). The mutant receptors confer constit utive activation of adenylyl cyclase when tested by transfection in CO S cells. This shows that G-protein-coupled receptors are susceptible t o constitutive activation by spontaneous somatic mutations10,11 and ma y thus behave as proto-oncogenes.