title: Evaluation of the biological activity of a growth hormone (GH) mutant (R77C) and its impact on GH responsiveness and stature.
abstract: OBJECTIVE
  A single missense mutation in the GH-1 gene converting codon 77 from arginine (R) to cysteine (C) yields a mutant GH-R77C peptide, which was described as natural GH antagonist.
  
  
  METHODS
  Heterozygosity for GH-R77C/wt-GH was identified in a Syrian family. The index patient, a boy, was referred for assessment of his short stature (-2.5 SD score) and partial GH insensitivity was diagnosed. His mother and grandfather were also carrying the same mutation and showed partial GH insensitivity with modest short stature.
  
  
  RESULTS
  Functional characterization of the GH-R77C was performed through studies of GH receptor binding and activation of Janus kinase 2/Stat5 pathway. No differences in the binding affinity and bioactivity between wt-GH and GH-R77C were found. Similarly, cell viability and proliferation after expression of both GH peptides in AtT-20 cells were identical. Quantitative confocal microscopy analysis revealed no significant difference in the extent of subcellular colocalization between wt-GH and GH-R77C with endoplasmic reticulum, Golgi, or secretory vesicles. Furthermore studies demonstrated a reduced capability of GH-R77C to induce GHR/GHBP gene transcription rate when compared with wt-GH.
  
  
  CONCLUSIONS
  Reduced GH receptor/GH-binding protein expression might be a possible cause for the partial GH insensitivity with delay in growth and pubertal development found in our patients. In addition, this group of patients deserves further attention because they could represent a distinct clinical entity underlining that an altered GH peptide may also have a direct impact on GHR/GHBP gene expression causing partial GH insensitivity.
authors.affiliation: Department of Pediatric Endocrinology, Diabetology and Metabolism, University Children's Hospital, Inselspital, CH-3010 Bern, Switzerland.
authors.forename: Vibor
authors.initials: V
authors.lastname: Petkovic
authors.forename: Amélie
authors.initials: A
authors.lastname: Besson
authors.forename: Mario
authors.initials: M
authors.lastname: Thevis
authors.forename: Didier
authors.initials: D
authors.lastname: Lochmatter
authors.forename: Andrée
authors.initials: A
authors.lastname: Eblé
authors.forename: Christa E
authors.initials: CE
authors.lastname: Flück
authors.forename: Primus E
authors.initials: PE
authors.lastname: Mullis
mesh_terms: D000483:Alleles; D000818:Animals; D001827:Body Height / Q000187:drug effects*; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D005455:Fluorescent Antibody Technique; D017930:Genes, Reporter; D005822:Genetic Vectors; D006128:Growth / Q000502:physiology; D013006:Growth Hormone / Q000627:therapeutic use*; D006579:Heterozygote; D019382:Human Growth Hormone / Q000037:antagonists & inhibitors* / Q000097:blood / Q000235:genetics*; D006801:Humans; D007525:Isoelectric Focusing; D008156:Luciferases / Q000235:genetics; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D009154:Mutation; D010375:Pedigree; D011627:Puberty / Q000502:physiology; D011986:Receptors, Somatotropin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D011986:Receptors, Somatotropin; D019382:Human Growth Hormone; D013006:Growth Hormone; D008156:Luciferases