Activating mutations of the TSH receptor gene cause thyroid diseases

Spontaneous mutations have been identified in the gene encoding the thyrotropin receptor, the effect of which is to activate the receptor in the absence of hormone. When they occur within thyrocytes (somatic mutations) activating mutations cause clonal expansion of the cells into a hyperfunctional thyroid adenoma (toxic nodule). Our results demonstrate that this pathophysiologic mechanism accounts for the majority of toxic adenomas (9 mutations found out of 11 adenomas). The remaining cases are probably secondary to mutations in the G protein Gs. When similar mutations are present in the germ line, they cause a form of non-autoimmune hyperthyroidism transmitted as an autosomal dominant trait. Mutations of the tsh receptor gene have been found in five different families, including that corresponding to the original description of the syndrome by J. Leclère (Nancy). Structure/function studies of the various mutant receptors will contribute to our understanding of the mecanisms involved in the activation of G protein-coupled receptors.