Alternative titles; symbols
HGNC Approved Gene Symbol: GHRH
Cytogenetic location: 20q11.23 Genomic coordinates (GRCh38): 20:37,251,086-37,261,814 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q11.23 | ?Isolated growth hormone deficiency due to defect in GHRF | 1 | ||
| Gigantism due to GHRF hypersecretion | 1 |
GHRH is a hypothalamic peptide that stimulates synthesis and proliferation of pituitary somatotroph cells as well as secretion of growth hormone (see 139250). GHRH is initially synthesized as a preprohormone whose N-terminal signal sequence is enzymatically cleaved to generate the mature 44-amino acid form of GHRH and a C-terminal GHRH-related peptide (GHRH-RP) (Alba and Salvatori, 2004).
Careful clinical observations in a woman with Turner syndrome led to the characterization of growth hormone-releasing factor (GHRF) as a molecular entity (Thorner et al., 1982). The patient presented with classic acromegaly and an enlarged pituitary fossa, but the pituitary was hyperplastic, not adenomatous, suggesting stimulation from another source. Thorner et al. (1982) discovered that the patient had a pancreatic tumor that was stimulating the pituitary. The pancreatic tumor was removed, its GHRF activity was purified and sequenced, and its cDNA and gene were subsequently cloned.
Gubler et al. (1983) proposed the name somatocrinin as a substitute for growth hormone-releasing factor. Preliminary evidence suggested that the 44-amino acid peptide isolated from human pancreatic tumors is identical to hypothalamic GHRF. Gubler et al. (1983) cloned and sequenced the cDNA for the precursor of somatocrinin. They estimated that the preprosomatocrinin has a molecular mass of 13 kD.
Mayo et al. (1985) isolated and characterized overlapping clones from phage lambda and cosmid human genomic libraries that predict the entire structure of the gene encoding GHRF. The gene has 5 exons spanning 10 kb.
Dot blot analysis of DNA from high resolution dual-laser-sorter human chromosomes indicated that the GHRF gene is located on chromosome 20 (Lebo et al., 1984; Mayo et al., 1985). By means of a gene probe in somatic cell hybrids, Riddell et al. (1985) confirmed the assignment.
Perez Jurado et al. (1994) identified 2 PCR RFLPs in introns A and C of the GHRF gene and used these in linkage analysis with the CEPH panel to show that GHRF is located in a region near the centromere between D20S27 (assigned to 20p12.1-p11.23) and D20S16 (assigned to 20q12).
Gross (2014) mapped the GHRH gene to chromosome 20q11.23 based on an alignment of the GHRH sequence (GenBank BC098109) with the genomic sequence (GRCh37).
Presumably the GHRF polypeptide is mutant in some cases of isolated growth hormone deficiency. Of 15 patients with growth hormone deficiency, 3 appeared to have a primary defect at the pituitary level and 8 a secondary defect because they responded to the administration of GHRH (Mitrakou et al., 1985). Thorner et al. (1988) reported on the use of GHRH in the treatment of 24 growth hormone-deficient children.
Zimmerman et al. (1993) described congenital gigantism due probably to central hypersecretion of GHRH. Normal at birth (4.4 kg; 53 cm), the male patient was 182 cm tall with a weight of 99.4 kg at the age of 7 years. The markedly increased baseline plasma levels of growth hormone did not suppress during a standard 3-hour oral glucose tolerance test, but did increase 54% after intravenous infusion of GHRH. Baseline plasma levels of insulinlike growth factor I, prolactin (PRL), and immunoreactive GHRH were also markedly elevated. Computed imaging of the head showed a large, partially cystic sellar and suprasellar mass. Preoperative treatment with octreotide and bromocriptine resulted in a 25% reduction of suprasellar tissue mass. The pituitary tissue removed at transsphenoidal and transfrontal operations showed massive hyperplasia of somatotrophs, lactotrophs, and mammosomatotrophs. Areas of adenomatous transformation of GH-secreting and PRL-secreting cells were also evident. No histologic or immunochemical evidence of a pituitary source of GHRH was found. Peripheral plasma immunoreactive GHRH concentrations remained unaffected by pharmacologic and surgical interventions. A congenital hypothalamic regulatory defect was thought to be responsible for the GHRH excess. Zimmerman et al. (1993) suggested that congenital GHRH hypersecretion may have been the cause of gigantism in other cases that presented during infancy, such as the Alton giant (Behrens and Barr, 1932). Called the Alton giant because he came from Alton, Illinois, R.W. was studied at Barnes Hospital in 1930 at which time he was 12 years old and 208 cm tall. Acromegalic gigantism occurs with the McCune-Albright syndrome (174800). It is unknown whether any of these disorders have excessive production of pituitary growth hormone as the result of hypersecretion of GHRF. Scheithauer et al. (1984) reviewed the occurrence of acromegaly with bronchial carcinoid tumor due to ectopic secretion of growth hormone-releasing factor. Pancreatic islet cell tumors also secrete GHRF. Scheithauer et al. (1984) used the term somatolibrinoma for this functionally unique group of neoplasms.
