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Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature
Jacques Pantel, … , Yves Le Bouc, Serge Amselem
Jacques Pantel, … , Yves Le Bouc, Serge Amselem
Published March 1, 2006
Citation Information: J Clin Invest. 2006;116(3):760-768. https://doi.org/10.1172/JCI25303.
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Research Article Endocrinology Article has an altmetric score of 10

Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature

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Abstract

The growth hormone (GH) secretagogue receptor (GHSR) was cloned as the target of a family of synthetic molecules endowed with GH release properties. As shown recently through in vitro means, this receptor displays a constitutive activity whose clinical relevance is unknown. Although pharmacological studies have demonstrated that its endogenous ligand — ghrelin — stimulates, through the GHSR, GH secretion and appetite, the physiological importance of the GHSR-dependent pathways remains an open question that gives rise to much controversy. We report the identification of a GHSR missense mutation that segregates with short stature within 2 unrelated families. This mutation, which results in decreased cell-surface expression of the receptor, selectively impairs the constitutive activity of the GHSR, while preserving its ability to respond to ghrelin. This first description, to our knowledge, of a functionally significant GHSR mutation, which unveils the critical importance of the GHSR-associated constitutive activity, discloses an unusual pathogenic mechanism of growth failure in humans.

Authors

Jacques Pantel, Marie Legendre, Sylvie Cabrol, Latifa Hilal, Yassir Hajaji, Séverine Morisset, Sylvie Nivot, Marie-Pierre Vie-Luton, Dominique Grouselle, Marc de Kerdanet, Abdelkrim Kadiri, Jacques Epelbaum, Yves Le Bouc, Serge Amselem

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Figure 6

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Ligand-mediated signal transduction of the A204E GHSR1a in transiently t...
Ligand-mediated signal transduction of the A204E GHSR1a in transiently transfected HEK293 cells. Cells expressing WT GHSR1a, GHSR1a A204E, or mock-transfected cells were incubated either in the absence or in the presence of an agonist (ghrelin at 10–6 M), or of an inverse agonist ([D-Arg1, D-Phe5, D-Trp7,9, Leu11]-substance P, or SPA, at 10–6 M). The transcriptional activity in each condition (RLU/μg proteins) is expressed as a percentage of the basal activity of the WT GHSR1a receptor. Values are the mean ± SD of 1 representative experiment performed in triplicate among 6 independent experiments. *P < 0.05 and **P < 0.01 (ligand-induced signal versus basal level). (A) CRE-mediated transcriptional activity. Cells were cotransfected with 100 ng of each expression plasmid and 250 ng of the pPOU1F1-Luc reporter plasmid. (B) SRE-mediated transcriptional activity. Cells were cotransfected with 10 ng of each expression plasmid and 500 ng of the pSRE-Luc reporter plasmid.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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