ABSTRACT
The principal mode of action of steroid hormones is to modulate the transcription of target genes in the nucleus, leading to alterations in levels of mRNA synthesis. Characterization of the various receptor genes has enabled direct sequencing approaches to dissect the molecular abnormality present in many cases of hormone resistance. Generalized inherited glucocorticoid resistance is characterized by hypercortisolaemia with excess adrenocorticotrophic hormone production due to impaired negative feedback by glucocorticoid on the hypothalamus and pituitary. The histology in sg mice is similar to that seen in hypothyroidism, except that it is not alleviated by thyroid hormone treatment. In keeping with their location, mutant receptors in resistance to thyroid hormone (RTH) exhibit impaired hormone binding and transcriptional activity. In addition, the mutant receptors are capable of inhibiting the action of their wild-type counterparts when co-expressed. The ‘dominant-negative’ inhibitory effects of mutant receptors in vivo are supported by the finding of a unique family with recessively inherited RTH.
