HGNC Approved Gene Symbol: GHSR
Cytogenetic location: 3q26.31 Genomic coordinates (GRCh38): 3:172,443,291-172,448,456 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q26.31 | Growth hormone deficiency, isolated partial | 615925 | Autosomal dominant; Autosomal recessive | 3 |
Ghrelin (GHRL; 605353) is a pleiotropic hormone secreted by stomach that promotes food-seeking behavior and positive energy balance. GHSR is a G protein-coupled receptor found peripherally and in several brain regions that mediates the biologic effects of ghrelin. GHSR can also signal in the absence of ligand due to high constitutive activity and selectively modulate dopamine signaling through heterodimerization with dopamine receptors (e.g., DRD1; 126449) (summary by Chebani et al. (2016)).
Growth hormone (GH; 139250) release is reciprocally regulated by 2 hypothalamic peptides, GH-releasing hormone (GHRH; 139190) and somatostatin (SST; 182450), via specific cell surface receptors on anterior pituitary somatotrophs. Several synthetic molecules termed growth hormone secretagogues (GHSs) are known to stimulate release of GH by a pathway distinct from that of GHRH, implying the existence of a third receptor. Howard et al. (1996) cloned a G protein-coupled receptor of the pituitary and hypothalamus (GHSR) of humans and swine, and showed it to be the target of GHSs. Nucleotide sequence analysis revealed 2 types of cDNAs, apparently derived from the same gene, which the authors referred to as Ia and Ib. The human full-length type Ia cDNA encodes a predicted polypeptide of 366 amino acids with 7 transmembrane domains, a feature typical of G protein-coupled receptors. Type Ib encodes a polypeptide of 289 amino acids with only 5 transmembrane domains. RNase protection assays confirmed the presence of human GHSR mRNA in pituitary gland; in situ hybridization detected type Ia mRNA in rhesus hypothalamus.
McKee et al. (1997) reported that human type Ia GHSR shares 96% amino acid identity with its rat ortholog.
McKee et al. (1997) isolated a rat pituitary Ghsr cDNA from an unspliced, precursor mRNA and found that a single intron of approximately 2 kb divides the open reading frame into 2 exons. Further, the authors confirmed the placement of an intron at this position in the human gene, thus placing GHSR into the intron-containing class of G protein-coupled receptors.
McKee et al. (1997) stated that the GHSR gene maps to chromosome 3q26.2.
Hartz (2016) mapped the GHSR gene to chromosome 3q26.31 based on an alignment of the GHSR sequence (GenBank AY429112) with the genomic sequence (GRCh38).
Howard et al. (1996) found that Xenopus oocytes expressing type Ia responded to GHS exposure similarly to the native pituitary receptor. However, type Ib cRNAs injected into oocytes failed to give a response.
Kaji et al. (2001) analyzed hormonal regulation of GHSR gene expression by transfecting a pituitary tumor cell line with the 5-prime flanking region of GHSR subcloned into a luciferase reporter plasmid. Luciferase activity was inhibited by the simultaneous addition of TPA and a calcium channel agonist, or by the addition of hydrocortisone.
Garcia et al. (2001) determined whether the synthetic hexapeptide GHRP-6, a reference GH secretagogue compound, as well as an endogenous ligand, ghrelin, regulate PIT1 (173110) expression. By a combination of Northern and Western blot analysis, they found that GHRP-6 elicits a time- and dose-dependent activation of Pit1 expression in monolayer cultures of infant rat anterior pituitary cells. This effect was blocked by pretreatment with actinomycin D, but not by cycloheximide, suggesting that this action was due to direct transcription activation of Pit1. Using an established cell line (HEK293-GHSR) that overexpresses GHSR, they showed a marked stimulatory effect of GHRP-6 on the PIT1 -2,500 bp 5-prime-region driving luciferase expression. Similarly, they showed that the endogenous GHSR ligand ghrelin exerts a similar effect on the PIT1 promoter. They concluded that these data provide the first evidence that ghrelin is also capable of regulating PIT1 transcription through the GHSR in the pituitary.
Dixit et al. (2004) demonstrated that GHSR and its ligand ghrelin are expressed in human T lymphocytes and monocytes, where ghrelin acts via GHSR to inhibit specifically the expression of proinflammatory anorectic cytokines such as IL1-beta (147720), IL6 (147620), and TNF-alpha (191160). Ghrelin led to a dose-dependent inhibition of leptin (164160)-induced cytokine expression, whereas leptin upregulated GHSR expression on human T lymphocytes. Dixit et al. (2004) proposed the existence of a reciprocal regulatory network by which ghrelin and leptin control immune cell activation and inflammation.
