A Novel Exonic GHR Splicing Mutation (c.784G > C) in a Patient with Classical Growth Hormone Insensitivity Syndrome

AKINCI A. , Rosenfeld R. G. , Hwa V.

HORMONE RESEARCH IN PAEDIATRICS, cilt.79, ss.32-38, 2013 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Cilt numarası: 79 Konu: 1
  • Basım Tarihi: 2013
  • Doi Numarası: 10.1159/000341527
  • Sayfa Sayıları: ss.32-38


Context: Undetectable circulating growth hormone-binding protein (GHBP) can be indicative of a GH receptor (GHR) defect and cause GH insensitivity (GHI) syndrome. Case Report: The proband, severely growth retarded from birth, had a height of 73 cm (-6 SDS) and weight of 10.5 kg (-2.5 SDS) at the age of 3.25 years; her consanguineous parents were normal statured. Basal serum GH measurement was high, >40 ng/ml, while serum insulin-like growth factor-I (IGF-I; 8.5 ng/ml; normal, 13-100), IGF-binding protein 3 (126 ng/ml; normal, 365-1,294), acid labile subunit (0.59 mg/l; normal, 5.6-16), and GHBP (120 pmol/l; normal, 431-1,892) concentrations were all markedly low. Recombinant IGF-I therapy improved height to -4.4 SDS after 2.5 years of treatment. Results: GHR gene analysis revealed a homozygous c.784G>C transversion, the last nucleotide of exon 7; the parents were heterozygous for the mutation. Evaluation of GHR mRNA indicated c.784G>C was not a missense mutation but induced exon 7 excision, leading to a frame shift and predicted early protein termination. Conclusion: A novel homozygous GHR c.784G>C mutation, identified in a GHI patient, induced functional loss of the native intron 7 donor splice site, demonstrating, for the first time, the importance of exonic nucleotides at exon-intron junctions for normal GHR splicing. Copyright (C) 2012 S. Karger AG, Basel