{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:46:45Z","timestamp":1787014005342,"version":"build-2736575974"},"reference-count":19,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,1,22]],"date-time":"2020-01-22T00:00:00Z","timestamp":1579651200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Endocrinology"],"published-print":{"date-parts":[[2020,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      To report a novel mutation in\n                      <jats:italic>GHR<\/jats:italic>\n                      and to characterize a novel mechanism of nonclassical growth hormone insensitivity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Context<\/jats:title>\n                    <jats:p>Laron syndrome (LS) is a well\u2010described disorder of growth hormone insensitivity due to mutations in the growth hormone receptor (GHR) that leads to short stature. Biochemically, LS patients classically have elevated levels of growth hormone (GH), but low levels of insulin\u2010like growth factor (IGF)\u20101, IGF binding protein (IGFBP)\u20103 and GH binding protein (GHBP).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>Case presentation with in vitro functional studies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Patients<\/jats:title>\n                    <jats:p>A young male Caucasian child with short stature was found to have growth hormone insensitivity manifested by elevated levels of GH and GHBP.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements<\/jats:title>\n                    <jats:p>\n                      Growth hormone stimulation tests revealed baseline GH level of 20.9\u00a0\u00b5g\/L and maximum stimulated GH level of 52.7\u00a0\u00b5g\/L and GHBP level of 4868\u00a0pmol\/L.\n                      <jats:italic>GHR<\/jats:italic>\n                      gene sequencing revealed a novel heterozygous nonsense mutation (c.800G\u00a0&gt;\u00a0A, p.Trp267*) in the transmembrane domain of the receptor. Immunoblot analysis of transfected GHR p.Trp267* in HEK293 revealed inhibition of GH\u2010induced STAT5 signalling that was overcome with increasing doses of recombinant human GH.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Using an in vitro model, we show that elevated levels of GHBP inhibit the action of GH. Furthermore, our studies demonstrate that this inhibition by GHBP can be overcome by increasing doses of recombinant human GH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      To our knowledge, this is the first study to demonstrate in vitro that elevated levels of GHBP attenuate the effect of GH and inhibit GH\u2010induced signalling, thereby leading to short stature. Though this inhibition was overcome in vitro with supraphysiologic doses of GH, significantly above endogenously available GH, it remains to be seen whether such an effect can be replicated in vivo\n                      <jats:italic>.<\/jats:italic>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/cen.14148","type":"journal-article","created":{"date-parts":[[2019,12,28]],"date-time":"2019-12-28T13:46:30Z","timestamp":1577540790000},"page":"331-337","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Severe growth failure associated with a novel heterozygous nonsense mutation in the\n                    <i>GHR<\/i>\n                    transmembrane domain leading to elevated growth hormone binding protein"],"prefix":"10.1111","volume":"92","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3998-4516","authenticated-orcid":false,"given":"Ankur","family":"Rughani","sequence":"first","affiliation":[{"name":"Section of Diabetes and Endocrinology Department of Pediatrics University of Oklahoma Health Sciences Center Oklahoma City Oklahoma"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongsheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Endocrinology Cincinnati Center for Growth Disorders Cincinnati Children's Hospital Medical Center Cincinnati Ohio"},{"name":"Department of Pediatrics University of Cincinnati College of Medicine Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1596-7762","authenticated-orcid":false,"given":"Kanimozhi","family":"Vairamani","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Cincinnati College of Medicine Cincinnati Ohio"},{"name":"Division of Oncology, Cancer and Blood Diseases Institute Cincinnati Children's Hospital Medical Center Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4890-0262","authenticated-orcid":false,"given":"Andrew","family":"Dauber","sequence":"additional","affiliation":[{"name":"Division of Endocrinology Children's National Hospital Washington District of Columbia"},{"name":"Department of Pediatrics George Washington School of Medicine and Health Sciences Washington District of Columbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0517-9049","authenticated-orcid":false,"given":"Vivian","family":"Hwa","sequence":"additional","affiliation":[{"name":"Division of Endocrinology Cincinnati Center for Growth Disorders Cincinnati Children's Hospital Medical Center Cincinnati Ohio"},{"name":"Department of Pediatrics University of Cincinnati College of Medicine Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5600-0753","authenticated-orcid":false,"given":"Sowmya","family":"Krishnan","sequence":"additional","affiliation":[{"name":"Section of Diabetes and Endocrinology Department of Pediatrics University of Oklahoma Health Sciences Center Oklahoma City Oklahoma"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,1,22]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecl.2012.04.010"},{"issue":"11","key":"e_1_2_6_3_1","first-page":"4079","article-title":"Growth hormone receptor mutations in children with idiopathic short stature","volume":"83","author":"Sanchez JE","year":"1998","journal-title":"J Clin Endocrinol 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