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The GH receptor and GH insensitivity.

R J Ross1

  • 1Division of Clinical Sciences, Sheffield University, Northern General Hospital, UK. r.j.ross@sheffield.ac.uk

Growth Hormone & IGF Research : Official Journal of the Growth Hormone Research Society and the International IGF Research Society
|November 5, 1999
PubMed
Summary

Growth hormone insensitivity (GHIS) occurs when the body doesn't respond to growth hormone (GH). A specific mutation causes a truncated GH receptor, leading to GHIS by blocking normal receptor function.

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Area of Science:

  • Endocrinology
  • Molecular Biology
  • Genetics

Background:

  • Growth hormone insensitivity (GHIS) is characterized by elevated GH levels and reduced GH biological actions.
  • Congenital GHIS often results from mutations in the GH receptor (GHR), with over 30 identified.
  • The GH receptor signaling pathway involves JAK2, STAT proteins, and MAP kinases.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying GHIS, particularly in cases with normal or high GH binding protein (GHBP) levels.
  • To characterize a specific splice-site mutation in the GHR leading to a truncated receptor and GHIS.
  • To elucidate the role of the truncated GHR in dominant-negative inhibition of GH signaling.

Main Methods:

  • Analysis of GHR mutations in patients with GHIS.

Related Experiment Videos

  • In vitro studies to assess the function of the truncated GHR.
  • Investigation of GHR trafficking and cell surface expression.

    • Main Results:

    • A splice-site mutation causing exon 9 skipping results in a truncated GHR lacking most of its intracellular domain.
    • This truncated GHR leads to GHIS in heterozygous patients.
    • The truncated receptor acts as a dominant-negative inhibitor by heterodimerizing with the full-length GHR and blocking signaling.

    Conclusions:

    • GHIS can result from truncated GHR variants that interfere with normal receptor function.
    • The truncated GHR is highly expressed on the cell surface due to impaired internalization.
    • Understanding these mechanisms enhances knowledge of GHR regulation and GHIS pathophysiology.