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

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.

Ghrelin in obesity and endocrine diseases

“…to French reference values) was found to carry the Ala204Glu mutation in the homozygous state; whilst the parents were heterozygous for this mutation (maternal and paternal height was noted to be 2.7SD and 3.7SD below the mean, respectively). In addition, several members of family 1 were overweight or obese -BMI of the 13 year old proband was 26.2kg/m 2 (Pantel et al, 2006). In family 2, the 11 year old female proband was found to carry the same mutation in the heterozygous state, and the affected father (height 2SD below mean) was also heterozygous for the mutation (Pantel et al, 2006).…”

“…In addition, several members of family 1 were overweight or obese -BMI of the 13 year old proband was 26.2kg/m 2 (Pantel et al, 2006). In family 2, the 11 year old female proband was found to carry the same mutation in the heterozygous state, and the affected father (height 2SD below mean) was also heterozygous for the mutation (Pantel et al, 2006).…”

“…Ala204Glu (Pantel et al, 2006;Wang et al, 2004) and Phe279Leu (Wang et al, 2004) are rare GHS-R mutations which lead to loss of constitutive activity of GHS-R and subsequent short stature and obesity (Holst & Schwartz, 2006). Obesity would be unexpected in loss-of-function mutations of GHS-R, however compensatory changes in related pathways may account for the obese phenotype in subjects with the inactivating mutations (Holst & Schwartz, 2006).…”

Inactivation of the Constitutively Active Ghrelin Receptor Attenuates Limbic Seizure Activity in Rodents

“…This ligand-independent activity was recently proven to be an intrinsic feature of the GHSR protein and not merely the consequence of an influence of the cellular environment [42]. The constitutive activity of GHSR appears to be important in humans, since a missense mutation of the GHSR, which leads in the loss of the constitutive activity of the receptor while retaining its ability to respond to ghrelin-induced signaling, resulted in familial short stature [43]. In light of this knowledge, we wondered whether the constitutive activity of GHSR needed to be reduced to attenuate seizure activity.…”

Ghrelin and the growth hormone secretagogue receptor in growth and development

“…In mice, loss of function of the GHSR gene is associated with lower insulin-like growth factor 1 concentrations and a lower body mass in adult animals that is independent of food intake and energy expenditure. 4 In humans, Pantel et al 19 found a mutation of the GHSR gene in two families in which short stature was inherited in a dominant manner. In keeping with a dominant inheritance with variable penetrance, short stature was present in the proband, who was homozygous for the mutation, and in some of the family members who were heterozygous for the mutation.…”