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Pediatric Endocrinology, University Children’s Hospital, University of Ulm, Prittwitzstrasse 43, D-89075 Ulm, Germany
¹ Institute of Molecular Pharmacology, 13125 Berlin, Germany
² INSERM U584, Hôpital Necker, 75006 Paris, France
³ Division of Endocrinology, Department of Internal Medicine, University of Ulm, 89081 Ulm, Germany

(Requests for offprints should be addressed to B Karges; Email: beate.karges{at}medizin.uni-ulm.de)

^* (B Karges and G Krause contributed equally to this work)

Mutations of the human thyrotrophin receptor (TSH-R) are a cause of thyroid adenomas and hyperthyroidism. Here we study mechanisms of receptor activation in a genomic TSH-R variant V509A located in transmembrane helix (TMH) 3, which we identify in a family with congenital hyperthyroidism, multiple adenomas and follicular thyroid cancer. Using molecular modelling and dynamic simulation, we predicted the release of amino acid residue A593 (located opposite in domain TMH5) from a tight ‘knob-and-hole’ interaction with TMH3, physiologically constrained in the native receptor state by the bulky side chain of V509. To experimentally validate this concept, we generated mutant TSH-R expression constructs for functional in vitro studies. TSH-R mutant V509A showed a 2.8-fold increase in basal cAMP production, confirming constitutive TSH-R activation. The addition of a second site suppressor mutant A593V to TSH-R V509A resulted in the normalization of basal cAMP release, and the dose-responsiveness to TSH ligand was maintained. These data thus demonstrate that TSH-R V509A activation is caused by the release of TMH3–TMH5 interhelical constraints, while the native TSH-R conformation is re-stabilized by the introduction of a spacious valine residue at position 593. In conclusion, we delineate a novel mechanism of constitutive TSH-R activation, leading to thyroid hyperfunction and neoplasia.

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