Molecular approaches to growth disorders

Abstract

As the complexity of the growth hormone (GH)/insulin-iike growth factor (IGF) axis unfolds, defects other than primary GH deficiency appear responsible for some reported cases of short stature. The molecular nature of such defects and new insights into the poorly understood mechanism of action of GH have recently been defined due to the application of new approaches/technologies to GH/GH receptor (GHR) biology. The cloned GHR is a single membrane-spanning protein which belongs to a new superfamily which includes receptors for the interleukins, erythropoietin, colony stimulating factor and prolactin. The GHR sequence gave no clues as to possible second messenger signalling systems. Recent biological studies, however, suggest that protein kinase C and GTP-binding proteins (G-proteins) may mediate GH action. Recently a soluble, truncated form of GHR was identified in cell cytoplasm and in serum. This GH binding protein (GHBP) is generated by proteolytic cleavage of the extracellular (GH-binding) domain of the membrane receptor and/or by an alternative mRNA splicing event. In humans, the serum GHBP binds up to 50% of circulating GH, so accounting for much of the known size heterogeneity of serum GH. It does not appear to have a significant effect on GH radioimmunoassays. In rat tissues GHR and GHBP mRNAs are co-expressed but not always co-ordinately expressed suggesting differential regulation and therefore implying distinct biological roles for these two related proteins. The functional role of the serum BP and whether it is a valid marker of GHR status in humans is under investigation. One striking example of the utility of these approaches to understanding GH action is the Laron dwarf -a severe form of short stature characterized by high GH levels and a marked GH resistance. We and others have shown that due to various mutations the GHR gene is transcribed and translated, but into an inactive, non GH-binding receptor/GHBP. Knowing the molecular nature of this and other defects in GH receptor/post-receptor interactions allows one to potentially devise and test a new generation of appropriate treatment protocols.