title: Growth hormone (GH) deficiency type II: a novel GH-1 gene mutation (GH-R178H) affecting secretion and action.
abstract: OBJECTIVE
  Main features of the autosomal dominant form of GH deficiency (IGHD II) include markedly reduced secretion of GH combined with low concentrations of IGF-I leading to short stature.
  
  
  METHODS
  A female patient presented with short stature (height -6.0 sd score) and a delayed bone age of 2 yr at the chronological age of 5 yr. Later, at the age of 9 yr, GHD was confirmed by standard GH provocation test, which revealed subnormal concentrations of GH and a very low IGF-I. Genetic analysis of the GH-1 gene revealed the presence of a heterozygous R178H mutation.
  
  
  RESULTS
  AtT-20 cells coexpressing both wt-GH and GH-R178H showed a reduced GH secretion after forskolin stimulation compared with the cells expressing only wt-GH, supporting the diagnosis of IGHD II. Because reduced GH concentrations found in the circulation of our untreated patient could not totally explain her severe short stature, functional characterization of the GH-R178H performed by studies of GH receptor binding and activation of the Janus kinase-2/signal transducer and activator of transcription-5 pathway revealed a reduced binding affinity of GH-R178H for GH receptor and signaling compared with the wt-GH.
  
  
  CONCLUSIONS
  This is the first report of a patient suffering from short stature caused by a GH-1 gene alteration affecting not only GH secretion (IGHD II) but also GH binding and signaling, highlighting the necessity of functional analysis of any GH variant, even in the alleged situation of IGHD II.
authors: University Children's Hospital, Pediatric Endocrinology, Inselspital CH-3010 Bern, Switzerland.
authors: Vibor
authors: V
authors: Petkovic
authors: Michela
authors: M
authors: Godi
authors: Amit V
authors: AV
authors: Pandey
authors: Didier
authors: D
authors: Lochmatter
authors: Charles R
authors: CR
authors: Buchanan
authors: Mehul T
authors: MT
authors: Dattani
authors: Andrée
authors: A
authors: Eblé
authors: Christa E
authors: CE
authors: Flück
authors: Primus E
authors: PE
authors: Mullis
mesh_terms: D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D002648:Child; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D019382:Human Growth Hormone / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000502:physiology; D051379:Mice; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011986:Receptors, Somatotropin / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000502:physiology; D015032:Zinc / Q000378:metabolism
chemical_list: D011986:Receptors, Somatotropin; D050799:STAT5 Transcription Factor; D019382:Human Growth Hormone; D053614:Janus Kinase 2; D015032:Zinc