We present here two mutations of the growth hormone (GH) receptor (GHR) gene in Japanese patients with GH insensitivity syndrome (GHIS) or idiopathic short stature (ISS). One is a heterozygous point mutation of the donor splice site in intron 9 of the GHR gene in 2 siblings with GHIS, whose serum GHBP levels were high. The same mutation was also found in their mother as well. The analysis of RNA from the peripheral leukocytes revealed complete skipping of exon 9 from one allele, but not the other, in the GHR cDNA and appearance of a premature stop codon in exon 10. This mutation caused truncation of GHR with a dominant negative effect on GH signaling, which is probably responsible for their short stature and high serum GHBP levels. The other mutation is a heterozygous missense mutation, C422F, in the intracellular domain of GHR. Although this mutation was previously reported in a patient with GH insensitivity syndrome (GHIS), it has not been clear whether this mutation causes GH insensitivity. To clarify the effect of this mutation on GH signal transduction, mutant GHR was expressed in CHO cells and its functional properties were investigated. Neither GH-induced tyrosine phosphorylation of STAT5b nor STAT5-mediated transcriptional activation were found in GHR-C422F-expressing cells. In addition, the analysis of genotypes and phenotypes of this family revealed that a C422F mutation was found in family members showing normal height, indicating that the C422F missense mutation of GHR is not responsible for short stature.
2001 by The Japanese Society for Pediatric Endocrinology