TSH Receptor Mutations and Thyroid Disease

Mutations of the thyrotropin receptor (TSHr) can be loss of function or gain of function. Loss-of-function mutations can affect a variety of loci in the TSHr gene. Their most common manifestation is resistance to TSH; they may also be the cause of a subset of cases of congenital hypothyroidism. Gain-of-function mutations are of greater theoretical interest. Somatic mutations constitutively activating the TSHr are the major cause of benign toxic thyroid adenomas, and of some cases of multinodular goiters. They underlie hereditary toxic thyroid hyperplasia, and have been found in cases of sporadic congenital non-autoimmune hyperthyroidism. A role for TSHr polymorphisms in Graves' disease has not been documented.