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 mutations 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 compatible with a model in which the activity of the unliganded receptor is kept at a low level by an inhibitory interaction between the N-terminal domain and the serpentine portion of the receptor.
Duprez
L
L
Institut de Recherche Interdisciplinaire, Faculty of Medicine, University of Brussels, Belgium.
Parma
J
J
Costagliola
S
S
Hermans
J
J
Van Sande
J
J
Dumont
J E
JE
Vassart
G
G
D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D005091:Exons; D005786:Gene Expression Regulation; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D009154:Mutation; D017434:Protein Structure, Tertiary; D011989:Receptors, Thyrotropin / Q000235:genetics*; D014162:Transfection
D007295:Inositol Phosphates; D011989:Receptors, Thyrotropin