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Ghrelin receptor mutations — too little height and too much hunger
Birgitte Holst, Thue W. Schwartz
Birgitte Holst, Thue W. Schwartz
Published March 1, 2006
Citation Information: J Clin Invest. 2006;116(3):637-641. https://doi.org/10.1172/JCI27999.
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Ghrelin receptor mutations — too little height and too much hunger

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Abstract

The ghrelin receptor is known from in vitro studies to signal in the absence of the hormone ghrelin at almost 50% of its maximal capacity. But, as for many other 7-transmembrane receptors, the in vivo importance of this ligand-independent signaling has remained unclear. In this issue of the JCI, Pantel et al. find that a natural mutation in the ghrelin receptor, Ala204Glu, which is associated with a selective loss of constitutive activity without affecting ghrelin affinity, potency, or efficacy, segregates in 2 families with the development of short stature (see the related article beginning on page 760). By combination of the observations from this study with those related to the phenotype of subjects carrying another natural ghrelin receptor mutation, Phe279Leu, having identical molecular-pharmacological properties, it is proposed that selective lack of ghrelin receptor constitutive signaling leads to a syndrome characterized not only by short stature, but also by obesity that apparently develops during puberty.

Authors

Birgitte Holst, Thue W. Schwartz

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Figure 2

Natural mutations selectively eliminating the constitutive signaling of the ghrelin receptor that are associated with short stature and possible obesity.

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Natural mutations selectively eliminating the constitutive signaling of ...
(A) Serpentine model of the human ghrelin receptor in which residues that are identical (white on black) or structurally conserved (white on gray) between the ghrelin receptor and its closest homologue, the motilin receptor, are indicated. Note that a Cys residue in the middle of extracellular loop 2 forms a disulfide bridge with a Cys residue at the extracellular end of transmembrane segment III (TM-III), which is a highly conserved structural feature of 7TM receptors. The location of the Ala204Glu mutation in the part of extracellular loop 2 connecting the extracellular end of TM-III with TM-V, which Pantel et al. describe in this issue of the JCI (6), is highlighted with a red circle (6). As indicated in the red box at the top left, this mutation selectively eliminates constitutive signaling by the ghrelin receptor and is associated with short stature (6). This mutation has previously been identified in a very obese child by Wang et al. (15). Also highlighted with a red circle is the location of the Phe279Leu mutation in TM-VI. The constitutive activity of the ghrelin receptor is highly dependent on the presence of an aromatic residue at position VI:16 (16), and Wang et al. found the Phe279Leu mutation in a child with short stature and in his mother, who was also of short stature (157 cm) and who was very obese (BMI = 34.6) (15). (B) Schematic diagram of the effects of these natural mutations in eliminating the constitutive signaling of the ghrelin receptor (red arrow to the left) without affecting the potency or efficacy of the natural ligand, ghrelin (dotted vertical line corresponding to the EC50).

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

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