Absence of serum growth hormone binding protein in patients with growth hormone receptor deficiency (Laron dwarfism).

Abstract

It has recently been recognized that human serum contains a protein that specifically binds human growth hormone (hGH). This protein has the same restricted specificity for hGH as the membrane-bound GH receptor. To determine whether the GH-binding protein is a derivative of, or otherwise related to, the GH receptor, we have examined the serum of three patients with Laron-type dwarfism, a condition in which GH refractoriness has been attributed to a defect in the GH receptor. The binding of 1251-labeled hGH incubated with serum has been measured after gel filtration of the serum through an Ultrogel AcA 44 minicolumn. Nonspecific binding was determined when '25I-hGH was incubated with serum in tho presence of an excess of GH. Results are expressed as percent of specifically bound 251-hGH and as specific binding relative to that of a reference serum after correction is made for endogenous GH. The mean ± SEM of specific binding of sera from eight normal adults (26-46 years of age) was 21.6 ± 0.45%, and the relative specific binding was 101.1 ± 8.6%. Sera from 11 normal children had lower specific binding of 12.5 ± 1.95% and relative specific binding of 56.6 ± 9.1%. Sera from three children with Laron-type dwarfism lacked any demonstrable GH binding, whereas sera from 10 other children with other types of nonpituitary short stature had normal relative specific binding. We suggest that the serum GHbinding protein is a soluble derivative of the GH receptor. Measurement of the serum GH-binding protein may permit recognition of other abnormalities of the GH receptor.When normal human serum is subjected to gel filtration in neutral buffers, higher-molecular-weight forms of growth hormone (GH) have been frequently reported (1, 2). While these big forms of GH have been attributed to incompletely processed precursor forms of the hormone or aggregated GH molecules, there is now evidence that complexes of GH with a specific serum binding protein exist in human serum and the serum of a number of mammals.The presence of a specific GH-binding protein (GH-BP) was first convincingly established in rabbit serum by Ymer and Herington (3). They added "25I-labeled human GH (hGH) or 125mlabeled bovine GH to normal rabbit serum, and after 2 hr of incubation, the reaction mixture was filtered through Ultrogel. As much as 45% of the added 125I-labeled hGH (125I-hGH) was bound to a component with a Mr of >100,000. Rabbit OH-BP had little affinity for either prolactin or human placental lactogen. The serum GH-BP, like a cytosolic GH-BP found in liver, exhibited 100% cross-reactivity with a monoclonal antireceptor antibody raised by Simpson et al. (4,5) against GH receptors isolated from rabbit liver membranes. These observations led Ymer and Herington to suggest that the serum GH-BP arises from the liver and might be structurally related to the membrane-bound GH receptor. Herington et al. (6) then demonstrated a similar GH-BP in human serum by gel filtration. The techniques of charcoal adsorption and PEG precipitation, which are oft...

New molecular mechanisms of GH resistance

“…Direct evidence of a GH receptor (GHR) abnormality was provided by Eshet et al (3), who demonstrated that hepatic microsomes obtained from two patients failed to bind radiolabeled GH. Subsequent studies indicated that serum concentrations of GH binding protein (GHBP), the extracellular domain of the GHR, were reduced in patients, consistent with an underlying receptor defect (4).…”

The D152H mutation found in growth hormone insensitivity syndrome impairs expression and function of human growth hormone receptor but is silent in rat receptor

“…In most cases, GH binding activity of binding protein (BP)/receptor is undetectable and this is consistent with a defect in the extracellular domain of the GHR, which results in impaired hormone binding (Daughaday & Trivedi 1987). However, recent reports have described patients with positive GHBP (Buchanan et al 1991, Savage et al 1993.…”

Whole Body Nitrogen Kinetics and Their Relationship to Growth in Short Children Treated with Recombinant Human Growth Hormone

“…There was no gross structural abnormality of the circulating growth hormone molecule as probed by radioreceptor and monoclonal antibody assays (47,48). No child had absent growth hormone receptors as assessed by assaying circulating growth hormone binding protein levels (49). Each subject's cultured fibroblasts were normally sensitive to IGF-I with regard to uptake of aminoisobutyric acid (55).…”

“…Plasma growth hormone concentrations were quantified by conventional polyclonal RIA, by IM-9 lymphocyte (47) or human liver radioreceptor assay (48), and by two-site monoclonal IRMA (Hybridtech, San Diego, CA). Serum growth hormone binding protein (49) and circulating IGF-I concentration (50) were measured as described previously. Osteocalcin was measured by specific RIA using a commercial antibody (Incstar Corp., Stillwater, MN).…”