A novel mutation in the thyrotropin (TSH) receptor gene causing loss of TSH binding but constitutive receptor activation in a family with resistance to TSH

J Clin Endocrinol Metab. 2000 Nov;85(11):4238-42. doi: 10.1210/jcem.85.11.6985.


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Arginine
  • CHO Cells
  • Cell Line
  • Cricetinae
  • Cysteine
  • Drug Resistance
  • Exons
  • Female
  • HLA-DR Antigens / analysis
  • Homozygote
  • Humans
  • Male
  • Middle Aged
  • Pedigree
  • Point Mutation*
  • Receptors, Thyrotropin / genetics*
  • Receptors, Thyrotropin / metabolism*
  • Thyrotropin / blood
  • Thyrotropin / metabolism*
  • Thyroxine / blood
  • Transfection
  • Triiodothyronine / blood


  • HLA-DR Antigens
  • Receptors, Thyrotropin
  • Triiodothyronine
  • Thyrotropin
  • Arginine
  • Cysteine
  • Thyroxine