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Constitutive activation of the TSH receptor by spontaneous mutations affecting the N‐terminal extracellular domain
Author(s) -
Duprez Laurence,
Parma Jasmine,
Costagliola Sabine,
Hermans Jacques,
Van Sande Jacqueline,
Dumont Jacques E,
Vassart Gilbert
Publication year - 1997
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(97)00532-2
Subject(s) - ectodomain , receptor , mutant , thyrotropin receptor , 5 ht5a receptor , transfection , extracellular , mutation , enzyme linked receptor , microbiology and biotechnology , interleukin 21 receptor , point mutation , chemistry , biology , gene , endocrinology , genetics , thyroid , graves' disease
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.