Syndrome of Resistance to Thyroid Hormone: Insights into Thyroid Hormone Action

Abstract

Thyroid hormones (T3, T4) exert multiple cellular effects through nuclear thyroid hormone receptors (TR alpha, TR beta). Thyroid hormone receptors are transcription factors that act by altering patterns of gene expression. Resistance to thyroid hormone (RTH) is a rare disorder caused by mutations in the TR beta gene. Biochemically, the syndrome is defined by elevated circulating levels of free thyroid hormones due to reduced target tissue responsiveness and normal, or elevated, levels of thyroid-stimulating hormone (TSH). This "inappropriate" TSH elevation contrasts with the situation in hyperthyroidism, where the pituitary secretion of TSH is suppressed. Patients with RTH usually present with goiter and an euthyroid or mildly hypothyroid metabolic state. Thus, pituitary resistance results in hypersecretion of TSH, which compensates, at least in part, for hormone resistance in peripheral tissues. Despite this compensation, clinical effects of RTH can include short stature, delayed bone maturation, hyperactivity, learning disabilities, and hearing defects, as well as variable features of hyper- and hypothyroidism. With the exception of a single sibship, which harbored a deletion of the entire coding sequence of the TR beta gene and a recessive pattern of inheritance, all other cases of RTH have been inherited in an autosomal dominant manner or have been de novo heterozygous mutations of the TR beta gene. The dominant pattern of inheritance is explained by the functional properties of the mutant receptors which act in a dominant negative manner to block the activity of normal TR alpha and TR beta receptors. Now that a large number of different RTH mutations have been identified, it is striking that the mutations are clustered within restricted domains in the carboxyterminal region of the receptor. Mutations in these regions have been shown to preserve critical receptor functions such as dimerization and DNA binding, while inactivating other activites such as T3 binding and transcriptional activation. The examination of patients with RTH and their mutated receptors has provided important insights into the mechanisms of thyroid hormone action, the structure-function relationship of the receptors, and the molecular mechanisms of dominant negative activity.

Thyroid hormone receptors mutated in liver cancer function as distorted antimorphs

“…RTH-Syndrome TR mutants exhibit dominant-negative properties virtually identical to those described here for the HCC TR mutants, are expressed in a wide range of tissues, including hepatocytes, yet RTH Syndrome is not known to increase the incidence of HCC (Refetoff, 1993;DeGroot, 1996;Kopp et al, 1996;Chaterjee, 1997;. Notably, RTH-Syndrome mutations are characteristically single substitutions that map to the hormone-binding domain, whereas many of the HCC mutants have sustained multiple substitutions that encompass lesions in the DNA recognition domain of the receptor (Refetoff, 1993;DeGroot, 1996;Kopp et al, 1996;Chaterjee, 1997;Lin et al, 1999).…”

“…Notably, RTH-Syndrome mutations are characteristically single substitutions that map to the hormone-binding domain, whereas many of the HCC mutants have sustained multiple substitutions that encompass lesions in the DNA recognition domain of the receptor (Refetoff, 1993;DeGroot, 1996;Kopp et al, 1996;Chaterjee, 1997;Lin et al, 1999). This suggests the possibility that the altered disease proclivities of these HCC TR mutants might be because of an alteration in their DNA sequence recognition specificity.…”

“…Inherited defects in TR function result in a human endocrine disorder, denoted Resistance to Thyroid Hormone (RTH) Syndrome (Refetoff, 1993;DeGroot, 1996;Kopp et al, 1996;Chaterjee, 1997;. RTH Syndrome is associated with mutations at the TRb locus that disrupt the triggering mechanism by which hormone binding induces corepressor release and coactivator acquisition (Yoh et al, 1997;Liu et al, 1998;Safer et al, 1998;Tagami and Jameson, 1998;Matsushita et al, 2000;Yoh and Privalsky, 2000).…”

Retarded bone growth in thyroid hormone resistance. A clinical study of a large family with a novel thyroid hormone receptor mutation

“…This may be explained by individual differences in the distribution of TRa and TRb in the tissues (2,3,26). Moreover, variations in expression of the mutant TRb and the extent to which it inhibits the wild-type TRb (4,27) or other nuclear receptors (28) may contribute to this diversity. Our study demonstrated no significant difference in FT4 and T4 levels between unaffected family members and unrelated spouse controls.…”

Identification and characterization of a novel de novo mutation (L346V) in the thyroid hormone receptor beta gene in a family with generalized thyroid hormone resistance

“…This syndrome is associated with diverse mutations in the thyroid hormone receptor b (hTRb) gene which encodes a ligand-dependent nuclear transcription factor that modulates the transcription of target genes by interacting with thyroid response elements (TREs) in their promoter region (3)(4)(5)(6). The TRb gene undergoes alternate splicing to generate two receptor isoforms, TRb1 and TRb2, the latter differing from b1 in the N-terminus and being mainly expressed in the pituitary (7).…”