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The syndrome of resistance to thyroid hormone (RTH) is an inherited autosomal dominant human disease (1). It is most commonly caused by point mutations in the THRB gene that encodes TRβ, 1 of 2 thyroid hormone (TH) receptors (TRs) in humans (2, 3). TRs are ligand-gated transcription factors (4), and most RTH mutations affect the C-terminal ligand-binding domain and reduce TRβ affinity for hor-mone [triiodothyronine (T3)]. Pa-tients frequently display defects in the hypothalamic–pituitary–thyroid (H-P-T) axis, resulting in elevated circulating TH and goiter, along with other symptoms. Interestingly, there appear to be 2 distinct forms of the disease; generalized resistance (GRTH) affects all tissues, whereas patients with isolated central resistance (CRTH, or pituitary resistance) exhibit specific defects in feedback inhibition of TH production with normal peripheral responses (2, 5). However, there have been doubts that GRTH and CRTH are clinically-distinct entities (6, 7). Investigators have often proposed that the 2 forms of RTH represent part of the same continuum of variable symptoms (8) and have pointed out that there is no consistent functional difference between GRTH and CRTH mutations (9). In this issue of PNAS, Wondisford and colleagues (10) report a mouse model for CRTH and discover a startlingly simple explanation for the phenotype: hormone binding is specifically uncoupled from transcriptional inhibition, leaving transcriptional activation intact. RTH is consistently associated with elevated circulating levels of TH and thyroid-stimulating hormone (TSH), which triggers TH release in the thyroid gland (Fig. 1A). Usually, THs repress the genes that …

Another story of mice and men: The types of RTH