title: Primary growth hormone (GH) insensitivity and insulin-like growth factor deficiency caused by novel compound heterozygous mutations of the GH receptor gene: genetic and functional studies of simple and compound heterozygous states.
abstract: BACKGROUND
  Primary GH insensitivity (GHI) or Laron syndrome, caused by mutations of the GH receptor (GHR) gene, has a clinical phenotype of postnatal growth failure associated with normal elevated serum concentrations of GH and low serum levels of IGF-I.
  
  
  OBJECTIVE
  We investigated the clinical and biochemical implications of molecular defects in the GHR gene in an Austrian family with two daughters who were GHI.
  
  
  METHODS
  Patient 1 [height, -4.8 sd score (SDS)] and patient 2 (height, -5.0 SDS) had elevated circulating levels of GH, low-normal levels of GH-binding protein, and abnormally low IGF-I (-5.0 SDS and -2.6 SDS, respectively) and IGF-binding protein-3 (-2.6 SDS and -2.0 SDS, respectively).
  
  
  RESULTS
  Both patients carry novel compound, missense, heterozygous GHR mutations, C94S and H150Q. In vitro reconstitution experiments demonstrated that whereas each of the mutants could be stably expressed, GHR(C94S) lost its affinity for GH and could neither activate signal transducer and activator of transcription (STAT)-5b nor drive STAT5b-dependent gene transcription in response to GH (1-100 ng/ml). GHR(H150Q) showed normal affinity for GH but impaired capacity for signal transduction. The compound heterozygote and C94S heterozygote, but not the H150Q heterozygote, showed significant deficiency in activating GH-induced gene expression, corroborating diminished GH-induced STAT5b activation in fibroblasts carrying GHR(C94S) as either a compound heterozygote (in the patients) or a simple heterozygote (in one parent).
  
  
  CONCLUSIONS
  Each of the compound heterozygous mutations contributed additively to the pathological condition seen in the patients, and the more detrimental of the two mutations, C94S, may cause (partial) primary GHI, even in a heterozygous state.
authors.affiliation: Department of Pediatrics, University of Vienna, 1090 Vienna, Austria.
authors.forename: Peng
authors.initials: P
authors.lastname: Fang
authors.forename: Stefan
authors.initials: S
authors.lastname: Riedl
authors.forename: Serge
authors.initials: S
authors.lastname: Amselem
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Pratt
authors.forename: Brian M
authors.initials: BM
authors.lastname: Little
authors.forename: Gabriele
authors.initials: G
authors.lastname: Haeusler
authors.forename: Vivian
authors.initials: V
authors.lastname: Hwa
authors.forename: Herwig
authors.initials: H
authors.lastname: Frisch
authors.forename: Ron G
authors.initials: RG
authors.lastname: Rosenfeld
mesh_terms: D002478:Cells, Cultured; D002648:Child; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D018628:Gene Dosage; D006579:Heterozygote; D019382:Human Growth Hormone / Q000097:blood; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007334:Insulin-Like Growth Factor I / Q000172:deficiency* / Q000378:metabolism; D046150:Laron Syndrome / Q000235:genetics* / Q000378:metabolism*; D020125:Mutation, Missense; D011986:Receptors, Somatotropin / Q000235:genetics* / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D011986:Receptors, Somatotropin; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I