Heterozygous GHR gene mutation in a child with idiopathic short stature

Pagani, Sara; Petkovic, Vibor; Messini, Beatrice; Meazza, Cristina; Bozzola, Elena; Mullis, Primus-Eugen; Bozzola, Mauro

doi:10.1515/jpem-2013-0359

Cited by 4 publications

(5 citation statements)

References 21 publications

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“…Several defects have been reported to be associated with body dwarfism. For instance, the G62V mutation in exon 4 [ 53 ], a heterozygous mutation (V144I) within exon 6 of the GHR [ 13 ], a dinucleotide deletion on exon 7 of the GHR gene [ 61 ], and even a GT-repeat microsatellite in the GHR 5’UTR [ 7 ] can result in dwarfism. However, not all mutations in GHR cause body dwarfism.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, compared to the average individual height and weight in a population, skeletal development is different. Individual dwarfism caused by GHR disorders are LS and ISS in humans [ 12 , 13 , 22 , 37 , 38 , 39 ], miniature pigs [ 15 , 16 , 40 ], cattle and sheep [ 17 ], and sex-linked dwarfism (SLD) in chickens [ 2 , 18 , 20 ].…”

Section: Ghr Polymorphisms and Individual Dwarfismmentioning

confidence: 99%

“…Dwarfism is characterized by normal or elevated serum GH and low levels of IGF-1 [ 10 ]. Dwarf phenotypes exist in humans [ 3 , 7 , 11 , 12 , 13 ], mice [ 14 ], pigs [ 15 , 16 ], cattle, and sheep [ 17 ], and sex-linked dwarfism (SLD) occurs in chicken [ 2 , 18 , 19 , 20 ]. For example, Laron syndrome (LS), also known as growth hormone insensitivity syndrome, and idiopathic short stature (ISS) are autosomal recessive genetic disorders associated with severe postnatal growth failure and is mostly caused by mutation in the human GHR .…”

Section: Introductionmentioning

confidence: 99%

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Growth Hormone Receptor Mutations Related to Individual Dwarfism

Lin

et al. 2018

IJMS

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Growth hormone (GH) promotes body growth by binding with two GH receptors (GHRs) at the cell surface. GHRs interact with Janus kinase, signal transducers, and transcription activators to stimulate metabolic effects and insulin-like growth factor (IGF) synthesis. However, process dysfunctions in the GH–GHR–IGF-1 axis cause animal dwarfism. If, during the GH process, GHR is not successfully recognized and/or bound, or GHR fails to transmit the GH signal to IGF-1, the GH dysfunction occurs. The goal of this review was to focus on the GHR mutations that lead to failures in the GH–GHR–IGF-1 signal transaction process in the dwarf phenotype. Until now, more than 90 GHR mutations relevant to human short stature (Laron syndrome and idiopathic short stature), including deletions, missense, nonsense, frameshift, and splice site mutations, and four GHR defects associated with chicken dwarfism, have been described. Among the 93 identified mutations of human GHR, 68 occur extracellularly, 13 occur in GHR introns, 10 occur intracellularly, and two occur in the transmembrane. These mutations interfere with the interaction between GH and GHRs, GHR dimerization, downstream signaling, and the expression of GHR. These mutations cause aberrant functioning in the GH-GHR-IGF-1 axis, resulting in defects in the number and diameter of muscle fibers as well as bone development.

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Section: Discussionmentioning

confidence: 99%

Section: Ghr Polymorphisms and Individual Dwarfismmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Growth Hormone Receptor Mutations Related to Individual Dwarfism

Lin

et al. 2018

IJMS

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“…3 Schematic representation of reported variants in the GHR gene and the corresponding protein structure including the signal peptide, an extracellular domain consisting of two FN3 subdomains, a transmembrane domain, and an intracellular domain. The identified variant in this study was marked in red [ 2 – 6 , 8 , 12 , 13 , 15 , 17 – 19 , 21 , 23 , 26 – 29 , 31 , 34 , 36 , 37 , 43 , 47 , 48 , 50 , 51 , 54 – 56 , 58 – 60 , 64 , 65 , 68 – 70 , 72 – 74 ] …”

