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

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.