Russo D, Betterle C, Arturi F, Chiefari E, Girelli M E, Filetti S
Dipartimento di Scienze Farmacobiologiche, Facoltà di Farmacia, Università di Catanzaro, Italy.
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.
促甲状腺激素抵抗是一种由于甲状腺对生物活性促甲状腺激素反应性降低所致的综合征。在部分和完全性、散发性和家族性促甲状腺激素抵抗的几例病例中均检测到促甲状腺激素受体（TSH-R）的失活突变。在本研究中，我们描述了一个家族，该家族中来自近亲父母的两名同胞存在促甲状腺激素抵抗，导致甲状腺功能正常的高促甲状腺素血症。通过对促甲状腺激素受体基因进行直接测序，我们在TSH-R的细胞外结构域中鉴定出一个新的突变，该突变导致第310位的精氨酸被半胱氨酸取代。该突变在两名兄弟中为纯合子；在父母、一名叔叔和一名未受影响的兄弟中为杂合子；在另一名未受影响的兄弟中不存在。当稳定转染到中国仓鼠卵巢细胞中时，Cys310突变型TSH-R在cAMP刺激方面显示出对促甲状腺激素反应丧失。然而，与野生型TSH-R相比，在Cys310突变体中检测到基础cAMP产生方面的组成性活性。我们的数据表明，这种Cys310 TSH-R突变体可能决定了该家族中检测到的促甲状腺激素抵抗和临床甲状腺功能正常状态。
