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The growth hormone receptor (GHR) c.899dupC mutation functions as a dominant negative: insights into the pathophysiology of intracellular GHR defects.

Abstract

CONTEXT
GH insensitivity (GHI) is a condition characterized by pronounced IGF-I deficiency and severe short stature. We previously identified a novel compound heterozygous GH receptor (GHR) mutation, GHR:p.R229H/c.899dupC, in a patient presenting with GHI. The heterozygous p.R229H (prepeptide) variant was previously associated with GHI despite a lack of adequate functional studies. The novel heterozygous GHR:c.899dupC variant affects the critical JAK2-binding Box 1 region of the GHR intracellular domain; the duplication predicted a frameshift and early protein termination.
OBJECTIVE
The individual and synergistic effect(s) of the p.R229H and c.899dupC mutations on GHR function(s) were evaluated in reconstitution studies.
RESULTS
The recombinant human GHR (hGHR):p.R229H variant was readily expressed, and unexpectedly, GH-induced signal transducer and activator of transcription 5b (STAT5b) phosphorylation was comparable to that induced by wild-type hGHR. The truncated, immunodetected hGHR:c.899dupC variant, in contrast, was unresponsive to GH. To mimic a compound heterozygous state, the two variants were coexpressed, and strikingly, the presence of the hGHR:c.899dupC effectively abolished the GH-induced STAT5b activities that were observed with hGHR:p.R229H alone. Furthermore, hGHR:c.899dupC dose-dependently reduced the GH-induced STAT5b activities associated with hGHR:p.R229H. This dominant negative effect was also observed when hGHR:c.899dupC was coexpressed with wild-type hGHR.
CONCLUSION
The p.R229H variant, contrary to an earlier report, appeared to function like wild-type GHR and, therefore, is unlikely to cause GHI. The c.899dupC variant is a novel dominant negative mutation that disrupted normal GHR signaling and is the cause for the GHI phenotype of the reported patient.

Links

  • Publisher Full Text
  • Authors

    Derr MA, Aisenberg J, Fang P, Tenenbaum-Rakover Y, Rosenfeld RG, Hwa V

    Source

    The Journal of clinical endocrinology and metabolism 96:11 2011 Nov pg E1896-904

    MeSH

    HEK293 Cells
    Humans
    Insulin-Like Growth Factor I
    Laron Syndrome
    Mutation
    Phosphorylation
    Receptors, Somatotropin
    STAT5 Transcription Factor
    Signal Transduction

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    21900382