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Ghrelin Receptor Mutation: A Novel Pathogenic Mechanism of Growth Failure« Back to Volume 22, Issue 2, June 2006 - Table of Contents In 1996, a leading article published in Science1 described “a new receptor in the pituitary and hypothalamus that stimulates growth hormone release.” it was cloned as the target of a family of synthetic molecules and named the growth hormone secretagogue receptor (GHSR).The endogenous ligand of this receptor is ghrelin, a hormone predominantly produced by the stomach, whose plasma levels fluctuate with food intake.2 This hormone stimulates GH secretion and increases food intake and body weight. The G protein-coupled receptor (GPCR) displays a constitutive activity at almost 50% of its maximal capacity. The ligand-independent activity has remained unclear until the present study by Pantel and colleagues. This is the first report which identifies a GHSR missense mutation, Ala204Glu in the first exon, that segregates with short stature within 2 unrelated families, one of which also had GH deficiency (GHD). Initially, there was a systematic search among subjects with short stature leading to the identification of the same nucleotide variation in 2 unrelated patients: one with idiopathic GHD (IGHD) was found to be heterozygous for the mutation, whereas the other with idiopathic short stature (ISS) was homozygous. The families of the 2 probands were analyzed. Altogether, the data showed that all individuals with short stature (n=7) carried at least one mutated allele. Conversely,3 heterozygous individuals had a normal height. The finding is in keeping with a dominant mode of inheritance and incomplete penetrance (Figure). Idiopathic GHD, diagnosed by low response to standard stimulation tests, was found in 2 cases, one in each family and both heterozygous. The 3 patients who received GH treatment increased their growth velocity. The mode of action of this mutation was carefully analyzed showing that it was a significantly impaired functional activity of the receptor:
Pantel et al concluded that the involvement of the GHSR A204E mutation in short stature transmitted over 2 generations was supported by the following evidence: all patients within the 2 families carried this mutation which in turn was absent in an appropriate control population; the mutation and the amino acid polarity predicts changes in molecular activity; and the findings point to a functional importance of the GHSR constitutional activity. The authors speculated that given the documented pharmacological effects of ghrelin on GH release, the short stature results from abnormal regulation of the GH axis. The heterogeneity of the findings related to GH and insulin-like growth factor (IGF)-I in the 2 families may be related to the well-known limitations of the current methods of clinical investigation. This study, along with the mutated murine models, supports the (debated) view that ghrelin and GH/IGF-I interact in the control of growth. Inheritance of the A204E GHSR mutation in families 1 and 2. (A) Family 1. (B) Family 2. Circles and squares denote female and male family members, respectively. The SD to mean height for age is given below each symbol; height values are before GH treatment. Black symbols denote a short stature. The probands are indicated by arrows. The segregation of the GHSR A204E allele within both families was carried out by means of a specific restriction fragment length polymorphism (the A204E mutation creates an MnlI site). Reprinted with permission: Pantel J, et al. J Clin Invest. 2006;116:760-768. Copyright © American Society for Clinical Investigation. 2006. All rights reserved. Editor’s CommentThis is an elegant and well-conducted study that introduces the concept of fine regulation of growth by a mutation of a receptor which until now did not prove to be essential in achieving normal stature. In addition, it provides evidence for the in vivo importance of its ligand independent signalling as expressed by its constitutive activity. An interesting “commentary” paper is published in the same issue by Holst and Schwartz3; they refer to a previous German case of ISS and the same mutation4 and also point out that obesity is an additional symptom that segregates with this mutation and a Phe279Leu mutation which shares the same effect on receptor constitutive activity. Holst and Schwartz suggest that selective loss of ghrelin receptor constitutive activity causes a syndrome of short stature and obesity developing around puberty. How these molecular changes impair growth and GH secretion and furthermore, how they are involved in hunger control and obesity, remains in part speculative and challenging for future research. It is interesting that clinical and genetic investigation essentially by systematic structure-function analysis opens new physiological concepts. It should be taken into account when performing population studies on the multifactorial control of growth and, more specifically, by GH and IGF secretion and activity. In addition, these studies open to new possible mechanisms on the weight-to-height relationship in patients with short stature. The authors briefly commented on the positive response to GH therapy in 3 patients. Eventually, their data, part of which are presented in the Table, would deserve an additional publication. More studies need to be performed in order to consider the potential development of pharmacological tools in relation to this uncommon and likely pathophysiology of short stature and/or obesity. Raphaël Rappaport , MD References - (linked to
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Volume 26 Number 1
September 2010
www.GGHjournal.com
ISSN 1932-9032
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