Pituitary resistance to thyroid hormone syndrome is associated with T 3 receptor mutants that selectively impair β2 isoform function

Wei Wan, Behnom Farboud, Martin L. Privalsky

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


Resistance to thyroid hormone (RTH) syndrome is an inherited inability to respond appropriately to T3 hormone. In generalized RTH, the T 3 response of both the pituitary and periphery is disrupted. In pituitary (or central) RTH, the ability of the pituitary to sense (and down-regulate) elevated T3 is selectively impaired, whereas the periphery remains relatively T3 responsive, resulting in peripheral thyrotoxicity. Both forms of disease are linked to mutations in thyroid hormone receptor (TR)-β. TRβis expressed by alternate mRNA splicing as two isoforms: TRβ2, found primarily in the pituitary/hypothalamus, and TRβ1, expressed broadly in many tissues. We report here that the wild-type TRβ2 isoform displays an enhanced T3 response relative to the TRβ1 isoform. Mutations associated with generalized RTH (P453S, G345S) impair both TRβ2 and TRβ1 function proportionally, whereas mutations associated with pituitary-specific RTH (R338L, R338W, R429Q) disproportionately disrupt TRβ2 function. We propose that in the normal organism, and in generalized RTH, TRβ2 in the pituitary can sense rising T3 levels in advance of TRβ1 in the periphery, preventing thyrotoxicity. In contrast, the TRβ mutations associated with pituitary RTH disproportionately disrupt the pituitary's ability to sense and suppress elevated T3 levels in advance of the periphery, producing symptoms of thyrotoxicity.

Original languageEnglish (US)
Pages (from-to)1529-1542
Number of pages14
JournalMolecular Endocrinology
Issue number6
StatePublished - Jun 2005

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism


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