Pantel et al. (2006) identified a functionally significant missense mutation in the GHSR gene (601898.0001) that segregated with isolated partial growth hormone deficiency and short stature (GHDP; 615925) in 2 unrelated Moroccan families.
In a 17.4-year-old male proband with short stature and endocrine analysis consistent with isolated partial growth hormone deficiency, Pantel et al. (2009) identified compound heterozygosity for a nonsense and a missense mutation (601898.0002 and 601898.0003, respectively) in the GHSR gene.
Zigman et al. (2005) generated Ghsr-null mice and observed that ghrelin administration failed to acutely stimulate food intake or activate arcuate nucleus neurons. When fed a high-fat diet, both female and male Ghsr-null mice ate less food, stored less of their consumed calories, preferentially utilized fat as an energy substrate, and accumulated less body weight and adiposity than control mice. Ghsr-null mice also demonstrated statistically significant reductions in both respiratory quotient and locomotor activity compared to wildtype, and their blood glucose levels were significantly lower than wildtype mice of similar weight and body composition. Zigman et al. (2005) concluded that ghrelin-responsive pathways are an important component of coordinated body weight control, and suggested that ghrelin signaling is required for development of the full phenotype of diet-induced obesity.
Chebani et al. (2016) studied a rat line with a gln343-to-ter (Q343X) mutation in Ghsr. The mutation deleted most of the phosphorylation sites in the distal half of the Ghsr C-terminal domain, which is predicted to be involved in signal termination. Rat Ghsr(Q343X) impaired ghrelin-induced internalization and impaired recruitment of beta-arrestin-2 (ARRB2; 107941) in transfected HEK293 cells. Ghsr(Q343X) also caused enhanced ligand-induced responses. Rats homozygous for the Q343X mutation (Ghsr M/M) showed increased sensitivity to endogenous acyl-ghrelin, exogenous ghrelin, or agonist. Ghsr M/M rats lost significantly less weight than wildtype littermates when subjected to caloric restriction. Ghsr M/M rats also showed increased food intake, increased body mass and adiposity, and decreased glucose tolerance, concomitant with elevated plasma leptin (LEP; 164160) levels and decreased insulin sensitivity. Chebani et al. (2016) concluded that the C-terminal domain of GHSR is required for signal termination.
In affected members of 2 unrelated Moroccan families with growth hormone deficiency and short stature (GHDP; 615925), Pantel et al. (2006) identified homozygosity or heterozygosity for a 611C-A transversion in exon 1 of the GHSR gene, resulting in an ala204-to-glu (A204E) substitution. The authors noted that the polar and charged glu204 replaces a highly conserved apolar and neutral ala204. Transient expression studies in HEK293 cells demonstrated decreased cell-surface expression of the mutant receptor and selective impairment of constitutive activity with preservation of the ability to respond to ghrelin. One family was consanguineous, and the proband was homozygous for the mutation; 2 affected sibs and the affected parents were all heterozygous for the mutation, as was an unaffected sib whose height was in the low range of normal (-1.1 SD below the mean). In the other family, a father and daughter with short stature were both heterozygous for the mutation, as were 2 unaffected sibs, 1 of normal height and the other in the low range of normal (-1.2 SD below the mean). Pantel et al. (2006) noted that 2 of the affected children had a phenotype compatible with idiopathic short stature, whereas the other 2 had isolated growth hormone deficiency confirmed by testing.
In a 17.4-year-old male proband with short stature and endocrine analysis consistent with isolated partial growth hormone deficiency (GHDP; 615925), Pantel et al. (2009) identified compound heterozygosity for a 6G-A transition in exon 1 of the GHSR gene, resulting in a trp2-to-ter (W2X) substitution with very early termination of the protein, and a 709A-T transversion in exon 1 predicted to result in an arg237-to-trp (R237W; 601898.0003) substitution at an evolutionarily invariant residue in the third intracellular loop near the fifth transmembrane domain. In vitro studies showed that the R237W mutation would result in partial loss of constitutive activity of GHSR, whereas both its ability to respond to ghrelin and its cell surface expression are preserved. The patient's unaffected mother and an unaffected brother were heterozygous for the missense mutation; his father, who was reported to have had delayed puberty, was heterozygous for the nonsense mutation.
