CONSTITUTIVE ACTIVATION OF THE TSH RECEPTOR BY SPONTANEOUS MUTATIONS AFFECTING THE N-TERMINAL EXTRACELLULAR DOMAIN

Activating mutations of the TSH receptor gene have been found in toxic adenomas and hereditary toxic thyroid hyperplasia, Up to now, all mut ations have been located in the serpentine portion of the receptor, We now describe two additional mutations affecting Ser-281 (Ser-281-Thr and Ser-281-Asn) in the ectodomain of the receptor, After transfection in COS cells, both mutants displayed increased constitutive activity for cAMP generation despite expression at a lower level than the wild type, The mutants were responsive to TSH, The present results are comp atible with a model in which the activity of the unliganded receptor i s kept at a low level by an inhibitory interaction between the N-termi nal domain and the serpentine portion of the receptor. (C) 1997 Federa tion of European Biochemical Societies.