GH-Releasing Hormone Receptor Gene: A Novel Splice-Disrupting Mutation and Study of Founder Effects

Abstract

Background: Mutations in GH-releasing hormone receptor gene (GHRHR) are emerging as the most common cause of autosomal recessive isolated GH deficiency (IGHD). Objective: To search for GHRHR mutations in patients with familial or sporadic IGHD and to investigate founder effects in recurring mutations. Methods: The coding region of GHRHR was entirely amplified and sequenced from DNA of 18 patients with IGHD (16 unrelated) with topic posterior pituitary lobe on MRI. Haplotypes containing promoter SNPs and microsatellites flanking GHRHR were analyzed in patients with c.57+1G>A (IVS1+1G>A) mutation of our previously published kindred and also a Brazilian patient and 2 previously reported Japanese sisters with c.1146G>A (p.E382E) mutation. Results: A novel homozygous intronic GHRHR c.752-1G>A (IVS7-1G>A) mutation, predicting loss of the constitutive splice acceptor site, was identified in two siblings with IGHD. A compound heterozygous c.[57+1G>A];[1146G>A] and a heterozygous c.527C>T (p.A176V) were found in two sporadic cases. Haplotype analysis provided evidence for a founder effect for the c.57+1G>A mutation and independent recurrence for the c.1146G>A mutation. Conclusion: We report a novel splice-disrupting mutation in GHRHR in 2 siblings and provide evidence that all c.57+1G>A (IVS1+1G>A) mutant chromosomes have the same haplotype ancestor, indicating the occurrence of a founder effect in Brazilian patients with IGHD.

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

“…This mutation likely leads to retention of intron 1 and insertion of a premature stop codon 213 bases from exon-intron junction, similarly to what was later described for a different mutation in the same splice site (18). A founder effect has been demonstrated in this cohort and in other Brazilian patients (residing in different areas of Brazil) with the same mutation (19). It is chronologically the second discovery of about twenty inactivating GHRHR mutations described to date (14), but the one involving the largest number of individuals.…”

“…These features have been published in 42 different publications (2,19,22,25,27,29,30,31,32,33,36,37,38,40,41,44,45,46,47,48,49,50,51,52,53,54,56,57,61,62,63,64,66,67,68,74,75,76,77,78,79,80). We have used this experiment of nature to discover 'usual laws of nature' as suggested by William Harvey, and to understand some aspects of more common conditions such as short stature, insulin resistance, diabetes, atherosclerosis, osteoporosis, cancer and ultimately longevity.…”

Relatively high frequency of non‐synonymous GLI2 variants in patients with congenital hypopituitarism without holoprosencephaly

“…). In 27 patients, homozygous mutations in PROP1 , GH1 , GHRH receptor or HESX1 explained the phenotype (Table ) . In the remaining 180 cases, in whom the genetic aetiology remained unknown, GLI2 was studied.…”

“…In all patients with IGHD and a normally placed posterior pituitary lobe, GHRH receptor, GHRH and GH1 mutations had been excluded. 7,18,19 In most patients with an ectopic/undescended posterior lobe, mutations in HESX1 and LHX4 had also been excluded. 20,21 The control group consisted of 50-155 healthy adult individuals without personal or familial history of pituitary hormone deficiencies.…”

Diagnóstico molecular na prática clínica: visão do endocrinologista

“…Finally, despite the lack of a direct effect on the protein amino acid sequence, synonymous SNVs or those located in untranslated, intronic or promoter regions may still have important biological repercussions, particularly if affecting gene expression or mRNA splicing. For example, somatic mutations in the promoter region of TERT may lead to thyroid cancer, with potential diagnostic implications 37 , and homozygous splice site mutations in the GH-releasing hormone receptor (GHRHR) can lead to short stature due to growth hormone deficiency 38 .…”