Syndrome of resistance to thyroid hormone: Insights into thyroid hormone action (43951)

Peter Andreas Kopp, Koichi Kitajima, J. Larry Jameson*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

53 Scopus citations


Thyroid hormones (T3, T4) exert multiple cellular effects through nuclear thyroid hormone receptors (TRα, TRβ). 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 TRβ 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 TRβ 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 TRβ 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 TRα and TRβ 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 activities 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.

Original languageEnglish (US)
Pages (from-to)49-61
Number of pages13
JournalExperimental Biology and Medicine
Issue number1
StatePublished - Jan 1 1996

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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