SOMATIC MUTATIONS IN THE VI-TRANSMEMBRANE SEGMENT OF THE THYROTROPIN RECEPTOR CONSTITUTIVELY ACTIVATE CAMP SIGNALING IN THYROID HYPERFUNCTIONING ADENOMAS

We have discovered two somatic mutations in the VI transmembrane domai n of the thyrotropin receptor gene in thyroid hyperfunctioning adenoma s, The mutated amino acid residues are phenylalanine 631 (to cysteine) and threonine 632 (to isoleucine), Cloning and expression of the muta ted versions of the receptor in COS cells increased significantly the basal and the TSH-induced cAMP levels compared to the wild type recept or, Moreover, the expression of a reporter gene under the control of t he cAMP-inducible promoter, was likewise constitutively activated in c ells expressing the 631 and 632 TSH receptor mutants relative to the w ild type, These data indicate that the VI transmembrane segment in the TSH receptor and presumably in the other G-protein coupled receptors is a critical domain for the activation of G-protein signalling and th at the mutations described here may be the cause of the thyroid hyperf unctioning adenoma.