Hyperfunctioning Thyroid Adenoma and Activating Mutations in the TSH Receptor Gene

Thyrotropin (TSH) positively controls the function, differentiation, and growth of thyrocytes. TSH interacts with thyrocytes through the TSH receptor and its action is mediated by cyclic AMP-dependent mechanisms. From data gathered on adrenergic receptors, it was hypothesized that TSH receptor mutations that lead to constitutive activation of the TSH receptor would also result in autonomous thyroid growth and function. Indeed, such mutations were shown to be the main molecular mechanisms leading to toxic thyroid adenomas. The same mechanism was shown to be operating in “hot” thyroid nodules from multinodular goiter. A low iodine supply seems to increase the clinical expression of such somatic mutations responsible for thyroid autonomy. Moreover, the presence of such mutations has helped to define a working model for TSH receptor physiology. The unliganded TSH receptor maintains a negative constraint on the signal transduced, whereas the presence of specific mutations activates the receptor.