K. Iida et al., Functional characterization of truncated growth hormone (GH) receptor-(1-277) causing partial GH insensitivity syndrome with high GH-binding protein, J CLIN END, 84(3), 1999, pp. 1011-1016
We have previously reported a novel heterozygous donor splice site mutation
in intron 9 of the GH receptor (GHR) gene in Japanese siblings who showed
partial GH insensitivity and high serum GH-binding protein (GHBP) levels. T
his mutation caused the splicing abnormality and produced the truncated GHR
consisting of 277 amino acids (GHR-277), which lacked most of the intracel
lular domain of GHR, including both boxes 1 and 2. In this study, we have c
haracterized the function of GHR-277 expression in COS-7 and CHO cells in v
itro. Scatchard analysis revealed that GHR-277 possessed approximately 1.5
times higher affinity to GH and twice the number of binding sites compared
to wild-type full-length GHR (GHR-fl). The GHBP level in culture medium of
GHR-277-expressing cells was approximately 3 times higher than that in GHR-
fl-expressing cells. Interestingly, the ligand-induced internalization of G
HR-277 was significantly reduced compared with that of GHR-fl. Moreover, in
GH-induced tyrosine phosphorylation of signal transducer and activator of
transcription-5 (STAT5), GHR-277 exerted a dominant negative effect when GH
R-277 and GHR-fl were cotransfected. These in vitro data would well explain
the clinical characteristics in our patients showing high serum GHBP level
s and development of short stature despite a heterozygous mutation of the G
HR gene.