Pathogenic and likely pathogenic genetic alterations and polymorphisms in growth hormone gene (GH1) and growth hormone releasing hormone receptor gene (GHRHR) in a cohort of isolated growth hormone deficient (IGHD) children in Sri Lanka

Sundralingam, Tharmini; Tennekoon, Kamani Hemamala; Silva, Shamya De; Silva, Sumadee De; Hewage, Asanka Sudeshini

doi:10.1016/j.ghir.2017.08.006

Cited by 10 publications

(5 citation statements)

References 35 publications

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“…The aggregate signal was associated with a 0.34SD (3.11cm) reduction in height. One of the 9 variants, which replicated, was independently associated with height (17:63918961:A:G, β = -4.24cm [95% CI -5.53, -2.94cm], P = 1.46 × 10 −10 , MAF = 0.04%), and has previously been reported as a variant of unknown significance in multiple clinical cohorts for idiopathic short stature as NM_000515.5_c.185T > C. These findings in clinical cohorts of idiopathic short stature include: three carriers of the variant we identified (c.185T > C) were previously identified in a Sri Lankan cohort of patients with Isolated Growth Hormone deficiency 34 (IGHD) ; three siblings with consanguineous parents with IGHD 35 . The variant was originally identified in a cohort of 41 unrelated children with short stature, and 11 unrelated patients with IGHD 36 (as - 123T>C).…”

Section: Resultssupporting

confidence: 67%

Whole genome association testing in 333,100 individuals across three biobanks identifies rare non-coding single variant and genomic aggregate associations with height

Hawkes,

Beaumont,

et al. 2023

Preprint

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The role of rare non-coding variation in complex human phenotypes is still largely unknown. To elucidate the impact of rare variants in regulatory elements, we performed a whole-genome sequencing association analysis for height using 333,100 individuals from three datasets: UK Biobank (N=200,003), TOPMed (N=87,652) and All of Us (N=45,445). We performed rare (<0.1% minor-allele-frequency) single-variant and aggregate testing of non-coding variants in regulatory regions based on proximal, intergenic and deep-intronic annotation. We observed 29 independent variants associated with height atP< 6 × 10−10after conditioning on previously reported variants, with effect sizes ranging from -7cm to +4.7cm. We also identified and replicated non-coding aggregate-based associations proximal toHMGA1containing variants associated with a 5cm taller height and of highly-conserved variants inMIR497HGon chromosome 17. We have developed a novel approach for identifying non-coding rare variants in regulatory regions with large effects from whole-genome sequencing data associated with complex traits.

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Section: Resultssupporting

confidence: 67%

Whole genome association testing in 333,100 individuals across three biobanks identifies rare non-coding single variant and genomic aggregate associations with height

Hawkes,

Beaumont,

et al. 2023

Preprint

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“…According to Provean Protein software, p.Ala39Val substitution is predicted as deleterious, in spite of the fact that both amino acids (alanine and valine) belong to the same nonpolar, hydrophobic amino acid group. Interestingly, another substitution at the same amino acid position (39) (p.Ala39Thr) was reported by Sundralingam et al [14], who suggested that its significance was uncertain. Our study of family A showed that the minor variant was inherited by the patient and his brother (who also suffered from short stature, but was not diagnosed earlier) from the father, who was also short (−2.88 hSDS).…”

Section: Discussionmentioning

confidence: 82%

“…The final missense polymorphism (rs5388), which we found in four patients and four controls, was located in exon 4 (p.Val136Ile), and our in silico study predicted the effect as benign, because valine and isoleucine are both nonpolar hydrophobic amino acids. Interestingly, the valine to phenylalanine substitution at the same position (p.Val136Phe) has previously been described [14,17]; it was classified as likely to be pathogenic, since phenylalanine is a nonpolar aromatic amino acid.…”

Section: Discussionmentioning

confidence: 98%

“…There are numerous genes that control growth, variants of which can contribute or cause short stature [11]. Growth hormone (GH) plays a crucial role among these as a major regulator of growth, and its variants may cause GHD, leading to short stature [12][13][14][15]. However, it should be pointed out that short stature can be caused by variants of other genes (such as GHRHR, POU1F1, PROP1, and IGF1) and other mechanisms, including chromosomal abnormalities, copy number variation polymorphisms, and disrupted genomic imprinting [12].…”

