Identification of novel GHRHR and GH1 mutations in patients with isolated growth hormone deficiency

Birla, Shweta; Khadgawat, Rajesh; Jyotsna, Viveka P; Jain, Vandana; Garg, MK; Bhalla, Ashu Seith; Sharma, Aruna

doi:10.1016/j.ghir.2016.04.001

Cited by 17 publications

(19 citation statements)

References 37 publications

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“…Our previous study was conducted with a broad aim to ensure a widespread analysis of the genomic regions including the whole GH1 gene deletion, the GH1 promoter, and all 5 GH1 exons along with complete screening (13 exons) of the GHRHR gene in IGHD patients and all the coding exons of PROP1, POU1F1, and HESX1 in CPHD patients. The detailed findings on the molecular screening in IGHD and CPHD were reported separately [7,8]. In the present study, we build on our previous findings where several known and novel mutations were identified.…”

Section: Introductionmentioning

confidence: 65%

“…Participants were recruited as described previously [7,8]. Briefly, a total of 160 consecutive patients, diagnosed with IGHD or CPHD were recruited from the Pediatric and Adolescence Endocrine Clinic (PAEC); Department of Endocrinology & Metabolism, Pediatric Endocrine Clinic (PEC); Department of Pediatrics, AIIMS, New Delhi; and Department of Endocrinology and Metabolism, Army Hospital (Referral & Research, New Delhi).…”

Section: Participant's Recruitmentmentioning

confidence: 99%

“…Briefly, a total of 160 consecutive patients, diagnosed with IGHD or CPHD were recruited from the Pediatric and Adolescence Endocrine Clinic (PAEC); Department of Endocrinology & Metabolism, Pediatric Endocrine Clinic (PEC); Department of Pediatrics, AIIMS, New Delhi; and Department of Endocrinology and Metabolism, Army Hospital (Referral & Research, New Delhi). Diagnosis was based on clinical, biochemical, and imaging investigations as described previously [7,8]. The study protocol adhered to the tenets of Declaration of Helsinki and was approved by the AIIMS Ethics Committee, New Delhi.…”

Section: Participant's Recruitmentmentioning

confidence: 99%

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Characterization of a Novel POU1F1 Mutation Identified on Screening 160 Growth Hormone Deficiency Patients

et al. 2019

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The objective of the study is the functional characterization of a novel POU1F1 c.605delC mutation in combined pituitary hormone deficiency (CPHD) and to report the clinical and genetic details of 160 growth hormone deficiency patients. Screening of GH1, GHRHR, POU1F1, PROP1, and HESX1 genes by Sanger sequencing was carried out in 160 trios and 100 controls followed by characterization of the POU1F1 c.605delC mutation by expression studies including site directed mutagenesis, co-transfection, protein degradation, and luciferase assays to compare the wild type and mutant POU1F1. In vitro studies showed that the POU1F1 c.605delC mutation codes for a truncated protein with reduced transactivation capacity on its downstream effectors, viz., growth hormone (GH) and prolactin (PRL) causing severe CPHD. Experiments using different protease inhibitors reveal rescue of the protein upon blockage of the lysosomal pathway that might be useful in novel drug designing using targeted approach thereby maintaining the milieu and preventing/delaying the disease. The study provides an insight into the disease causing mechanism of POU1F1 c.605delC mutation identified in a CPHD child with severe short stature and failure to thrive. It also shows mutation effect on the expression, function and turnover of protein and highlights mechanistic details by which these potent regulators may operate.

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Section: Introductionmentioning

confidence: 65%

Section: Participant's Recruitmentmentioning

confidence: 99%

Section: Participant's Recruitmentmentioning

confidence: 99%

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Characterization of a Novel POU1F1 Mutation Identified on Screening 160 Growth Hormone Deficiency Patients

et al. 2019

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“…Although several studies have described genetic variations in the GH1 promoter region and their effect on GH1 expression (5,12,13,14,15,16,17,18), a point mutation in the promoter region that leads to IGHD with complete penetrance has never been found.…”

Section: Discussionmentioning

confidence: 99%

“…Although several studies have investigated the effect of SNPs and mutations in the promoter region on GH1 expression in both healthy and affected individuals (5,12,13,14,15,16,17,18), a mutation in the promoter region leading to IGHD with complete penetrance has never been described. This study describes a double homozygous allelic variant (c.-223C>T and c.-185T>C) in the GH1 promoter region in a consanguineous family with severe isolated GH deficiency.…”

Section: Introductionmentioning

confidence: 99%

A homozygous point mutation in the GH1 promoter (c.-223C>T) leads to reduced GH1 expression in siblings with isolated GH deficiency (IGHD)

Madeira¹,

Jorge

Martin³

et al. 2016

European Journal of Endocrinology

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Context: Mutations in the GH1 promoter are a rare cause of isolated growth hormone deficiency (IGHD). Objective: To identify the molecular aetiology of a family with IGHD. Design: DNA sequencing, electromobility shift (EMSA) and luciferase reporter assays. Setting: University Hospital. Patients: Three siblings (2M) born to consanguineous parents presented with IGHD with normal pituitary on MRI. Methods: The GH1 proximal promoter, locus control region, five exons and four introns as well as GHRHR gene were sequenced in genomic DNA by Sanger method. DNA-protein interaction was evaluated by EMSA in nuclear extracts of GH3 pituitary cells. Dual-luciferase reporter assays were performed in cells transiently transfected with plasmids containing four different combinations of GH1 allelic variants (AV). Results: The patients harboured two homozygous variants (c.-185T>C and c.-223C>T) in the GH1 promoter within a highly conserved region and predicted binding sites for POU1F1/SP1 and SP1 respectively. The parents and brother were carriers and these variants were absent in 100 controls. EMSA demonstrated absent binding of GH3 nuclear extract to the c.-223C>T variant and normal binding of both POU1F1 protein and GH3 nuclear extract to the c.-185T>C variant. In contrast to GH1 promoter with AV only at c.-185, the GH1 promoter containing the AV only at c.-223 and at both positions drove significantly less expression of luciferase compared with the promoter containing either positions wild type in luciferase reporter assays. Conclusion: To our knowledge, c.-223C>T is the first homozygous point mutation in the GH1 promoter that leads to short stature due to IGHD.

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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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Identification of novel GHRHR and GH1 mutations in patients with isolated growth hormone deficiency

Cited by 17 publications

References 37 publications

Characterization of a Novel POU1F1 Mutation Identified on Screening 160 Growth Hormone Deficiency Patients

Characterization of a Novel POU1F1 Mutation Identified on Screening 160 Growth Hormone Deficiency Patients

A homozygous point mutation in the GH1 promoter (c.-223C>T) leads to reduced GH1 expression in siblings with isolated GH deficiency (IGHD)

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

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