Functional characterization of truncated growth hormone (GH) receptor-(1-277) causing partial GH insensitivity syndrome with high GH-binding protein

J Clin Endocrinol Metab. 1999 Mar;84(3):1011-6. doi: 10.1210/jcem.84.3.5566.

Abstract

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. This mutation caused the splicing abnormality and produced the truncated GHR consisting of 277 amino acids (GHR-277), which lacked most of the intracellular domain of GHR, including both boxes 1 and 2. In this study, we have characterized the function of GHR-277 expression in COS-7 and CHO cells in vitro. 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 GHR-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 GHR-277 and GHR-fl were cotransfected. These in vitro data would well explain the clinical characteristics in our patients showing high serum GHBP levels and development of short stature despite a heterozygous mutation of the GHR gene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Animals
  • CHO Cells
  • COS Cells
  • Carrier Proteins / metabolism*
  • Child
  • Cricetinae
  • Culture Media / metabolism
  • Drug Resistance
  • Female
  • Genes, Dominant / physiology
  • Human Growth Hormone / pharmacology
  • Human Growth Hormone / physiology*
  • Humans
  • Male
  • Middle Aged
  • Peptide Fragments / physiology*
  • Receptors, Somatotropin / physiology*
  • Signal Transduction / physiology
  • Time Factors

Substances

  • Carrier Proteins
  • Culture Media
  • Peptide Fragments
  • Receptors, Somatotropin
  • Human Growth Hormone
  • somatotropin-binding protein