Extreme elevation of serum growth hormone-binding protein concentrations resulting from a novel heterozygous splice site mutation of the growth hormone receptor gene

Anna M. Aalbers, Daisy Chin, Katherine L. Pratt, Brian M. Little, Stuart J. Frank, Vivian Hwa, Ron G. Rosenfeld

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Background/Aims: Circulating growth hormone-binding protein (GHBP), in humans, is the proteolytic product of the growth hormone receptor (GHR). We investigated a prepubertal male subject who was of short stature, but who had a markedly elevated serum level of GHBP. Methods: Serum and DNA from the patient and his mother were analyzed. Results: Both the patient and mother had serum GHBP concentrations over 100-fold higher than normal, by assays, and Western and ligand blot analysis. Sequencing of the GHR gene revealed a novel heterozygous C>A transversion at position 785-3 in the acceptor splice site of intron 7. Conclusion: In silico analysis of the altered sequence suggested that 785-3(C>A) is a splicing mutation, with either retention of intron 7 or the skipping of exon 8. The consequence is a truncated GHR lacking the transmembrane domain (encoded by exon 8) and the cytoplasmic domain. We hypothesize that this GHR variant cannot anchor to the cell membrane, and the continual secretion into the circulation explains the elevated levels of serum GHBP detected in the patient and his mother. Despite this mutation, the presence of the wild-type GHR allele, presumably, permits some normality in GH-induced action.

Original languageEnglish (US)
Pages (from-to)276-284
Number of pages9
JournalHormone Research
Volume71
Issue number5
DOIs
StatePublished - May 1 2009

Keywords

  • Growth hormone receptor defect
  • Growth hormone-binding protein
  • Short stature

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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