Identification and functional analysis of novel human growth hormone-releasing hormone receptor (GHRHR) gene mutations in Japanese subjects with short stature

Inoue, Hiroshi; Kangawa, Natsumi; Kinouchi, Atsuko; Sakamoto, Yukiko; Kimura, Chizuko; Horikawa, Reiko; Shigematsu, Yosuke; Itakura, Mitsuo; Ogata, Tsutomu; Fukui, Kenji

doi:10.1111/j.1365-2265.2010.03911.x

Cited by 22 publications

(23 citation statements)

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“…On the other hand, our observations are consistent with those in Ghsr -/-mice supporting that ghrelin-GHSR signal is not a key contributor to somatic growth in rodents (10). In contrast, several genetic studies support the role of GHSR as a physiological contributor in humans both to the adult height variance among individuals (23)(24)(25) and to the nosology of somatic growth disorders (22,45,46).…”

Section: Discussionsupporting

confidence: 87%

Enhanced responsiveness of Ghsr ^Q343X rats to ghrelin results in enhanced adiposity without increased appetite

et al. 2016

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The ability of the gut hormone ghrelin to promote positive energy balance is mediated by the growth hormone secretagogue receptor (GHSR). GHSR is a G protein-coupled receptor (GPCR) that is found centrally and peripherally and that can signal in a ligand-independent manner basally or when heterodimerized with other GPCRs. However, current Ghsr knockout models cannot dissect ghrelindependent and -independent signaling, precluding assessment of the physiological importance of these signaling pathways. An animal model carrying a Ghsr mutation that preserves GHSR cell surface abundance, but selectively alters GHSR signaling, would be a useful tool to decipher GHSR signaling in vivo. We used rats with the Ghsr Q343X mutation (Ghsr M/M ), which is predicted to delete the distal part of the GHSR C-terminus tail, a domain critical for the signal termination processes of receptor internalization and -arrestin recruitment. In cells, the Q343X GHSR mutant showed enhanced ligandinduced G protein-dependent signaling and blunted activity of processes involved in GPCR signal termination. Ghsr M/M rats displayed enhanced responses to submaximal doses of ghrelin or GHSR agonist. Moreover, Ghsr M/M rats had a more stable body weight under caloric restriction, a condition that increases endogenous ghrelin tone, whereas under standard housing conditions, Ghsr M/M rats showed increased body weight, adiposity and reduced glucose tolerance. Overall, our data stresses the physiological role of the distal domain of GHSR C-terminus as a suppressor of ghrelin sensitivity and we propose using the Ghsr M/M rat as a physiological model of gain-of-function in Ghsr to identify treatments for obesity-related conditions.3

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Section: Discussionsupporting

confidence: 87%

Enhanced responsiveness of Ghsr ^Q343X rats to ghrelin results in enhanced adiposity without increased appetite

et al. 2016

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“…c.1146G>A is located in the last nucleotide of exon 12, immediately upstream of the splice donor site. This mutation was previously reported [12]. Although it does not predict change of amino acids, in vitro splicing studies showed skipping of exon 12 [12].…”

Section: Resultsmentioning

confidence: 94%

“…Patient 3 and her parents were evaluated, and these results compared with previously published data from Japanese c.1146G>A mutated patients [12]. …”

Section: Methodsmentioning

confidence: 99%

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

Marui¹,

Trarbach

Boguszewski

et al. 2012

Horm Res Paediatr

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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.

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“…GHRH-R mutations were not observed or were rare in several other populations. Mutations were not found among Dutch and Argentinean children with IGHD and were found only in three out of a cohort of 127 Japanese children, 14 with IGHD and 113 with idiopathic short stature [14][15][16]. Thus the lower prevalence of GHRH-R codon 72 mutation observed by us is not unexpected.…”

Section: Age Groups (Years) ≤5mentioning

confidence: 64%

Growth hormone releasing hormone receptor codon 72 mutation in a cohort of Sri Lankan patients with growth hormone deficiency

et al. 2016

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Introduction Growth hormone releasing hormone receptor (GHRH-R) codon 72 mutation is recognised as a common genetic cause of growth hormone deficiency (GHD) in the Indian subcontinent resulting in a characteristic lean phenotype. Genetic studies have not been previously carried out in Sri Lankans with GHD.Methods Patients with GHD presenting to a tertiary care referral centre were studied for GHRH-R codon 72 mutation by PCR amplification and sequencing. The phenotype of the cohort was described as the BMI SDS (Body mass index standard deviation score) based on the anthropometric data at the time of diagnosis.Results Among 91 patients from 88 families studied, eight (6 boys) carried the codon 72 mutation. The presence of this mutation was low among the Sinhalese ethnicity (3 out of 68) than among Tamil and Moor ethnicities. BMI SDS of <-2 was seen in 71% of mutation positive and 45.8% of mutation negative patients. ConclusionsPrevalence of GHRH-R codon 72 mutation in this group of GH deficient patients was 8.8%. The lean phenotype observed in 71% of the mutation positive patients was not a significant association when compared to a similar phenotype in 45.8% of the mutation negative patients. Growth hormone releasing hormone receptor codon 72 mutation in a cohort of Sri Lankan patients with growth hormone deficiency

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Identification and functional analysis of novel human growth hormone-releasing hormone receptor (GHRHR) gene mutations in Japanese subjects with short stature

Abstract: The homozygous GHRHR mutation was rare, being detected in only one Japanese IGHD family. Future research is needed to clarify the genetic contributions of heterozygous functional promoter variants to GHD, ISS and normal-stature variations.

Cited by 22 publications

References 34 publications

Enhanced responsiveness of Ghsr ^Q343X rats to ghrelin results in enhanced adiposity without increased appetite

Enhanced responsiveness of Ghsr ^Q343X rats to ghrelin results in enhanced adiposity without increased appetite

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

Growth hormone releasing hormone receptor codon 72 mutation in a cohort of Sri Lankan patients with growth hormone deficiency

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Identification and functional analysis of novel human growth hormone-releasing hormone receptor (GHRHR) gene mutations in Japanese subjects with short stature

Abstract: The homozygous GHRHR mutation was rare, being detected in only one Japanese IGHD family. Future research is needed to clarify the genetic contributions of heterozygous functional promoter variants to GHD, ISS and normal-stature variations.

Cited by 22 publications

References 34 publications

Enhanced responsiveness of Ghsr Q343X rats to ghrelin results in enhanced adiposity without increased appetite

Enhanced responsiveness of Ghsr Q343X rats to ghrelin results in enhanced adiposity without increased appetite

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

Growth hormone releasing hormone receptor codon 72 mutation in a cohort of Sri Lankan patients with growth hormone deficiency

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Enhanced responsiveness of Ghsr ^Q343X rats to ghrelin results in enhanced adiposity without increased appetite

Enhanced responsiveness of Ghsr ^Q343X rats to ghrelin results in enhanced adiposity without increased appetite