Molecular and Clinical Aspects of GHRH Receptor Mutations

Abstract

The growth hormone (GH)-releasing hormone (GHRH) receptor (GHRHR) belongs to the G protein-coupled receptor family. It binds GHRH resulting in somatotroph cell proliferation and stimulation of GH secretion. Mutations in the gene encoding for GHRHR (GHRHR, OMIM No. 139191) are being reported with increasing frequency in familial isolated GH deficiency. To date, the reported GHRHR mutations include eight missense, seven splice, three microdeletions, and two non-sense mutations. One promoter mutation has also been reported. Most of these mutations show a recessive mode of inheritance. The phenotype includes reduced but not absent serum GH, with abnormal response to a variety of stimuli, and low serum insulin-like growth factor-1 levels, resulting in proportionate growth failure which becomes evident in the first year of life. These patients respond well to GH replacement therapy. Phenotypical observations coming from some unusually large kindreds with untreated GH deficiency due to homozygous GHRHR mutations have allowed the study of the consequences of lifetime lack of GH. This chapter reviews the structure and the role of the GHRHR together with the clinical aspects associated with its mutations.

MECHANISMS IN ENDOCRINOLOGY: The multiple facets of GHRH/GH/IGF-I axis: lessons from lifetime, untreated, isolated GH deficiency due to a GHRH receptor gene mutation

“…MRIs from adults and children of Itabaianinha kindred show obvious anterior pituitary hypoplasia (APH) (33), as it had been previously shown in 4 adult individuals from the Sindh kindred (17). APH is not due to reduction of cranial volume (33).…”

“…The binding of GHRH causes conformational changes, resulting in the activation of the G s α subunit, stimulation of the membrane-bound adenylyl cyclase, increase of intracellular cyclic adenosine monophosphate (cAMP) and activation of protein kinase A (PKA) pathways. This translocates to the nucleus and phosphorylates the transcription factor cAMP-response element-bindingprotein (CREB) causing the transcription of GH through binding to response elements in the target genes promoter region (17).…”

Contribution of functionally assessed GHRHR mutations to idiopathic isolated growth hormone deficiency in patients without GH1 mutations

“…This is, however, not the case for GHRHR mutations. Indeed, the 21 GHRHR disease-causing mutations identified worldwide correspond mainly to case reports (reviewed in Corazzini & Salvatori, 2013), and according to the very rare studies performed in cohorts of patients with IGHD (Alatzoglou et al, 2009;Graaff et al, 2009;Birla et al, 2016;Desai et al, 2013), the estimated contribution of GHRHR mutations to IGHD ranges from 0% to 15% (Graaff et al, 2009;(Desai et al, 2013). In addition, all (Desai et al, 2013) or several families with an identified GHRHR defect were found to carry the p.(E72*) mutation, which results from a founder effect (Wajnrajch et al, 2003).…”

Growth hormone, insulin-like growth factor system and carcinogenesis

“…Moreover, LOI of IGF-II gene has been identified as an individual risk factor for developing colorectal carcinoma and, more recently, with poor prognosis of patients with oesophageal squamous cell carcinoma [2,11,62,63]. LOI can be assayed with a DNA-based blood test, and it has been proposed as a predictive marker of an individual's risk for colorectal cancer [2,11,62].…”