Computational Investigation of Growth Hormone Receptor Trp169Arg Heterozygous Mutation in a Child With Short Stature

Porto, William F.; Marques, Felipe Albuquerque; Pogue, Huri Brito; Cardoso, Maria Teresinha de Oliveira; Vale, Maria Gabriela Rodrigues do; Pires, Állan da Silva; Franco, Octávio L.; Alencar, Sérgio Amorim de; Pogue, Robert

doi:10.1002/jcb.26144

Cited by 8 publications

(8 citation statements)

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“…Mutations in the GHR gene can alter the ability of GHR to interact with the GH peptide [ 8 ]. Nearly 30 GHR mutations have been reported to be associated with disturbing the GH–GHR combination ( Table 1 and Table 2 ).…”

Section: Ghr Polymorphisms and Individual Dwarfismmentioning

confidence: 99%

“…In this axis, as an essential cytokine, GHR introduces the GH signal into the cell and then regulates the expression of IGFs, thereby regulating individual growth. Hence, the expression level and normal functioning of GHR in cells and tissues directly affects the physiological effects of GH [ 7 , 8 ]. Individuals with dysfunctional GHR, experiencing a loss or an abnormality in the GHR response to GH, are extremely short.…”

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: Ghr Polymorphisms and Individual Dwarfismmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Growth Hormone Receptor Mutations Related to Individual Dwarfism

Lin

et al. 2018

IJMS

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“…In general, slight phenotypic effects of wt/- in autosomal recessive diseases cannot be excluded [ 28 ]. Mono-allelic likely pathogenic variants in proteins with structural similarity to LEP/LEPR are known, comparable to variants in growth hormone [ 29 ], growth hormone receptor [ 30 ], and G-CSF receptor [ 31 ]. In one study of Farooqi et al, LEP wt/- showed lower leptin levels and increased prevalence of obesity than controls [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

A fresh look to the phenotype in mono-allelic likely pathogenic variants of the leptin and the leptin receptor gene

Koerber-Rosso¹,

Brandt²,

Schnurbein³

et al. 2021

Mol Cell Pediatr

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Leptin (LEP) and leptin receptor (LEPR) play a major role in energy homeostasis, metabolism, and reproductive function. While effects of biallelic likely pathogenic variants (-/-) on the phenotype are well characterized, effects of mono-allelic likely pathogenic variants (wt/-) in the LEP and LEPR gene on the phenotype compared to wild-type homozygosity (wt/wt) have not been systematically investigated. We identified in our systematic review 44 animal studies (15 on Lep, 29 on Lepr) and 39 studies in humans reporting on 130 mono-allelic likely pathogenic variant carriers with 20 distinct LEP variants and 108 heterozygous mono-allelic likely pathogenic variant carriers with 35 distinct LEPR variants. We found indications for a higher weight status in carriers of mono-allelic likely pathogenic variant in the leptin and in the leptin receptor gene compared to wt/wt, in both animal and human studies. In addition, animal studies showed higher body fat percentage in Lep and Lepr wt/- vs wt/wt. Animal studies provided indications for lower leptin levels in Lep wt/- vs. wt/wt and indications for higher leptin levels in Lepr wt/- vs wt/wt. Data on leptin levels in human studies was limited. Evidence for an impaired metabolism in mono-allelic likely pathogenic variants of the leptin and in leptin receptor gene was not conclusive (animal and human studies). Mono-allelic likely pathogenic variants in the leptin and in leptin receptor gene have phenotypic effects disposing to increased body weight and fat accumulation.

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“…Then, to improve the accuracy of the predictions, other techniques, such as molecular dynamics, can be used [21]. This approach has been used by our group to study other mutations related to peptide hormones, such as guanylin [22], uroguanylin [23], lymphoguanylin [24] and growth hormone receptor [25]. Here we show that the rare mutations in mature amylin caused by SNPs are located in conserved position, maintaining the aggregation potential and a similar structure conformation to the wild-type after an unfolding dynamics simulation.…”

Section: Introductionmentioning

confidence: 99%

“…Then, to improve the accuracy of predictions, other techniques, such as molecular dynamics, can be used [21]–[25]. This approach has been used by our group to study other mutations related to peptide hormones, such as guanylin [26], uroguanylin [27], lymphoguanylin [28] and growth hormone receptor [29]. Our hypothesis is that mutations in the amylin gene can alter the peptide structure.…”

Section: Introductionmentioning

confidence: 99%

Structural effects driven by rare point mutations in amylin hormone, the type II diabetes-associated peptide

Mendes

Franco

Alencar

et al. 2021

Preprint

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Amylin is a 37 amino acid peptide hormone co-secreted with insulin, which participates in the glucose homeostasis. This hormone is able to aggregate in a β-sheet conformation and deposit in islet amyloids, a hallmark in type II diabetes. Since amylin is a gene encoded hormone, this peptide has variants caused by single nucleotide polymorphisms (SNPs) that can impact its functions. The effect of these variants can be evaluated by means of computational tools, such as molecular dynamics simulations. Here, we analyzed the structural effects caused by S20G and G33R point mutations, which, according to the 1,000 Genomes Project, have frequency in East Asian and Europe populations, respectively. By means of the aggrescan software and molecular dynamics, we found that both mutations have aggregation potential and cause changes in the monomeric forms when compared with wild-type amylin. The S20G mutation has been described as pathological related, and G33R mutation may have a deleterious effect. Furthermore, comparative analyses with pramlintide, an amylin drug analogue, allowed inferring the second α-helix maintenance may be related to the aggregation potential. Our data could help to better understand the mutations influence in the wild-type amylin sequence, being a starting point for the evaluation and characterization of other variations. The data presented here also propitiate new therapy opportunities, whether creating more effective drugs to diabetes or implementing a specific treatment to the patients with these mutations. Hence, these findings could improve the lifestyle to patients with type II diabetes.

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Computational Investigation of Growth Hormone Receptor Trp169Arg Heterozygous Mutation in a Child With Short Stature

Cited by 8 publications

References 77 publications

Growth Hormone Receptor Mutations Related to Individual Dwarfism

Growth Hormone Receptor Mutations Related to Individual Dwarfism

A fresh look to the phenotype in mono-allelic likely pathogenic variants of the leptin and the leptin receptor gene

Structural effects driven by rare point mutations in amylin hormone, the type II diabetes-associated peptide

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