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A Novel Mutation in the Thyrotropin (TSH) Receptor Gene Causing Loss of TSH Binding But Constitutive Receptor Activation in a Family with Resistance to TSH¹

Cattedra di Endocrinologia, Dipartimento di Medicina Sperimentale e Clinica (F.A., E.C., S.F.), and Dipartimento di Scienze Farmacobiologiche, Facoltà di Farmacia (D.R.), Università di Catanzaro, 88100 Catanzaro; and Cattedra di Endocrinologia, Istituto di Semeiotica Medica (C.B., M.E.G.), Università di Padova, Italy

Address correspondence and requests for reprints to: Sebastiano Filetti, M.D., Cattedra di Endocrinologia, Dipartimento di Medicina Sperimentale e Clinica, Policlinico Mater Domini, Via T. Campanella 115, 88100 Catanzaro, Italy. E-mail: filetti{at}tin.it

Resistance to TSH is a syndrome due to reduced responsiveness of the thyroid gland to biologically active TSH. Inactivating mutations of the TSH receptor (TSH-R) have been detected in several cases of resistance to TSH, both partial and complete, sporadic and familial. In this study, we describe a family with the presence of resistance to TSH responsible for euthyroid hyperthyrotropinemia in two siblings from consanguineous parents. By direct sequencing of the TSH receptor gene, we identified a new mutation responsible for the substitution of an arginine with a cysteine at position 310, in the extracellular domain of the TSH-R. The mutation was homozygous in two brothers; heterozygous in both parents, an uncle, and an unaffected brother; and absent in the other unaffected brother. When stably transfected in Chinese hamster ovary cells, the Cys310 mutant TSH-R showed loss of response to TSH in terms of cAMP stimulation. However, a constitutive activity in terms of basal cAMP production was detected in the Cys310 mutant, compared with the wild-type TSH-R.

Our data suggest that such a Cys310 TSH-R mutant may determine both the TSH resistance and the clinical euthyroidism detected in this family.

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