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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

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 1

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Identification of a GHSR mutation. (A) Electrophoregram spanning the GHS...
Identification of a GHSR mutation. (A) Electrophoregram spanning the GHSR mutation site from a proband presenting with ISS and a control. The sequence variation, present in the homozygous state, is a C-to-A transversion located within the first GHSR exon (c.611C→A). (B) Location of the predicted A204E mutation in the second extracellular loop of the GHSR1a, a 7-transmembrane G-coupled receptor. (C) Conservation of the GHSR1a amino acid sequence among species within the region bracketing the mutation site between the fourth (TM4) and the fifth (TM5) transmembrane domains; A204E is shown by an arrow.

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

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