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The clinical significance of mutations in TSH-R is a very "hot" area
in present thyroid research. Cuddihy, Rochester, MN, USA, studied
the presence of a genomic point mutation in the first codon 52, resulting
in a threonine for proline substitution and also the prevalence of HLA
class II genes DR3 and DRB3 in female patients with Graves' disease (n
= 42) and with Hashimoto's thyroiditis (n = 21). They found that the codon
52 mutation is highly associated with the presence of Graves' disease (p
= 0,010) and Hashimoto's thyroiditis (p < 0.010). Also a strong independent
correlation was found with DR3, both with Graves' disease and Hashimoto's
thyroiditis. No disease association was found with DRB3. (Comment: The
association with DR3 was expected, but that with the TSH-R mutation is
a new finding suggesting a central role in the development of autoimmune
thyroid disease.) Mutations in the TSH-R have also been found in hyperfunctioning
thyroid adenomas and shown to exert constitutive activation of adenylcyclase,
causing the hyperthyroidism in such patients.
Several more mutations were now reported by Pannain et al., Naples and Catanzaro, Italy, and by Paschke, Brussels, Belgium. It was also shown that, when transfected into other cell types not only basal cyclic AMP activity was increased, but when stimulated by TSH an increased biologic activity (cyclic AMP or inositol phosphate response) was elicited when compared to the wild (= normal) type transfected TSH-R. The possibility that TSH-r might also be responsible for the extra-thyroidal manifestations of Graves' disease (OGD and dermopathy) is currently under intensive investigation. If so, the TSH-R should be expressed in other tissues as well, in particular in fibroblasts and orbital muscle. Nakashima et al., New York, NY, USA, and Vancouver, Brit. Columbia, found indeed evidence for this when they studied mRNA expression of the TSH-r in orbital muscles of patients with Graves' disease with or without OGD. Kopp et al., Bern, Switzeland, Chicago, IL, USA, and Brussels, Belgium, reported an interesting case of congenital hyperthyroidism that was very difficult to treat in a boy of 8 years. They found a novel germline mutation (because it was not present in any family member) in the gene of the TSH-R responsible for the congenital goiter and hyperthyroidism. The child remained hyperthyroid, although only a few grams of thyroid tissue were left after operation and was therefore finally treated with radioiodine to control hyperthyroidism. |
