title: Short stature caused by a biologically inactive mutant growth hormone (GH-C53S).
abstract: Human GH has two disulfide bridges linking Cys-53 to Cys-165 and Cys-182 to Cys-189. Although absence of the first disulfide bridge has been shown to affect the bioactivity of GH in transgenic mice, little is known of the importance of this bridge in mediating the GH/GH-receptor (GHR) interaction in humans. However, we have identified a missense mutation (G705C) in the GH1 gene of a Serbian patient. This mutation was found in the homozygous state and leads to the absence of the disulfide bridge Cys-53 to Cys-165. To study the impact of this mutation in vitro, GHR binding and Janus kinase (Jak)2/signal transducer and activator of transcription (Stat)5 activation experiments were performed, in which it was observed that at physiological concentrations (3-50 ng/ml) both GHR binding and Jak2/Stat5 signaling pathway activation were significantly reduced in the mutant GH-C53S, compared with wild-type (wt)-GH. Higher concentrations (400 ng/ml) were required for this mutant to elicit responses similar to wt-GH. These results demonstrate that the absence of the disulfide bridge Cys-53 to Cys-165 affects the binding affinity of GH for the GHR and subsequently the potency of GH to activate the Jak2/Stat5 signaling pathway. In conclusion, we have demonstrated that GH-C53S is a bioinactive GH at the physiological range and that the disulfide bridge Cys-53 to Cys-163 is required for mediating the biological effects of GH.
authors.affiliation: University Children's Hospital, Pediatric Endocrinology and Metabolism, Inselspital, University of Bern, CH-3010 Bern, Switzerland.
authors.forename: Amélie
authors.initials: A
authors.lastname: Besson
authors.forename: Souzan
authors.initials: S
authors.lastname: Salemi
authors.forename: Johnny
authors.initials: J
authors.lastname: Deladoëy
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Vuissoz
authors.forename: Andrée
authors.initials: A
authors.lastname: Eblé
authors.forename: Martin
authors.initials: M
authors.lastname: Bidlingmaier
authors.forename: Sibylle
authors.initials: S
authors.lastname: Bürgi
authors.forename: Ulrich
authors.initials: U
authors.lastname: Honegger
authors.forename: Christa
authors.initials: C
authors.lastname: Flück
authors.forename: Primus E
authors.initials: PE
authors.lastname: Mullis
mesh_terms: D001827:Body Height; D002648:Child; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006130:Growth Disorders / Q000235:genetics*; D019382:Human Growth Hormone / Q000235:genetics*; D006801:Humans; D053614:Janus Kinase 2; D008297:Male; D008894:Milk Proteins / Q000378:metabolism; D020125:Mutation, Missense; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000032:analysis; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D011986:Receptors, Somatotropin; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D019382:Human Growth Hormone; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2