Search

The study of the different factors regulating the bioactivity of thyroid hormones is of utmost relevance for an adequate understanding of the glandular pathophysiology. These factors must be considered by the clinician in order to achieve a successful diagnosis and treatment of glandular diseases. Among the factors regulating bioactivity of thyroid hormones are the following: A) Plasmatic membrane hormone transporters, which tissue-specific expression is responsible for the cellular uptake of hormones, B) A set of deiodinating enzymes which activate or inactivate intracellular thyroid hormone, and C) Nuclear receptors which are responsible for the different cellular responses at the transcriptional level. This review compiles analysis and discusses the most recent findings regarding the regulation of thyroid hormone bioactivity, as well as the clinical relevance of different polymorphisms and mutations currently described for membrane transporters and deiodinases. In addition, the main issues and present and future study areas are identified.

Thyroid diseases constitute a heterogeneous collection of abnormalities associated with mutations in genes responsible for the development of thyroid: thyroid transcription factor-1 (TTF-1), thyroid transcriptions factor-2 (TTF-2) and PAX8, or in one of the genes coding for the proteins involved in thyroid hormone biosynthesis such as thyroglobulin (TG), thyroperoxidase (TPO), hydrogen peroxide-generating system (DUOX2), sodium/iodide symporter (NIS), pendrin (PDS), TSH and TSH receptor (TSHr). Congenital hypothyroidism occurs with a prevalence of 1 in 4000 newborns. Patients with this syndrome can be divided into two groups: nongoitrous (dysem/bryogenesis) or goitrous (dyshormonogenesis) congenital hypothyroidism. The dysembryogenesis group, which accounts for 85% of the cases, results from ectopy, agenesis and hypoplasia. In a minority of these patients, the congenital hypothyroidism is associated with mutations in TTF-1, TTF-2, PAX-8, TSH or TSHr genes. The presence of congenital goiter (15% of the cases) has been linked to mutations in the NIS, TG, TPO, DUOX2 or PDS genes. The congenital hypothyroidism with dyshormonogenesis is transmitted as an autosomal recessive trait. Somatic mutations of the TSHr have been identified in hyperfunctioning thyroid adenomas. Another established thyroid disease is the resistance to thyroid hormone (RTH). It is a syndrome of reduced tissue responsiveness to hormonal action caused by mutations located in the thyroid hormone receptor beta (TRbeta) gene. Mutant TRbetas interfere with the function of the wild-type receptor by a dominant negative mechanism. In conclusion, the identification of mutations in the thyroid expression genes has provided important insights into structure-function relationships. The thyroid constitutes an excellent model for the molecular study of genetic diseases.