title: Novel compound heterozygous mutations of the growth hormone-releasing hormone receptor gene in a case of isolated growth hormone deficiency.
abstract: OBJECTIVE
  To elucidate the pathogenesis of isolated growth hormone (GH) deficiency in a Japanese girl without consanguinity.
  
  
  METHODS
  A 2-year-old girl of height 77.2 cm (-3.0 SD for Japanese girls) was found to have an insulin-like growth factor (IGF)-1 level of 7 ng/mL and IGF binding protein-3 (IGFBP-3) level of 0.41 μg/mL. GH responded modestly to a series of pharmacological stimulants, increasing to 2.81 ng/mL with insulin-induced hypoglycemia, 3.78 ng/mL with arginine, and 3.93 with GH-releasing hormone (GHRH). Following direct sequencing of the GHRH receptor (GHRHR) gene, evaluation by the luciferase reporter assay, immunofluorescence study, and in vitro splicing assay with minigene constructs was conducted.
  
  
  RESULTS
  Novel compound heterozygous GHRHR gene mutations were identified in the patient. A p.G136V substitution elicited no luciferase activity increment in response to GHRH stimulation, with normal membranous expression. Splicing assay demonstrated that the IVS2+3a>g mutation would lead to aberrant splicing.
  
  
  CONCLUSIONS
  A case of isolated GH deficiency due to novel GHRHR gene mutations was identified.
authors.affiliation: Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Soneda
authors.forename: Masanori
authors.initials: M
authors.lastname: Adachi
authors.forename: Koji
authors.initials: K
authors.lastname: Muroya
authors.forename: Yumi
authors.initials: Y
authors.lastname: Asakura
authors.forename: Masaki
authors.initials: M
authors.lastname: Takagi
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Hasegawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Itakura
mesh_terms: D000595:Amino Acid Sequence; D015153:Blotting, Western; D049109:Cell Proliferation; D002675:Child, Preschool; D004393:Dwarfism, Pituitary / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D013007:Growth Hormone-Releasing Hormone / Q000378:metabolism*; D006579:Heterozygote; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012326:RNA Splicing; D018013:Receptors, Neuropeptide / Q000235:genetics*; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
chemical_list: D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D013007:Growth Hormone-Releasing Hormone; D008156:Luciferases; C048250:somatotropin releasing hormone receptor