Abnormal GH Receptor Signaling in Children with Idiopathic Short Stature

Abstract

Peripheral GH insensitivity may underlie idiopathic short stature in children. As the clinical and biochemical hallmarks of partial GH insensitivity have not yet been clearly elucidated, the identification of such patients is still difficult. We integrated functional, biochemical, and molecular studies to define the more reliable marker(s) of GH insensitivity. In particular, we measured GH receptor transducing properties through GH-induced protein tyrosine phosphorylation in patients' peripheral blood mononuclear cells and performed direct sequencing analysis of GH receptor-coding exons. Five of 14 idiopathic short stature patients with low basal IGF-I levels showed low or absent IGF-I increment after 4 d of GH administration. However, a prolonged GH stimulation induced in 3 of them an increase in IGF-I 40% above the baseline value. The IGF-binding protein-3 behavior paralleled that of IGF-I. The 2 GH-unresponsive subjects showed an abnormal tyrosine phosphorylation pattern after GH challenge. Sequence analysis of the GH receptor gene revealed a heterozygous mutation resulting in an Arg to Cys change (R161C) in exon 6 in only 1 patient, who had normal GH receptor responsiveness. Our findings indicate that abnormal GH receptor signaling may underlie idiopathic short stature even in the absence of GH receptor mutations. Thus, combining the 4-d IGF-I generation test and the analysis of GH-induced protein tyrosine phosphorylation is a useful tool to help identify idiopathic short stature patients with partial GH insensitivity.

New molecular mechanisms of GH resistance

“…Several other potential defects downstream of the GHR have been reported in patients with growth failure and apparent GHI, but underlying molecular defects have not been identified to date. Nevertheless, in two of the studies, GH failed to induce tyrosine phosphorylation of the STAT proteins, further underscoring the importance of this protein in GH action (21,22).…”

Genetic control of growth

“…Further, the concept of dysfunctional GH variants and/or bio-inactive GH molecules has been proposed for years (153) and opens an interesting platform to study the elements between GHD and IGFD, as some of these patients excellently respond to the exogenous GH treatment. In addition, there are reports on abnormal GHR signalling in children with ISS in the absence of any GHR or GH gene alteration (154,155).…”

“…Until recently, although several patients with a phenotype of GHIS and a normal GHR gene have been described and no specific molecular downstream defect of the GHR identified (154), there is only one patient reported so far with the clinical and biochemical characteristics of GHIS presenting a homozygous missense mutation in the gene for STAT5b (151). As child suffering from a IGF-I gene defect experienced respiratory difficulties with increased oxygen requirements (151,152).…”

“…However, it may be a challenging concept that GHR gene mutations are responsible for about 5% of all ISS patients and it underscores the fact that these mutations should be considered when other causes of short stature have been eliminated. In addition, abnormal GHR signalling may also underlie ISS even in the absence of GHR gene mutations (154,184). Although until recently it had been assumed that GH signalling following GHR homodimerization was mediated primarily by the JAK/STAT pathway and that the extracellular signal regulated kinase (ERK) pathway does not induce hepatic IGF-I production (185), a novel dysfunctional GH variant (I179M) exhibiting a decreased ability to activate the ERK pathway, resulting in short stature, has been described (186).…”

Bases Genéticas dos Distúrbios de Crescimento

“…descreveram pela primeira vez a presença de mutações no gene GHR em crianças com baixa estatura idiopática que apresentavam níveis baixos de IGF-I e de sua proteína carreadora (GHBP) (85). Outras publicações se seguiram e atualmente há 8 mutações descritas como responsáveis pela insensibilidade parcial ao GH com uma freqüência entre 3 a 5% em crianças com baixa estatura idiopática (82,(85)(86)(87)(88). Em nosso grupo encontramos 2 mutações em heterozigose em 47 crianças (4,2%) com baixa estatura idiopática selecionadas por apresentarem níveis de IGF-I e/ou IGFBP-3 ≤ -1 DP para idade e sexo (89).…”