The Growth Hormone Receptor (GHR) c.899dupC mutation functions as a dominant negative

Insights into the pathophysiology of intracellular GHR defects

Michael A. Derr, Javier Aisenberg, Peng Fang, Yardena Tenenbaum-Rakover, Ronald (Ron) Rosenfeld, Vivian Hwa

Research output: Contribution to journalArticle

17 Citations (Scopus)

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 onGHR function(s) were evaluated in reconstitution studies. Results: The recombinant human GHR (hGHR):p.R229H variant was readily expressed, and unexpectedly, GH-induced signal transducerandactivator of transcription5b(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.

Original languageEnglish (US)
JournalJournal of Clinical Endocrinology and Metabolism
Volume96
Issue number11
DOIs
StatePublished - Nov 2011

Fingerprint

Laron Syndrome
Somatotropin Receptors
Defects
Mutation
Phosphorylation
Insulin-Like Growth Factor I
Growth Hormone
Phenotype
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

The Growth Hormone Receptor (GHR) c.899dupC mutation functions as a dominant negative : Insights into the pathophysiology of intracellular GHR defects. / Derr, Michael A.; Aisenberg, Javier; Fang, Peng; Tenenbaum-Rakover, Yardena; Rosenfeld, Ronald (Ron); Hwa, Vivian.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 96, No. 11, 11.2011.

Research output: Contribution to journalArticle

Derr, Michael A. ; Aisenberg, Javier ; Fang, Peng ; Tenenbaum-Rakover, Yardena ; Rosenfeld, Ronald (Ron) ; Hwa, Vivian. / The Growth Hormone Receptor (GHR) c.899dupC mutation functions as a dominant negative : Insights into the pathophysiology of intracellular GHR defects. In: Journal of Clinical Endocrinology and Metabolism. 2011 ; Vol. 96, No. 11.
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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 onGHR function(s) were evaluated in reconstitution studies. Results: The recombinant human GHR (hGHR):p.R229H variant was readily expressed, and unexpectedly, GH-induced signal transducerandactivator of transcription5b(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.",
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