Analysis of the intracellular signalling domain of the human growth hormone receptor in children with idiopathic short stature

OBJECTIVE To investigate the hypothesis that intracellular, dominant-negati ve mutations of the growth hormone receptor (GHR) exist in children with id iopathic short stature (ISS) and partial growth hormone insensitivity (GHI) . SUBJECTS We studied 31 children aged 4.55-13.14 years with ISS (height less than or equal to -1.8 standard deviation scores, UK standards 1990). GH pr ovocation tests (glucagon 15 mu g kg(-1) i.m.) excluded GH deficiency in al l subjects. Serum IGF-I levels were below the 50th centile for age in all s ubjects and below the 10th centile in 64.5% of cases. GH binding protein le vels were normal in the 24 subjects in whom it was measured (mean 25.2%; ra nge 10-42.6%). METHODS Exons 9 and 10 of the GHR were amplified by PCR from leucocyte-deri ved DNA. Samples were directly sequenced on the ABI 377 DNA analyser using the - 21 m13 dye primer cycle sequencing protocol for optimum heterozygote detection. RESULTS No abnormalities were detected in exon 9 which encodes the proline- rich box 1 motif. In exon 10 two sequence variants were found; a heterozygo us, single base alteration (TCT to TCC) in codon 325 which does not change the amino acid sequence in one patient, and the L526I variant in 24 subject s. L526I is a conservative amino acid change and had an allele frequency of 0.53 in our patients, which is similar to that reported in a control popul ation. CONCLUSIONS The apparent partial growth hormone insensitivity in this group of idiopathic short-stature subjects is not related to heterozygous, domin ant-negative variants of the intracellular signalling domain of the GHR. He nce it is likely that other genetic and environmental factors may be involv ed.