title: Serum GH response to pharmacological stimuli and physical exercise in two siblings with two new inactivating mutations in the GH-releasing hormone receptor gene.
abstract: OBJECTIVE
  Inactivating mutations of the GH-releasing hormone receptor (GHRHR) gene (GHRHR) cause familial isolated GH deficiency (IGHD) type IB. The GH response to physical exercise (PE) in patients lacking GHRHR has never been studied. We hypothesized that subjects lacking functional GHRHR may be a model to study GH response to PE.
  
  
  METHODS
  We have analyzed peripheral genomic DNA of a family with two sibs affected by IGHD IB for mutations in the GHRHR, studied the patients' GH response to different GH secretagogues and to PE, and examined the morphology of their pituitary gland by magnetic resonance imaging (MRI).
  
  
  METHODS
  The GHRHR was analyzed by direct sequencing of the 13 exons, intron-exon boundaries, and of the proximal 327 bp of the promoter region in the index case. The patients' GH response to GHRH and standardized PE was studied twice, using a GH ultrasensitive assay in the second round of testing.
  
  
  RESULTS
  Both subjects were compound heterozygotes for two previously undescribed mutations in the GHRHR that are predicted to cause complete lack of functional GHRHR protein: a nonsense mutation in codon 43 (Q43X), and a splice mutation at the beginning of intron 3 (IVS3+1G-->A). MRI showed hypoplasia of their anterior pituitaries. Both subjects had a small but detectable increase in serum GH after maximal PE.
  
  
  CONCLUSIONS
  GHRHR mutations need to be considered in IGHD IB patients even in the absence of parental consanguinity, and patients lacking GHRHR may provide a model to study the mechanism by which PE influences GH secretion.
authors.affiliation: Division of Endocrinology, Department of Medicine and The Ilyssa Center for Molecular and Cellular Endocrinology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. Salvator@jhmi.edu
authors.forename: Roberto
authors.initials: R
authors.lastname: Salvatori
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Fan
authors.forename: Johannes D
authors.initials: JD
authors.lastname: Veldhuis
authors.forename: Robert
authors.initials: R
authors.lastname: Couch
mesh_terms: D001483:Base Sequence / Q000235:genetics; D002648:Child; D015444:Exercise / Q000502:physiology*; D013007:Growth Hormone-Releasing Hormone / Q000235:genetics* / Q000494:pharmacology; D019382:Human Growth Hormone / Q000097:blood* / Q000378:metabolism*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000502:physiology*; D010375:Pedigree; D010903:Pituitary Gland, Anterior / Q000473:pathology
chemical_list: D019382:Human Growth Hormone; D013007:Growth Hormone-Releasing Hormone