title: Short stature in two siblings heterozygous for a novel bioinactive GH mutant (GH-P59S) suggesting that the mutant also affects secretion of the wild-type GH.
abstract: OBJECTIVE
  Short stature caused by biologically inactive GH is clinically characterized by lack of GH action despite normal-high secretion of GH, pathologically low IGF1 concentrations and marked catch-up growth on GH replacement therapy.
  
  
  METHODS
  Adopted siblings (girl and a boy) of unknown family history were referred for assessment of short stature (-4.5 and -5.6 SDS) at the age of 10 and 8.1 years respectively. They had delayed bone ages (6.8 and 4.5 years), normal GH peaks at stimulation tests, and severely reduced IGF1 concentrations (-3.5 and -4.0 SDS). Genetic analysis of the GH1 gene showed a heterozygous P59S mutation at position involved in binding to GH receptor (GHR).
  
  
  RESULTS
  Isoelectric focusing analysis of secreted GH in patient serum revealed the presence of higher GH-P59S peak compared with that of wt-GH. Furthermore, computational simulation of GH-P59S binding to GHR suggested problems in correct binding of the mutant to the GHR. In vitro GHR binding studies revealed reduced binding affinity of GH-P59S for GHR (IC₅₀, 30  ng/ml) when compared with the wt-GH (IC₅₀, 11.8  ng/ml) while a significantly decreased ability of the mutant to activate the Jak2/Stat5 signaling pathway was observed at physiological concentrations of 25-100  ng/ml.
  
  
  CONCLUSIONS
  The clinical and biochemical data of our patients support the diagnosis of partial bioinactive GH syndrome. The higher amount of GH-P59S secreted in their circulation combined with its impact on the wt-GH function on GHR binding and signaling may alter GHR responsiveness to wt-GH and could ultimately explain severe short stature found in our patients.
authors: Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Clinical Research, University Children's Hospital Bern, Inselspital, CH-3010 Bern, Switzerland. vibor.petkovic@dkf.unibe.ch
authors: Vibor
authors: V
authors: Petkovic
authors: Maria Consolata
authors: MC
authors: Miletta
authors: Annemieke M
authors: AM
authors: Boot
authors: Monique
authors: M
authors: Losekoot
authors: Christa E
authors: CE
authors: Flück
authors: Amit V
authors: AV
authors: Pandey
authors: Andrée
authors: A
authors: Eblé
authors: Jan Maarten
authors: JM
authors: Wit
authors: Primus E
authors: PE
authors: Mullis
mesh_terms: D019943:Amino Acid Substitution; D001827:Body Height; D002648:Child; D005260:Female; D006579:Heterozygote; D020249:Hormone Replacement Therapy; D019382:Human Growth Hormone / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D011986:Receptors, Somatotropin / Q000378:metabolism; D035781:Siblings
chemical_list: D011986:Receptors, Somatotropin; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I