Physiology and disorders of the growth hormone receptor (GHR) and GH-GHR signal transduction.

GH exerts its actions through binding with two receptor molecules at the cell surface and interaction with Janus kinase and signal transducers and activators of transcription, and other likely effectors to stimulate metabolic effects and IGF synthesis. The circulating GH binding protein is the proteolytic product of the cell surface receptor and serves as a marker of receptor number and function. Thirty-six distinct mutations of the receptor in the extracellular and transmembrane domains cause a clinical picture of severe GH/IGF-I deficiency, whereas two dominant negative mutations of the intracellular domain result in a milder clinical syndrome. These mutations have provided insight into the physiology of the GH receptor. A few patients have been described with what appears to be primary GH insensitivity due to defective signal transduction by the GH-GH-receptor complex. Clinical and biochemical features of primary GH insensitivity are not a function of genotype, with as much variability in a genetically homogeneous population as in a heterogeneous one. Except for those dominant negative mutations where co-transfection of the mutant GH receptor gene with wild-type receptor gene has been informative, evidence for an effect of a single mutant allele remains speculative. Treatment of GH receptor deficiency with recombinant human IGF-I suggests that the absence of a direct effect of GH limits growth response.