ABSENCE OF THE PLASMA GROWTH HORMONE-BINDING PROTEIN IN LARON-TYPE DWARFISM^*

Abstract

We recently described a specific, high affinity binding protein (BP) for growth hormone (GH) in normal human plasma. Little is known about the source, regulation and biological role of this BP. Because its specificity is similar to that of the GH receptor, we considered the possibility that it represented a circulating receptor subunit or fragment. Laron-type dwarfism is a rare disorder characterized by severe growth failure, resistance to GH, and GH receptor deficiency. To probe the relationship between the receptor and the circulating binding protein, we measured the binding of GH to plasma from a child with Laron-type dwarfism and compared it with that in plasma of normal children and adults. Normal plasma samples were supplemented with unlabeled GH to the endogenous GH level in the plasma of the Laron patient to yield comparable saturation of the BP. After incubation of plasma with radiolabeled GH, bound GH was separated from free GH by gel filtration on Sephadex G-100. There was no detectable binding (less than 1.5%) of GH in the plasma of the Laron-type dwarf, whereas in normal children the bound GH fraction averaged 24.0 +/- 6.1% (mean +/- SD). Thus, the GH-BP is either absent or functionally abnormal in Laron-type dwarfism. This finding suggests that the circulating GH-BP is related to and/or may be derived from the GH receptor. Alternatively, it is possible that the BP plays an as yet poorly understood pivotal role in the promotion of somatic growth.

Recurrent nonsense mutations in the growth hormone receptor from patients with Laron dwarfism.

“…Overall, these genetic defects identified in LTD patients confirm the role of the GH-R cloned by Leung et al (5) in the transduction of the growth signal, and further illustrate the molecular heterogeneity of LTD. It is interesting that sequence homology between the extracellular domain of the GH-R and a soluble plasma growth hormone-binding protein (GH-BP) has been observed (23,24). In the light ofvarious observations (5,25,26) suggesting that GH-R could give rise to GH-BP, we expected the nucleotide changes in codons 38 and 43 to result in the absence of GH binding activity ofthe plasma GH-BP; this was indeed the case. This result throws light on the relationship between GH-R and GH-BP.…”

Influence of the high-affinity growth hormone (GH)-binding protein on plasma profiles of free and bound GH and on the apparent half-life of GH. Modeling analysis and clinical applications.

“…This observation has interesting implications in the interpretation ofhormone concentrations in conditions ofinborn deficiency ofa BP. For example, in Laron dwarfism, there is virtual absence of the GH-BP in plasma, while serum GH concentrations are very high ( 12,13,37,38). This increase in mean serum GH concentrations indicates mathematically that either the secretion rate and/or the t1/2 ofGH are increased (or the VO for GH is decreased) in Laron dwarfs.…”

“…This high-affinity GH-BP corresponds to the extracellular domain of the tissue growth hormone (GH) receptor (5)(6)(7)(8)(9), and contrasts with an incompletely character-ized low-affinity binding protein that is unrelated to the GH receptor (10,11). High-affinity GH-BP concentrations are very low or dysfunctional in Laron-type dwarfism ( 12,13) and decreased in fetal plasma and in certain GH-resistant populations such as pygmies in Africa or the New Guinea highlands ( 10,(14)(15)(16). Studies in heterologous species (e.g., injection of human GH-BP complexed with human GH into the rat) indicate that the presence of a high-affinity binding protein (BP) can prolong the apparent half-life of GH in plasma (17)(18)(19).…”

Long-term effects of insulin-like growth factor (IGF)-I on serum IGF-I, IGF-binding protein-3 and acid labile subunit in Laron syndrome patients with normal growth hormone binding protein

“…In most of the patients, the disease is caused by defects in the GH receptor gene, leading to absence of a functional GH receptor (3,4), or by defects in post-receptor mechanisms (5). Serum GH-binding protein (GHBP), which is identical to the extracellular domain of the GH receptor (6), was reported to be absent in patients with Laron syndrome (7,8) if the deletions or mutations are in the extracellular domain of the GH receptor (3). Several patients with Laron syndrome with detectable GHbinding activity have been reported (5, 9-11) suggesting that these patients have defects in either the transmembrane or intracellular domains of the GH receptor, or a post-receptor defect, all leading to deficiency in the biosynthesis of IGF-I.…”