The protein encoded by this gene is a receptor for thyrothropin (thyroid stimulating hormone or TSH) and plays a major role in controlling thyroid cell metabolism. Its activation stimulates thyroid epithelial cell proliferation, and regulates the expression of differentiation markers such as thyroglobulin, thyroperoxidase and the sodium iodide symporter (NIS), necessary for the synthesis of thyroid hormones. TSHR is also activated by other members of the glycoprotein hormone family, including human chorionic gonadotropin (hCG), luteinizing hormone (LH) and thyrostimulin (a heterodimer composed of A2 and B5 glycoprotein hormone subunits).
TSHR mutations may be gain-of-function resulting in constitutional activation of the receptor independently of TSH, or loss-of-function resulting in loss of TSH sensitivity.
Germline TSHR mutations include missense mutations, nonsense mutations, insertion/deletions, and exon skipping due to alternative splicing. Germinal activating mutations are associated with hereditary or sporadic congenital hyperthyroidism, whereas germinal inactivating mutations are a cause of TSH resistance associated with congenital hypothyroidism and euthyroid hyperthyrotropinaemia.
Somatic TSHR mutations include missense mutations and in-frame deletions. They are observed in about one-third of thyroid tumors (papillary and follicular cancers). There are frequently associated with amino acids 453, 619, 623 and 632. Activating mutations have been identified in hyper-functioning thyroid adenoma and toxic multi-nodular goiter; few cases are associated with thyroid carcinoma. No somatic inactivating mutations have been described so far.
References (open access):
TSH signalling and cancer. García-Jiménez C, Santisteban P. Arq Bras Endocrinol Metabol. 2007 Jul;51(5):654-71.