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      Novel Dominant-Negative GH Receptor Mutations Expands the Spectrum of GHI and IGF-I Deficiency

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          Autosomal-recessive mutations in the growth hormone receptor (GHR) are the most common causes for primary growth hormone insensitivity (GHI) syndrome with classical GHI phenotypically characterized by severe short stature and marked insulin-like growth factor (IGF)-I deficiency. We report three families with dominant-negative heterozygous mutations in the intracellular domain of the GHR causing a nonclassical GHI phenotype.


          To determine if the identified GHR heterozygous variants exert potential dominant-negative effects and are the cause for the GHI phenotype in our patients.


          All three mutations (c .964dupG, c.920_921insTCTCAAAGATTACA, and c.945+2T>C) are predicted to result in frameshift and early protein termination. In vitro functional analysis of variants c .964dupG and c.920_921insTCTCAAAGATTACA (c.920_921ins14) suggests that these variants are expressed as truncated proteins and, when coexpressed with wild-type GHR, mimicking the heterozygous state in our patients, exert dominant-negative effects. Additionally, we provide evidence that a combination therapy of recombinant human growth hormone (rhGH) and rhIGF-I improved linear growth to within normal range for one of our previously reported patients with a characterized, dominant-negative GHR ( c.899dupC) mutation.


          Dominant-negative GHR mutations are causal of the mild GHI with substantial growth failure observed in our patients. Heterozygous defects in the intracellular domain of GHR should, therefore, be considered in cases of idiopathic short stature and IGF-I deficiency. Combination therapy of rhGH and rhIGF-I improved growth in one of our patients.


          In patients with mild GHI, heterozygous, truncating GHR mutations exerted dominant-negative effects. A combined therapy of rhGH plus rhIGF-I is an effective treatment option.

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          Most cited references 20

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          Laron syndrome (primary growth hormone resistance or insensitivity): the personal experience 1958-2003.

           Zvi Laron (2004)
          Clinical and laboratory investigations starting in 1958 of a group of dwarfed children resembling isolated GH deficiency but who had very high serum levels of GH led to the description of the syndrome of primary GH resistance or insensitivity (Laron syndrome) and subsequently to the discovery of its molecular defects residing in the GH receptor and leading to an inability of IGF-I generation. With the biosynthesis of IGF-I in 1986, therapeutic trials started. Continuously more and more patients are being diagnosed in many parts of the world with a variety of molecular defects. This syndrome proved to be a unique model that enables the study of the consequences of GH receptor defects, the physiopathology of GH-IGF-I disruption, and comparison of the GH-independent IGF-I effects. This review presents the personal experience gained from the study follow-up and treatment of the 60 patients followed up for many years in the Israeli cohort.
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            Evidence for a continuum of genetic, phenotypic, and biochemical abnormalities in children with growth hormone insensitivity.

            GH insensitivity (GHI) presents in childhood as growth failure and in its severe form is associated with dysmorphic and metabolic abnormalities. GHI may be caused by genetic defects in the GH-IGF-I axis or by acquired states such as chronic illness. This article discusses the former category. The field of GHI due to mutations affecting GH action has evolved considerably since the original description of the extreme phenotype related to homozygous GH receptor (GHR) mutations over 40 yr ago. A continuum of genetic, phenotypic, and biochemical abnormalities can be defined associated with clinically relevant defects in linear growth. The role and mechanisms of the GH-IGF-I axis in normal human growth is discussed, followed by descriptions of mutations in GHR, STAT5B, PTPN11, IGF1, IGFALS, IGF1R, and GH1 defects causing bioinactive GH or anti-GH antibodies. These defects are associated with a range of genetic, clinical, and hormonal characteristics. Genetic abnormalities causing growth failure that is less severe than the extreme phenotype are emphasized, together with an analysis of height and serum IGF-I across the spectrum of different types of GHR defects. An overall view of genotype and phenotype relationships is presented, together with an updated approach to the assessment of the patient with GHI, focusing on investigation of the GH-IGF-I axis and relevant molecular studies contributing to this diagnosis.
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              Ligand-independent growth hormone receptor dimerization occurs in the endoplasmic reticulum and is required for ubiquitin system-dependent endocytosis.

              The regulatory effect of growth hormone (GH) on its target cells is mediated via the GH receptor (GHR). GH binding to the GHR results in the formation of a GH-(GHR)(2) complex and the initiation of signal transduction cascades via the activation of the tyrosine kinase JAK2. Subsequent endocytosis and transport to the lysosome of the ligand-receptor complex is regulated via the ubiquitin system and requires the presence of an intact ubiquitin-dependent endocytosis (UbE) motif in the cytosolic tail of the GHR. Recently, the model of ligand-induced receptor dimerization has been challenged. In this study, ligand-independent GHR dimerization is demonstrated in the endoplasmic reticulum and at the cell surface by coimmunoprecipitation of an epitope-tagged truncated GHR with wild-type GHR. In addition, evidence is provided that the extracellular domain of the GHR is not required to maintain this interaction. Internalization of a chimeric receptor, which fails to dimerize, is independent of an intact UbE-motif. Therefore, we postulate that dimerization of GHR molecules is required for ubiquitin system-dependent endocytosis.

                Author and article information

                J Endocr Soc
                J Endocr Soc
                Journal of the Endocrine Society
                Endocrine Society (Washington, DC )
                01 April 2017
                08 March 2017
                08 March 2017
                : 1
                : 4
                : 345-358
                [1 ]Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229
                [2 ]Division of Endocrinology & Diabetes, Seattle Children's Hospital, Seattle, Washington 98105
                [3 ]Division of Pediatric Endocrinology, Sant Joan de Déu Hospital, Center in Diabetes and Associated Metabolic Disorders, 08950 Barcelona, Spain
                [4 ]Centre for Bioinformatics and System Biology, Department of Life Sciences, Imperial College London, London, SW7 2AZ, United Kingdom
                [5 ]Centre for Endocrinology, William Harvey Research Institute, John Vane Science Centre, Queen Mary, University of London, Charterhouse Square, London, EC1M 6BQ, United Kingdom
                [6 ]Pediatric Endocrinology and Dysmorphology Unit, Hospital 12 de Octubre, 28041 Madrid, Spain
                [7 ]Department of Pediatrics, Oregon Health & Science University, Portland, Oregon 97239
                [8 ]Pediatrics Endocrinology, Hackensack University Medical Center, Hackensack, New Jersey 07601
                Author notes

                These authors contributed equally to this study.

                Address all correspondence to: Vivian Hwa, PhD, Division of Endocrinology, Cincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, Ohio 45229. E-mail: vivian.hwa@ 123456cchmc.org .
                Copyright © 2017 Endocrine Society

                This article is published under the terms of the Creative Commons Attribution-Non Commercial License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/).

                Page count
                Figures: 4, Tables: 2, Equations: 0, References: 21, Pages: 14
                Clinical Research Articles
                Growth, Growth Hormone, and Growth Factors


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