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Constitutively activating mutations in the TSH receptor gene have been found in various disorders. Somatic mutations were identified in autonomously functioning thyroid nodules(AFTNs) and toxic multinodular goiters(TMNGs). Germline mutations were identified in autosomal dominantly inherited non-autoimmune hyperthyroidism and sporadic congenital hyperthyroidism. Most of activating TSH receptor mutations were identified in western countries. Only one Japanese family has been reported to have an activating TSH receptor mutation. Previous very poor and insensitive study identified no somatic TSH receptor activating mutations in 45 AFTNs and TMNGs developed in Japanese. Our recent study completely reversed their observation; about half of AFTNs in Japanese had activating mutations.

Thyroid hormone receptors (TRs) are bound to the T3-responsive element of DNA as dimers and heterodimerization with TR-auxiliary protein (TRAP) strongly enhances this binding. In affected members of families with the thyroid hormone resistance syndrome, significant point mutations have been identified in the hormone-binding domain of one of the two alleles of the TR beta gene, especially in two "hot spot" regions, avoiding the regions required for DNA binding, dimerization or binding to TRAP. These findings suggested that DNA-binding and receptor dimerization are important for dominant negative inhibition by the mutant TR, which is responsible for thyroid hormone resistance in a heterozygous patient with a point mutation in the TR beta gene.

In order to elucidate a predisposition for so-called autoimmune thyroid disorders such as Graves' disease, chronic thyroiditis and myxedema, the incidence of thyroid antibodies was studied in relatives of patients with thyroid disorders. The relatives studied were all limited within a two degree relationship of the patients. Serum antibodies to thyroglobulin and thyroid microsome were determined by susing the method of a hemagglutination test. The following results were obtained; 1) Thirty six of 103 relatives (35%) were found to have such antibodies, and sixteen (7.0%) of 230 hospital controls were positive. This difference was significant (P less than 0.001). 2) There was no difference in the incidence among relatives of patients with Graves' disease and those chronic thyroiditis. 3) With regard to age, the incidence in the more than 20 years old group was significantly greater than that in the under 19 years old group. 4) There was no difference in the incidence between male and female. These results suggested that the relatives of patients with so-called autoimmune thyroid disorders may have a predisposition for thyroid disorders.