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      Growth Hormone Receptor Mutations Related to Individual Dwarfism

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          Abstract

          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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          Most cited references88

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          Human growth hormone and extracellular domain of its receptor: crystal structure of the complex

          Binding of human growth hormone (hGH) to its receptor is required for regulation of normal human growth and development. Examination of the 2.8 angstrom crystal structure of the complex between the hormone and the extracellular domain of its receptor (hGHbp) showed that the complex consists of one molecule of growth hormone per two molecules of receptor. The hormone is a four-helix bundle with an unusual topology. The binding protein contains two distinct domains, similar in some respects to immunoglobulin domains. The relative orientation of these domains differs from that found between constant and variable domains in immunoglobulin Fab fragments. Both hGHbp domains contribute residues that participate in hGH binding. In the complex both receptors donate essentially the same residues to interact with the hormone, even though the two binding sites on hGH have no structural similarity. Generally, the hormone-receptor interfaces match those identified by previous mutational analyses. In addition to the hormone-receptor interfaces, there is also a substantial contact surface between the carboxyl-terminal domains of the receptors. The relative extents of the contact areas support a sequential mechanism for dimerization that may be crucial for signal transduction.
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            Growth hormone — past, present and future

            Growth hormone (GH) research and its clinical application for the treatment of growth disorders span more than a century. During the first half of the 20th century, clinical observations and anatomical and biochemical studies formed the basis of the understanding of the structure of GH and its various metabolic effects in animals. The following period (1958-1985), during which pituitary-derived human GH was used, generated a wealth of information on the regulation and physiological role of GH - in conjunction with insulin-like growth factors (IGFs) - and its use in children with GH deficiency (GHD). The following era (1985 to present) of molecular genetics, recombinant technology and the generation of genetically modified biological systems has expanded our understanding of the regulation and role of the GH-IGF axis. Today, recombinant human GH is used for the treatment of GHD and various conditions of non-GHD short stature and catabolic states; however, safety concerns still accompany this therapeutic approach. In the future, new therapeutics based on various components of the GH-IGF axis might be developed to further improve the treatment of such disorders. In this Review, we describe the history of GH research and clinical use with a particular focus on disorders in childhood.
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              Melanocortin receptor 1 (MC1R) mutations and coat color in pigs.

              The melanocortin receptor 1 (MC1R) plays a central role in regulation of eumelanin (black/brown) and phaeomelanin (red/yellow) synthesis within the mammalian melanocyte and is encoded by the classical Extension (E) coat color locus. Sequence analysis of MC1R from seven porcine breeds revealed a total of four allelic variants corresponding to five different E alleles. The European wild boar possessed a unique MC1R allele that we believe is required for the expression of a wild-type coat color. Two different MC1R alleles were associated with the dominant black color in pigs. MC1R*2 was found in European Large Black and Chinese Meishan pigs and exhibited two missense mutations compared with the wild-type sequence. Comparative data strongly suggest that one of these, L99P, may form a constitutively active receptor. MC1R*3 was associated with the black color in the Hampshire breed and involved a single missense mutation D121N. This same MC1R variant was also associated with EP, which results in black spots on a white or red background. Two different missense mutations were identified in recessive red (e/e) animals. One of these, A240T, occurs at a highly conserved position, making it a strong candidate for disruption of receptor function.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                10 May 2018
                May 2018
                : 19
                : 5
                : 1433
                Affiliations
                [1 ]Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou 510642, Guangdong, China; shudailin@ 123456stu.scau.edu.cn
                [2 ]Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, South China Agricultural University, Guangzhou 510642, Guangdong, China
                [3 ]Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, South China Agricultural University, Guangzhou 510642, Guangdong, China
                [4 ]Animal Genomics and Improvement Laboratory, Agricultural Research Service, United States Department of Agriculture, Beltsville, MD 20705, USA; congjun.li@ 123456ars.usda.gov
                [5 ]Animal Biosciences and Biotechnology Laboratory, Agricultural Research Service, United States Department of Agriculture, Beltsville, MD 20705, USA; charles.li@ 123456ars.usda.gov
                Author notes
                [* ]Correspondence: xqzhang@ 123456scau.edu.cn ; Tel.: +86-20-8528-5703; Fax: +86-20-8528-0740
                Author information
                https://orcid.org/0000-0002-8520-8614
                https://orcid.org/0000-0003-1389-9820
                Article
                ijms-19-01433
                10.3390/ijms19051433
                5983672
                29748515
                d7dd508b-55ba-4f20-ae68-667e3cf67f69
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 31 March 2018
                : 07 May 2018
                Categories
                Review

                Molecular biology
                growth hormone receptor,mutation,dwarfism,dysfunction
                Molecular biology
                growth hormone receptor, mutation, dwarfism, dysfunction

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