Russell-Aulet et al. (1999) measured the suppressibility of spontaneous and GHRH-stimulated GH secretion by graded doses of a specific competitive GHRH receptor antagonist in healthy young and elderly men. Nocturnal GH was approximately 30% lower in the elderly than in the young. The dose-inhibition curve for spontaneous GH secretion was shifted to the left for the elderly compared to the young men (P of 0.01). The authors concluded that there is an age-dependent decrease in the endogenous hypothalamic GHRH output contributing to the age-associated GH decline.
Flavell et al. (1996) induced an autosomal dominant variety of dwarfism in the rat by local feedback inhibition of GHRF. This was done by expression of human growth hormone targeted to GHRF neurons in the hypothalamus of transgenic rats. By immunocytochemistry, the human growth hormone was detected in the brain of the transgenic rats, restricted to the median eminence of the hypothalamus. GHRF mRNA was reduced in the hypothalamus of these rats, in contrast to the increased GHRF expression that accompanies growth hormone deficiency in other dwarf rats. Endogenous GH mRNA, GH content, pituitary size, and somatotroph cell number were also reduced significantly in the transgenic rats. On the other hand, pituitary ACTH and TSH levels were normal.
Kiaris et al. (1999) investigated whether GHRH can function as an autocrine/paracrine growth factor in small cell lung carcinoma (SCLC; 182280). Two SCLC lines cultured in vitro expressed mRNA for GHRH, which apparently was translated into peptide GHRH and then secreted by the cells, as shown by the detection of GHRH-like immunoreactivity in conditioned media from the cells cultured in vitro. In addition, the levels of GHRH-like immunoreactivity in serum from nude mice bearing SCLC xenografts were higher than in tumor-free mice. These and other results suggested that GHRH can function as an autocrine growth factor in SCLCs. Treatment with antagonistic analogs of GHRH might offer a new approach to the treatment of SCLC and other cancers.
Gianotti et al. (2000) studied the mechanisms underlying insulin-like growth factor I (IGF1; 147440)-induced inhibition of somatotroph secretion in humans. In 6 normal young volunteers (all women), they studied the GH response to GHRH, both alone and combined with arginine, which is thought to act via inhibition of hypothalamic somatostatin (SS) release, after pretreatment with recombinant human IGF1 (rhIGF1) or placebo. Recombinant human IGF1 increased circulating IGF1 levels to a reproducible extent, and these levels remained stable and within the normal range until 90 minutes. The mean GH concentration over 3 hours before arginine and/or GHRH was not modified by placebo or rhIGF1. After placebo, the GH response to GHRH was strikingly enhanced by arginine coadministration. The authors concluded that arginine counteracts the inhibitory effect of rhIGF1 on somatotroph responsiveness to GHRH in humans. They also inferred that the acute inhibitory effect of rhIGF1 on the GH response to GHRH takes place on the hypothalamus, possibly via enhancement of SS release, and that arginine overrides this action.
Busto et al. (2002) identified the presence of an autocrine/paracrine stimulatory loop based on GHRH and a splice variant of GHRH receptors (139191) in human pancreatic, colorectal, and gastric cancers. This suggested an approach to an antitumor therapy based on the blockade of this receptor by specific GHRH antagonists.
Letsch et al. (2003) evaluated the antiproliferative effects of an antagonist of GHRH, JV-1-38, in nude mice bearing subcutaneous xenografts of 2 human androgen-sensitive and 1 androgen-independent prostate cancers. In the androgen-sensitive models, JV-1-38 greatly potentiated the antitumor effect of androgen deprivation induced by surgical castration, but was ineffective when given alone. However, in the androgen-independent cancer, JV-1-38 alone could inhibit tumor growth by 57% after 45 days. The results demonstrated that GHRH antagonists inhibit androgen-independent prostate cancer and, after combination with androgen deprivation, also androgen-sensitive tumors. Thus, GHRH antagonists could be considered for the management of both androgen-dependent or -independent prostate cancers.
