Partial Loss of Function of the GHRH Receptor Leads to Mild Growth Hormone Deficiency

Gregory, Louise; Alatzoglou, Kyriaki S.; McCabe, Mark J.; Hindmarsh, Peter Christopher; Saldanha, José W.; Romanò, Nicola; Tissier, Paul Le; Dattani, Mehul

doi:10.1210/jc.2016-2254

Cited by 9 publications

(8 citation statements)

References 22 publications

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“…Means are shown ± standard deviation the variant, Gregory et al (2016) showed in a recent report that the p.(R4Q) variant does not affect the response of HEK293 cells to GHRH. Third and most important, as shown here, the cAMPmediated transcriptional activity of the receptor carrying those variants was found to be similar to that of the normal GHRHR.…”

Section: Discussionmentioning

confidence: 96%

“…Under the hypothesis of a dominant transmission of the disease phenotype suggested for those variants, this would mean that 1.8% and 1% of subjects from these control populations may have IGHD, an estimate that largely overcomes the prevalence of the disease (1/10,000–1/4,000). In addition, as for the p.(R4W) the variant that involves the same residue as the p.(R4Q) the variant, Gregory et al () showed in a recent report that the p.(R4Q) variant does not affect the response of HEK293 cells to GHRH. Third and most important, as shown here, the cAMP‐mediated transcriptional activity of the receptor carrying those variants was found to be similar to that of the normal GHRHR.…”

Section: Discussionmentioning

confidence: 99%

“…When GH or IGF-I values were below the detection limit, half the detection limit was taken as a value. Means are shown ± standard deviation the variant,Gregory et al (2016) showed in a recent report that the p.(R4Q) variant does not affect the response of HEK293 cells to GHRH. Third and most important, as shown here, the cAMPmediated transcriptional activity of the receptor carrying those variants was found to be similar to that of the normal GHRHR.Overall, these data argue against the deleterious effect of all the heterozygous variants so far identified in the GHRHR signal peptide.…”

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confidence: 96%

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

et al. 2019

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Isolated growth hormone deficiency (IGHD) is a rare condition mainly caused by mutations in GH1. The aim of this study was to assess the contribution of GHRHR mutations to IGHD in an unusually large group of patients. All GHRHR coding exons and flanking intronic regions were sequenced in 312 unrelated patients with nonsyndromic IGHD. Functional consequences of all newly identified missense variants were assessed in vitro (i.e., study of the expression of recombinant GHRHRs and their ability to activate the cyclic adenosine monophosphate (cAMP) signaling pathway). Genotype‐phenotype correlation analyses were performed according to the nature of the identified mutation. We identified 20 different disease‐causing GHRHR mutations (truncating and missense loss‐of‐function mutations), among which 15 are novel, in 24 unrelated patients. Of note, about half (13/24) of those patients represent sporadic cases. The clinical phenotype of patients with at least one missense GHRHR mutation was found to be indistinguishable from that of patients with bi‐allelic truncating mutations. This study, which unveils disease‐causing GHRHR mutations in 8% (24/312) of IGHD cases, identifies GHRHR as the second IGHD gene most frequently involved after GH1. The finding that 8% of IGHD cases without GH1 mutations are explained by GHRHR molecular defects (including missense mutations), together with the high proportion of sporadic cases among those patients, has important implications for genetic counseling.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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confidence: 96%

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

et al. 2019

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“…Here, several patients exhibiting HPE anomalies present This functional study shows how haploinsufficiency of both the SHH and NOTCH signalling pathways may contribute to not only to HPE but also to congenital hypopituitarism. This study has clinical implications, as many cases are not yet fully explained by genetic testing (12,69).…”

Section: Accepted Manuscriptmentioning

confidence: 95%

Disrupted Hypothalamo-Pituitary Axis in Association With Reduced SHH Underlies the Pathogenesis of NOTCH-Deficiency

Hamdi-Rozé

Ware

Guyodo

et al. 2020

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context In human, Sonic hedgehog (SHH) haploinsufficiency is the predominant cause of holoprosencephaly, a structural malformation of the forebrain midline characterized by phenotypic heterogeneity and incomplete penetrance. The NOTCH signaling pathway has recently been associated with holoprosencephaly in humans, but the precise mechanism involving NOTCH signaling during early brain development remains unknown. Objective The aim of this study was to evaluate the relationship between SHH and NOTCH signaling to determine the mechanism by which NOTCH dysfunction could cause midline malformations of the forebrain. Design In this study, we have used a chemical inhibition approach in the chick model and a genetic approach in the mouse model. We also reported results obtained from the clinical diagnosis of a cohort composed of 141 holoprosencephaly patients. Results We demonstrated that inhibition of NOTCH signaling in chick embryos as well as in mouse embryos induced a specific downregulation of SHH in the anterior hypothalamus. Our data in the mouse also revealed that the pituitary gland was the most sensitive tissue to Shh insufficiency and that haploinsufficiency of the SHH and NOTCH signaling pathways synergized to produce a malformed pituitary gland. Analysis of a large holoprosencephaly cohort revealed that some patients possessed multiple heterozygous mutations in several regulators of both pathways. Conclusions These results provided new insights into molecular mechanisms underlying the extreme phenotypic variability observed in human holoprosencephaly. They showed how haploinsufficiency of the SHH and NOTCH activity could contribute to specific congenital hypopituitarism that was associated with a sella turcica defect.

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“…Null-type GHRH-R mutations lead to unmeasurable IGF-1 levels and are accompanied by mild ocular disorders ( 14 ). Missense GHRH-R variants -such as p.G369V or p.T257A- result in partial loss of receptor function due to defective ligand binding and milder phenotypes, occasionally accompanied by hypoglycemia ( 15 ). Splice site mutations of untranslated and coding regions have been reported to lead to gross indels with loss of 5’ regulatory/exon 1 region, leading to fully impaired GHRH-R expression ( 12 ).…”

Section: Discussionmentioning

confidence: 99%

A Novel Variant c.97C>T of the Growth Hormone Releasing Hormone Receptor Gene Causes Isolated Growth Hormone Deficiency Type Ib

Galli-Tsinopoulou

Kotanidou

Kleisarchaki

et al. 2018

Jcrpe

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Congenital isolated growth hormone deficiency (IGHD) type 1b is an autosomal recessive genetic condition caused by mutations of growth hormone (GH)-1 or the growth hormone releasing hormone receptor (GHRH-R) genes. Affected subjects present with symptoms of growth hormone deficiency (GHD) with low but detectable levels of growth hormone (GH), short stature and responsiveness to GH therapy. We describe a 13-month old girl with severe growth failure who showed a low GH response to two GH provocation tests and a modest increase of insulin-like growth factor-1 (IGF-1) to an IGF-1 generation test. Whole exome sequencing revealed a novel homozygous variant of the GHRH-R gene (c.97C>T), leading to a premature stop codon. Administration of recombinant human GH improved linear growth. This is the first report of a c.97C>T mutation of the GHRH-R gene.

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Partial Loss of Function of the GHRH Receptor Leads to Mild Growth Hormone Deficiency

Cited by 9 publications

References 22 publications

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

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

Disrupted Hypothalamo-Pituitary Axis in Association With Reduced SHH Underlies the Pathogenesis of NOTCH-Deficiency

A Novel Variant c.97C>T of the Growth Hormone Releasing Hormone Receptor Gene Causes Isolated Growth Hormone Deficiency Type Ib

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