Section: Case Presentationmentioning

confidence: 93%

Reporting a novel growth hormone receptor gene variant in an Iranian consanguineous pedigree with Laron syndrome: a case report

Bitarafan,

Khodaeian,

Garrousi

et al. 2023

BMC Endocr Disord

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Background Human growth hormone (hGH) plays a crucial role in growth by binding to growth hormone receptor (GHR) in target cells. Binding of GH molecules to their cognate receptors triggers downstream signaling pathways leading to the transcription of several genes, including insulin-like growth factor (IGF)-1. Pathogenic variants in the GHR gene can result in structural and functional defects in the GHR protein, leading to Laron Syndrome (LS) with the primary clinical manifestation of short stature. So far, around 100 GHR variants have been reported, mostly biallelic, as causing LS. Case presentation We report on three siblings from an Iranian consanguineous family who presented with dwarfism. Whole-exome sequencing (WES) was performed on the proband, revealing a novel homozygous missense variant in the GHR gene (NM_000163.5; c.610 T > A, p.(Trp204Arg)) classified as a likely pathogenic variant according to the recommendation of the American College of Medical Genetics (ACMG). Co-segregation analysis was investigated using Sanger sequencing. Conclusions To date, approximately 400–500 LS cases with GHR biallelic variants, out of them 10 patients originating from Iran, have been described in the literature. Given the high rate of consanguineous marriages in the Iranian population, the frequency of LS is expected to be higher, which might be explained by undiagnosed cases. Early diagnosis of LS is very important, as treatment is available for this condition.

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“…Previous reports have shown that hypothalamic-pituitary-gonadal (HPG) axis and growth hormone-Insulin-like growth factor (IGF) axis is the most vital hormonal axis governing growth [3]. Any level of abnormality of GH-IGF axis may cause short stature [4], such as GHR [5], IGF-1R [6,7], IGFALS [8] were associated with ISS, but fewer studies have investigated the association of HPG axis with the risk of ISS.…”

Section: Introductionmentioning

confidence: 99%

Association of single nucleotide polymorphisms in estrogen receptor 1 gene with the risk of idiopathic short stature

Yang¹,

Huang²,

Yuan³

et al. 2018

biomedicalresearch

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Estrogen is a hormone in hypothalamic-pituitary-gonadal (HPG) axis that plays an important role in the regulation of bone maturation and closure of the growth plate. The aim of this study was to investigate the association between single nucleotide polymorphisms (SNPs) in estrogen receptor 1 (ESR1) gene and susceptibility to idiopathic short stature (ISS) in the Chinese population. Six SNPs of the ESR1 gene (rs6557177, rs1884049, rs3020429, rs3798575, rs3778090, rs3798757) were genotyped and we found a significant positive association between rs6557177 genotype and susceptibility to ISS compare to control group in preliminary study (ISS=200, control=220, χ 2 =6.262, P =0.044). Validation of rs6557177 was conducted by further expanding the sample size to 400 ISS patients and 380 control subjects genotyped by SNaPshot Multiplex System. The frequencies of the rs6557177 CC genotype and C allele were observed to increased in ISS group compared with the control group (χ 2 =9.913, P =0.007; χ 2 =5.57, P = 0.018 OR: 1.502; 95% CI: 1.07-2.108 respectively). However, no significant correlation was observed between the rs6557177 and clinical characteristics of the study participants. We demonstrate for the first time that the presence of a C allele or CC genotype at rs6557177 of ESR1 constitutes risk factor for developing ISS in Chinese children.

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Heterozygous GHR gene mutation in a child with idiopathic short stature

Cited by 4 publications

References 21 publications

Growth Hormone Receptor Mutations Related to Individual Dwarfism

Growth Hormone Receptor Mutations Related to Individual Dwarfism

Reporting a novel growth hormone receptor gene variant in an Iranian consanguineous pedigree with Laron syndrome: a case report

Association of single nucleotide polymorphisms in estrogen receptor 1 gene with the risk of idiopathic short stature

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