Halmos et al. (2002) investigated the expression of GHRH and splice variants of GHRH receptors, and the binding characteristics of the GHRH receptor isoform, in 20 surgical specimens of organ-confined and locally advanced human prostatic adenocarcinomas. The affinity and density of receptors for GHRH were determined by ligand competition assays based on binding of 125I-labeled GHRH antagonist JV-1-42 tumor membranes. Twelve of 20 tumors (60%) exhibited specific, high affinity binding for JV-1-42. The mRNA of splice variant-1 was detected in 13 of 20 (65%) prostate cancer specimens and was consistent with the presence of GHRH binding. RT-PCR analyses also revealed the expression of mRNA for GHRH in 13 of 15 (86%) prostatic carcinoma specimens examined. The presence of GHRH and its tumoral receptor splice variants in prostate cancers suggested the possible existence of an autocrine mitogenic loop.
Kanashiro et al. (2003) found that the DMS-153 small cell lung carcinoma cell line expressed mRNAs for GHRH and GHRHR splice variants 1 and 2, suggesting that GHRH is an autocrine growth factor. In addition, proliferation of the cell line in vitro was stimulated by GRP (137260) and IGF2 (147470) and inhibited by a GHRH antagonist. Kanashiro et al. (2003) examined the effects of GHRH and GRP antagonists on tumors produced by DMS-153 cells xenografted into nude mice. Treatment with a GHRH antagonist reduced tumor volume by 28%, while a GRP antagonist reduced tumor volume by 77%. A combination of both antagonists reduced tumor volume by 95%. Western blot analysis indicated that the antitumor effects were associated with reduced expression of TP53 (191170) containing a tumor-associated mutation. Serum Igf1 levels were diminished in animals receiving GHRH antagonists, and the mRNA levels of Igf2, Igf receptor-1 (147370), Grp receptor (305670), and Egf receptor (131550) were reduced following the combined treatment.
Jessup et al. (2003) investigated whether endogenous GHRH has differential, gender-specific effects on the interpulse GH levels. Six healthy men and 5 healthy women, 20 to 28 years old, who were nonobese, did not smoke, and were on no medications known to influence GH secretion were studied. In both sexes during GHRH antagonist infusion, mean GH, pulse amplitude, and GH response to GHRH decreased significantly, whereas pulse frequency remained unchanged. However, during the GHRH antagonist infusion, trough GH did not significantly change in men (P = 0.54) but significantly decreased in women (P = 0.008). Deconvolution analysis confirmed the lack of a significant change in basal secretion in men (P = 0.81) as opposed to women (P = 0.006). Jessup et al. (2003) concluded that sexual dimorphism in the neuroendocrine regulation of GH secretion in humans involves a differential role of endogenous GHRH in maintaining baseline GH.
Alba and Salvatori (2004) generated mice lacking functional Ghrh by deleting intron 2 and most of exon 3 of the mouse Ghrh gene. This portion of the gene encodes the initial 14 amino acids of the mature protein, which are essential for biological activity. Ghrh -/- mice were born at the expected mendelian ratio and appeared normal at birth, but they showed evidence of growth retardation after the second week of life. Pituitary glands of Ghrh -/- mice were reduced in size and had abnormally low growth hormone mRNA and protein content. They also had reduced serum Igf1 (147440) and reduced liver Igf1 mRNA. Ghrh -/- mice showed normal fertility, but mutant females had consistent reduction in litter size. Pups of Ghrh -/- females showed elevated mortality and failure to thrive. Ghrh -/- males had normal Ghrh-rp protein expression in testis, suggesting that the gene trap used to ablate mature biologically active Ghrh expression maintained in-frame exon 4 and 5 sequence in Ghrh-rp mRNA.
Shohat et al. (1989, 1991) excluded the GHRH gene from 20pter-p11.23 because the gene was present in 2 copies in a patient with a deletion of this segment. The patient, however, had Rieger anomaly (see 180500) and a neurosecretory defect in growth hormone--features suggesting the SHORT syndrome (269880).
Using a radioactive cDNA probe for dot blot analysis of DNA from dual laser sorted chromosomes, Rao et al. (1991) localized the GHRF gene on or near band 20p12.
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Kanashiro, C. A., Schally, A. V., Groot, K., Armatis, P., Bernardino, A. L. F., Varga, J. L. Inhibition of mutant p53 expression and growth of DMS-153 small cell lung carcinoma by antagonists of growth hormone-releasing hormone and bombesin. Proc. Nat. Acad. Sci. 100: 15836-15841, 2003. [PubMed: 14660794] [Full Text: https://doi.org/10.1073/pnas.2536558100]
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