Volume 21, Issue 1, March 2005

Table of Contents 21-1

Growth Hormone Receptor and Responsiveness to Growth Hormone

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Intrigued by the clinical observation that the linear growth response to a similar dose of growth hormone (GH) in GH deficient (GHD) and in non-GHD children with idiopathic short stature (ISS) or children with intrauterine growth retardation (IUGR) varied substantially, the investigators correlated the biological effectiveness of recombinant human GH (rhGH) with 2 known isoforms of the GH receptor (GHR). The human gene GHR consists of 9 coding exons with exons 3–7 encoding the extracellular domain of 246 amino acids; there is one full-length isoform of GHR and a second isoform in which the 22 amino acid sequence coded by exon 3 is omitted by alternative splicing during transcription (d3-GHR). In prepubertal children with ISS or IUGR (defined by short birth length), the frequency of the d3-GHR isoform was comparable to that of normal subjects. The GHR genotype (GHR/GHR, GHR/d3-GHR, d3-GHR/d3-GHR) did not affect basal growth rate. When treated with rhGH, subjects with at least one d3-GHR isoform grew more rapidly in response to a standard dose of rhGH (0.36 or 0.23 mg/kg/week in 2 separate trials) than did those with the GHR/GHR genotype during the first 2 years of therapy. There was no difference in growth response to rhGH between children with 1 or 2 d3-GHR alleles or between those with ISS or IUGR. Expression of the GHR and d3-GHR isoforms in HEK fibroblasts in vitro demonstrated that in response to hGH the transcriptional activity of the luciferase reporter gene was ~30% greater in cells with d3-GHR than GHR (Figure). The authors concluded that analysis of the GHR genotype may permit more appropriate individualization of rhGH dosage (pharmacogenetic dose selection) in clinical conditions in which administration of rhGH is appropriate.

Dos Santos C, Essioux L, Teinturier C, Tauber M, Goffin V, Bougnères P. A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone. Nat Genet 2004. 36:720-4.

Editor’s Comment: The mechanism(s) by which the shorter d3-GHR transmits a more potent signal in response to ligand bind than does the full-length GHR is not known. The 22 amino acid sequence of exon 3 is not near the interface of ligand and receptor, and the mechanism by which its loss leads to increased receptor activity is unknown at present. It does not affect hGH/GHR binding or internalization. The d3-GHR polymorphism might permit more rapid propagation of signal to the intracellular signal transduction systems that mediate the cellular responses to hGH. In this regard, it would be of interest to study the dynamics of this system in cells expressing either the full-length or shortened GHR isoforms. The report also raises the question that if a polymorphism that increases responsiveness to hGH exists, might there not also be a subtle polymorphism that mildly depresses GHR transduction of the hGH signal? Might this be another pathway through which the “genetic” regulation of growth and adult stature is mediated?

Allen W. Root, MD

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