Endocrine Abstracts

The classical form of thyroid hormone resistance (RTH) is characterized by elevated levels of circulating T₄ and T₃ in the presence of measurable serum TSH concentrations as a consequence of mutations of thyroid hormone β receptor (TRβ). RTH is a rare disorder, inherited in an autosomal dominant fashion. In the majority of the subjects, RTH is associated with heterozygous mutations in the TRβ gene. The mutant receptors display either reduced affinity for T₃ or impaired interaction with the cofactors, thus losing its ability to modulate target gene expression in different tissues. In contrast to what observed for other nuclear receptors, no mutations have been identified in the DNA-binding domain or in other regions of the receptor. To explain the presence of resistance in individuals heterozygous for the mutation, it was discovered that the mutant receptor exerts a dominant negative effect, which occurs because the mutant protein inhibits the activity of the wild type β- and α-receptors. In order to exert this effect, mutant receptors must retain normal dimerization and DNA binding properties. In about 10–15% of the cases with clinical and biochemical phenotype of RTH, no mutation could be found in the TRβ gene and this situation is defined as ‘non-TRβ RTH’. It is speculated that these patients may have an abnormality of one of the cofactors or TH transporters into the cells. Heterozygous mutations in regions other than the three ‘hot spots’ may be clinically silent because lacking of dominant negative properties. RTH subjects are clinically defined as GRTH when display compensated hypothyroidism, or PRTH which exhibit variable symptoms of hyperthyroidism. There is a significant overlap between these two forms, being the symptoms variable. Differences in the degree of hormonal resistance are linked to the different levels of TRβ and TRα expression, in different tissues.