(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).