title: Analysis of the intracellular signalling domain of the human growth hormone receptor in children with idiopathic short stature.
abstract: OBJECTIVE
  To investigate the hypothesis that intracellular, dominant-negative mutations of the growth hormone receptor (GHR) exist in children with idiopathic short stature (ISS) and partial growth hormone insensitivity (GHI).
  
  
  METHODS
  We studied 31 children aged 4.55-13.14 years with ISS (height </= -1.8 standard deviation scores, UK standards 1990). GH provocation tests (glucagon 15 microg kg-1 i.m.) excluded GH deficiency in all subjects. Serum IGF-I levels were below the 50th centile for age in all subjects and below the 10th centile in 64.5% of cases. GH binding protein levels were normal in the 24 subjects in whom it was measured (mean 25.2%; range 10-42.6%).
  
  
  METHODS
  Exons 9 and 10 of the GHR were amplified by PCR from leucocyte-derived DNA. Samples were directly sequenced on the ABI 377 DNA analyser using the - 21 M13 dye primer cycle sequencing protocol for optimum heterozygote detection.
  
  
  RESULTS
  No abnormalities were detected in exon 9 which encodes the proline-rich box 1 motif. In exon 10 two sequence variants were found; a heterozygous, single base alteration (TCT to TCC) in codon 325 which does not change the amino acid sequence in one patient, and the L526I variant in 24 subjects. L526I is a conservative amino acid change and had an allele frequency of 0.53 in our patients, which is similar to that reported in a control population.
  
  
  CONCLUSIONS
  The apparent partial growth hormone insensitivity in this group of idiopathic short-stature subjects is not related to heterozygous, dominant-negative variants of the intracellular signalling domain of the GHR. Hence it is likely that other genetic and environmental factors may be involved.
authors.affiliation: Molecular Endocrinology Laboratory and Paediatric Endocrine Section, St Bartholomew's Hospital, London, UK.
authors.forename: L B
authors.initials: LB
authors.lastname: Johnston
authors.forename: F
authors.initials: F
authors.lastname: Pashankar
authors.forename: C
authors.initials: C
authors.lastname: Camacho-Hübner
authors.forename: M O
authors.initials: MO
authors.lastname: Savage
authors.forename: A J
authors.initials: AJ
authors.lastname: Clark
mesh_terms: D000293:Adolescent; D002352:Carrier Proteins / Q000097:blood; D002648:Child; D002675:Child, Preschool; D004586:Electrophoresis; D005091:Exons; D005260:Female; D006130:Growth Disorders / Q000235:genetics* / Q000378:metabolism; D013006:Growth Hormone / Q000097:blood; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008297:Male; D009154:Mutation; D016133:Polymerase Chain Reaction / Q000379:methods; D011986:Receptors, Somatotropin / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D002352:Carrier Proteins; D018972:Insulin-Like Growth Factor Binding Protein 3; D011986:Receptors, Somatotropin; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C051815:somatotropin-binding protein