Another story of mice and men: the types of RTH.

T he 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 TR , 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 TR affinity for hormone [triiodothyronine (T3)]. Patients 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 encode TSH-releasing hormone (TRH) in the hypothalamus, which triggers TSH release, and both subunits of TSH in the pituitary, thereby inhibiting their own synthesis and maintaining hormone levels within set concentration ranges. The system fails in RTH; TR is mutated and TH cannot repress TRH and TSH transcription (Fig. 1B). What are the consequences of elevated TH? In normal individuals, excess TH causes thyrotoxicosis, characterized by tachycardia, elevated metabolic rate, muscle and bone catabolism, and other effects (4). Most of these symptoms are absent in GRTH and patients often appear normal because elevated TH compensates for reduced affinity of the mutant TR for T3. In other cases, patients with more severe mutations display symptoms associated with TH deficit (4), mental retardation, deafness, and delayed bone growth and maturation. One exception is that GRTH patients can display tachycardia, a classic symptom of hyperthyroidism. This exception is because heart rate is predominantly controlled by the TR isoform, which is unaffected by RTH mutations and hyperstimulated by excess TH (4). What of CRTH? The first description of this disease emerged in 1975 (11), and there have been many subsequent diagnoses (8). Patients generally display hyperthyroid symptoms along with elevated TSH (which should be suppressed by high TH). However, RTH symptoms are highly variable (7, 8); members of the same kindred often exhibit different features and identical mutations have been detected in different families that have been classified as GRTH or CRTH. Thus, the separate existence of CRTH is controversial, and investigators have often suggested that GRTH and CRTH represent opposite poles of the same continuum of disease symptoms (6, 7). Further, detailed laboratory characterization of effects of GRTH and PRTH mutations on TR function have failed to reveal consistent features that distinguish the 2 forms of the disease (9). Interestingly, targeting of TR GRTH mutants to pituitary thyrotropes in transgenic mice does reproduce CRTH symptoms, confirming that a specific central defect can lead to phenotypes that resemble human disease (12, 13). However, debates about the nature of CRTH,