title: 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.
abstract: 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.
authors.affiliation: Dipartimento di Scienze Farmacobiologiche, Facoltà di Farmacia, Università di Catanzaro, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Russo
authors.forename: C
authors.initials: C
authors.lastname: Betterle
authors.forename: F
authors.initials: F
authors.lastname: Arturi
authors.forename: E
authors.initials: E
authors.lastname: Chiefari
authors.forename: M E
authors.initials: ME
authors.lastname: Girelli
authors.forename: S
authors.initials: S
authors.lastname: Filetti
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001120:Arginine; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003545:Cysteine; D004351:Drug Resistance; D005091:Exons; D005260:Female; D006684:HLA-DR Antigens / Q000032:analysis; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D017354:Point Mutation; D011989:Receptors, Thyrotropin / Q000235:genetics* / Q000378:metabolism*; D013972:Thyrotropin / Q000097:blood / Q000378:metabolism*; D013974:Thyroxine / Q000097:blood; D014162:Transfection; D014284:Triiodothyronine / Q000097:blood
chemical_list: D006684:HLA-DR Antigens; D011989:Receptors, Thyrotropin; D014284:Triiodothyronine; D013972:Thyrotropin; D001120:Arginine; D003545:Cysteine; D013974:Thyroxine