Resistance to thyroid hormone (RTH) is usually inherited in a dominant fashion, and is characterized by elevated serum thyroid hormone levels and failure to suppress pituitary secretion of thyroid-stimulating hormone, with variable refractoriness to hormone action in peripheral tissues. Two major forms of the disorder are recognized: asymptomatic individuals with generalized resistance (GRTH) and patients with thyrotoxic features suggesting predominant pituitary resistance (PRTH). In over 100 families with GRTH or PRTH, we have identified heterozygous mutations in the thyroid hormone receptor β isoform (TRβ), which localize to three regions (amino acids 234–282, 310–353 and 429–461) of the hormone-binding domain of the receptor. The mutant receptors are transcriptionally impaired, due either to reduced ligand binding or to attenuated interaction with co-activators, and inhibit wild-type TR action in a dominant-negative manner. In the TRβ crystal structure, most RTH mutations cluster around the hormone-binding pocket, with receptor regions that mediate functions (DNA binding, dimerization, corepressor recruitment) required for dominant-negative activity being devoid of natural mutations. The pathogenesis of variable tissue resistance is not fully understood, but may be related to the differing tissue distributions of TRα and TRβ, and to variable dominant-negative activity of mutant receptors on different target genes. The nuclear receptor peroxisome-proliferator-activated receptor γ (PPARγ) regulates adipogenesis and mediates the action of thiazolidinediones - novel antidiabetic agents which enhance tissue insulin sensitivity. The PPARγ gene was screened in 85 subjects with severe insulin resistance, and two different heterozygous receptor mutations (P467L and V290M) were identified in three affected individuals. The PPARγ mutants are markedly transcriptionally impaired due to altered ligand binding and co-activator recruitment. Analogous to RTH, they inhibit the function of wild-type PPARγ when co-expressed, and such dominant-negative inhibition is linked to their ability to silence basal gene transcription via aberrant interaction with co-repressors. In addition to insulin resistance, all three affected subjects developed Type II diabetes mellitus and hypertension at an unusually early age. Our findings provide compelling evidence that PPARγ is important in the control of insulin sensitivity, glucose homoeostasis and blood pressure in humans. Future studies aim to elucidate the mechanism by which this receptor regulates insulin action and vascular tone.

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