title: Isolated growth hormone (GH) deficiency due to compound heterozygosity for two new mutations in the GH-releasing hormone receptor gene.
abstract: OBJECTIVE
  Mutations in the GH releasing hormone receptor (GHRH-R) have recently been shown to cause autosomal recessive isolated GH deficiency (IGHD). Patients who are homozygous for GHRH-R mutations have a subnormal GH response to pharmacological agents that stimulate GH secretion and an appropriate response to exogenous GH therapy. We searched for mutations in the GHRH-R gene in a family in which two of three siblings were affected by IGHD.
  
  
  METHODS
  We sequenced the 13 coding exons, the intron-exon boundaries and 327 bases of the promoter of the GHRH-R gene from peripheral blood cell genomic DNA of an index patient.
  
  
  RESULTS
  Both affected individuals were compound heterozygotes for two previously undescribed GHRH-R mutations: a change in codon 137 that replaces histidine with leucine (H137L), and a 5 bp deletion in exon 11 (Del 1140-1144). The patients' father was heterozygous for the H137L mutation, and the mother was heterozygous for the exon 11 deletion. We used site-directed mutagenesis to create the mutants in wild-type GHRH-R cDNA. Transient transfection of GHRH-R cDNAs in Chinese hamster ovary cells showed that cells transfected with both mutant receptors failed to increase cyclic AMP after treatment with GHRH.
  
  
  CONCLUSIONS
  We describe a family in which two siblings with IGHD were compound heterozygotes for two new mutations in the GHRH-R gene. These results suggest that mutant alleles for GHRH-R gene may be more common than previously suspected.
authors.affiliation: Division of Endocrinology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. salvator@jhmi.edu
authors.forename: R
authors.initials: R
authors.lastname: Salvatori
authors.forename: X
authors.initials: X
authors.lastname: Fan
authors.forename: J A
authors.initials: JA
authors.lastname: Phillips
authors.forename: M
authors.initials: M
authors.lastname: Prince
authors.forename: M A
authors.initials: MA
authors.lastname: Levine
mesh_terms: D000818:Animals; D016466:CHO Cells; D002648:Child; D002675:Child, Preschool; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D017353:Gene Deletion; D013006:Growth Hormone / Q000172:deficiency*; D013007:Growth Hormone-Releasing Hormone; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D018013:Receptors, Neuropeptide / Q000235:genetics*; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000235:genetics*; D014162:Transfection
chemical_list: D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; C039542:somatocrinin receptor; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; D000242:Cyclic AMP