For discussion of the arg237-to-trp (R237W) mutation in the GHSR gene that was found in compound heterozygous state in a patient with short stature and endocrine analysis consistent with isolated partial growth hormone deficiency (GHDP; 615925) by Pantel et al. (2009), see 601898.0002.
Chebani, Y., Marion, C., Zizzari, P., Chettab, K., Pastor, M., Korostelev, M., Geny, D., Epelbaum, J., Tolle, V., Morisset-Lopez, S., Pantel, J. Enhanced responsiveness of Ghsr(Q343X) rats to ghrelin results in enhanced adiposity without increased appetite. Sci. Signal. 9: ra39, 2016. Note: Electronic Article. [PubMed: 27095593] [Full Text: https://doi.org/10.1126/scisignal.aae0374]
Dixit, V. D., Schaffer, E. M., Pyle, R. S., Collins, G. D., Sakthivel, S. K., Palaniappan, R., Lillard, J. W., Jr., Taub, D. D. Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells. J. Clin. Invest. 114: 57-66, 2004. [PubMed: 15232612] [Full Text: https://doi.org/10.1172/JCI21134]
Garcia, A., Alvarez, C. V., Smith, R. G., Dieguez, C. Regulation of PIT-1 expression by ghrelin and GHRP-6 through the GH secretagogue receptor. Molec. Endocr. 15: 1484-1495, 2001. [PubMed: 11518797] [Full Text: https://doi.org/10.1210/mend.15.9.0694]
Hartz, P. A. Personal Communication. Baltimore, Md. 5/17/2016.
Howard, A. D., Feighner, S. D., Cully, D. F., Arena, J. P., Liberator, P. A., Rosenblum, C. I., Hamelin, M., Hreniuk, D. L., Palyha, O. C., Anderson, J., Paress, P. S., Diaz, C., and 20 others. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273: 974-977, 1996. [PubMed: 8688086] [Full Text: https://doi.org/10.1126/science.273.5277.974]
Kaji, H., Kishimoto, M., Kirimura, T., Iguchi. G., Murata, M., Yoshioka, S., Iida, K., Okimura, Y., Yoshimoto, Y., Chihara, K. Hormonal regulation of the human ghrelin receptor gene transcription. Biochem. Biophys. Res. Commun. 284: 660-666, 2001. [PubMed: 11396952] [Full Text: https://doi.org/10.1006/bbrc.2001.5035]
McKee, K. K., Palyha, O. C., Feighner, S. D., Hreniuk, D. L., Tan, C. P., Phillips, M. S., Smith, R. G., Van der Ploeg, L. H. T., Howard, A. D. Molecular analysis of rat pituitary and hypothalamic growth hormone secretagogue receptors. Molec. Endocr. 11: 415-423, 1997. [PubMed: 9092793] [Full Text: https://doi.org/10.1210/mend.11.4.9908]
Pantel, J., Legendre, M., Cabrol, S., Hilal, L., Hajaji, Y., Morisset, S., Nivot, S., Vie-Luton, M.-P., Grouselle, D., de Kerdanet, M., Kadiri, A., Epelbaum, J., Le Bloc, Y., Amselem, S. Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature. J. Clin. Invest. 116: 760-768, 2006. [PubMed: 16511605] [Full Text: https://doi.org/10.1172/JCI25303]
Pantel, J., Legendre, M., Nivot, S., Morisset, S., Vie-Luton, M.-P., Le Bouc, Y., Epelbaum, J., Amselem, S. Recessive isolated growth hormone deficiency and mutations in the ghrelin receptor. J. Clin. Endocr. Metab. 94: 4334-4341, 2009. [PubMed: 19789204] [Full Text: https://doi.org/10.1210/jc.2009-1327]
Zigman, J. M., Nakano, Y., Coppari, R., Balthasar, N., Marcus, J. N., Lee, C. E., Jones, J. E., Deysher, A. E., Waxman, A. R., White, R. D., Williams, T. D., Lachey, J. L., Seeley, R. J., Lowell, B. B., Elmquist, J. K. Mice lacking ghrelin receptors resist the development of diet-induced obesity. J. Clin. Invest. 115: 3564-3572, 2005. [PubMed: 16322794] [Full Text: https://doi.org/10.1172/JCI26002]