Section: Introductionmentioning

confidence: 99%

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Polymorphism of the growth hormone gene GH1 in Polish children and adolescents with short stature

et al. 2020

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Purpose Short stature in children is a significant medical problem which, without proper diagnosis and treatment, can lead to long-term consequences for physical and psychological health in adult life. Since human height is a polygenic and highly heritable trait, numerous variants in the genes involved in growth-including the growth hormone (GH1) gene-have been identified as causes of short stature. Methods In this study, we performed for the first time molecular analysis of the GH1 gene in a cohort (n = 186) of Polish children and adolescents with short stature, suffering from growth hormone deficiency (GHD) or idiopathic short stature (ISS), and a control cohort (n = 178). Results Thirteen SNP variants were identified, including four missense variants, six in 5′UTR, and three in introns. The frequency of minor missense variants was low (<0.02) and similar in the compared cohorts. However, two of these variants, Ala39Val (rs151263636) and Arg42Leu (rs371953554), were found (heterozygote status) in only two GHD patients. These substitutions, according to databases, can potentially be deleterious. Conclusions Mutations of GH1 causing short stature are very rare in the Polish population, but two potentially causative variants need further studies in a larger cohort of GHD patients. Keywords GH1 gene • Mutation • Sequencing • SNP • Growth hormone deficiency (GHD) • Idiopathic short stature (ISS)

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“…Exons 1-4 encode the extracellular signaling domain, exons 5-12 the transmembrane domain and exons 12-13 the intracellular domains of the receptor. Moreover, exon 1 encodes the first 18 amino acids of GHRH-R which translates as the signal peptide; mutations (18, 19) or deletion (20) of which lead to GHRH-R loss-of-function and the development of isolated growth hormone deficiency (IGHD) in mice and humans. Accordingly, to knock-out the GHRH-R signaling peptide in hPSCs we generated a stable cell line expressing a tetracycline-inducible spCas9 and a gRNA spanning the ATG start sites of exon 1, with no predictable off target effects (Fig.…”

Section: Resultsmentioning

confidence: 99%

Oxygen-independent, hormonal control of HIF-1α regulates the developmental and regenerative growth of cardiomyocytes.

Wanschel

Salerno

Kuznetsov

et al. 2022

Preprint

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Differentiation and expansion of cardiomyocytes from human induced pluripotent stem cells is a poorly understood process, and the signals promoting differentiation of cardiomyocytes toward specific cell fates are not well defined. Here we show that the growth hormone-releasing hormone receptor (GHRH-R) signaling pathway controls this differentiation process and cell fate. Stimulation of hPSCs with GHRH promotes β-catenin stabilization through the GH/IGF1 axis. The presence of cell-surface GHRH-R differentiates between atrio-ventricular cardiomyocytes and non-cardiomyogenic cardiac cells, including coronary vascular, neuronal and pacemaker cells, such that selecting for GHRH-R allows for the elimination of pacemaker cells and derivation of a pure population of atrio-ventricular cardiomyocytes. Unlike SIRPA, cardiac GHRH-R identifies murine and human NKX2-5+ myocardial derivatives of both mesodermal and neuroectodermal lineages. Using RNA-seq to comprehensively characterize the GHRH-R signaling pathway, we identified that NKX2-5, a transcription factor involved in progenitor specification and differentiation into atrio-ventricular cardiomyocytes, is upregulated in response to GHRH. GHRH-R signaling also upregulated HIF-1α via the PI3k/Akt/mTOR pathway to enhance NKX2-5 transcription and stimulate a Warburg-like effect in developing cardiomyocytes. Together these findings provide crucial insights into human stem cell differentiation and offer a translationally useful tool to optimize the development of pure cardiomyocyte preparations derived from induced pluripotent stem cells.

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Pathogenic and likely pathogenic genetic alterations and polymorphisms in growth hormone gene (GH1) and growth hormone releasing hormone receptor gene (GHRHR) in a cohort of isolated growth hormone deficient (IGHD) children in Sri Lanka

Cited by 10 publications

References 35 publications

Whole genome association testing in 333,100 individuals across three biobanks identifies rare non-coding single variant and genomic aggregate associations with height

Whole genome association testing in 333,100 individuals across three biobanks identifies rare non-coding single variant and genomic aggregate associations with height

Polymorphism of the growth hormone gene GH1 in Polish children and adolescents with short stature

Oxygen-independent, hormonal control of HIF-1α regulates the developmental and regenerative growth of cardiomyocytes.

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