[Disorders caused by mutations of the thyrotropin receptor]

Since 1993, a number of mutations of the thyrotropin receptor(TSHR) gene causing human diseases have been reported; activating TSHR somatic mutations causing autonomously functioning thyroid nodules, activating TSHR germ-line mutations causing familial non-autoimmune hyperthyroidism, and inactivating TSHR germ-line mutations causing hypothyroidism due to TSH unresponsiveness. Activating TSHR mutations increase second messenger signals without stimulation of TSH or thyroid stimulating antibody, conferring autonomous growth and function upon thyroid cells. Most of activating TSHR mutations are located in the transmembrane domain of the receptor. One of most important mechanisms how these mutants activate the receptor constitutively is that inter-helical bonding(s) maintained in the silent receptor is/are disrupted by the mutations. Further investigation of activating mutations will provide insight into normal activating mechanism of the receptor.