{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T14:43:41Z","timestamp":1777301021014,"version":"3.51.4"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2023,3,21]],"date-time":"2023-03-21T00:00:00Z","timestamp":1679356800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000272","name":"NIHR","doi-asserted-by":"crossref","award":["NIHR300098"],"award-info":[{"award-number":["NIHR300098"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000272","name":"NIHR","doi-asserted-by":"crossref","award":["MGU0591"],"award-info":[{"award-number":["MGU0591"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000272","name":"NIHR","doi-asserted-by":"crossref","award":["1010180"],"award-info":[{"award-number":["1010180"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"crossref"}]},{"name":"ESPE"},{"name":"Medical Research Council","award":["MC_UU_12015\/2"],"award-info":[{"award-number":["MC_UU_12015\/2"]}]},{"name":"Medical Research Council","award":["MC_UU_00006\/2"],"award-info":[{"award-number":["MC_UU_00006\/2"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Growth hormone insensitivity (GHI) encompasses growth restriction, normal\/elevated growth hormone (GH), and low insulin-like growth factor I (IGF1). \u201cNonclassical\u201d GHI is poorly characterized and is rarely caused by heterozygous dominant-negative (DN) variants located in the intracellular or transmembrane domains of the GH receptor (GHR). We sought to determine the molecular mechanisms underpinning the growth restriction in 2 GHI cases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Design<\/jats:title><jats:p>A custom-made genetic investigative pipeline was exploited to identify the genetic cause of growth restriction in patients with GHI. Nanoluc binary technology (NanoBiT), in vitro splicing assays, western blotting, and flow cytometry, characterized the novel GHR variants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Novel heterozygous GHR variants were identified in 2 unrelated patients with GHI. In vitro splicing assays indicated both variants activated the same alternative splice acceptor site resulting in aberrant splicing and exclusion of 26 base pairs of GHR exon 9. The GHR variants produced truncated receptors and impaired GH-induced GHR signaling. NanoBiT complementation and flow cytometry showed increased cell surface expression of variant GHR homo\/heterodimers compared to wild-type (WT) homodimers and increased recombinant human GH binding to variant GHR homo\/heterodimers and GH binding protein (GHBP) cleaved from the variant GHRs. The findings demonstrated increased variant GHR dimers and GHBP with resultant GH sequestration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We identified and characterized 2 novel, naturally occurring truncated GHR gene variants. Intriguingly, these DN GHR variants act via the same cryptic splice acceptor site, highlighting impairing GH binding to excess GHBP as a potential therapeutic approach.<\/jats:p><\/jats:sec>","DOI":"10.1093\/ejendo\/lvad039","type":"journal-article","created":{"date-parts":[[2023,3,21]],"date-time":"2023-03-21T01:17:08Z","timestamp":1679361428000},"page":"353-365","source":"Crossref","is-referenced-by-count":4,"title":["Characterization of dominant-negative growth hormone receptor variants reveals a potential therapeutic target for short stature"],"prefix":"10.1093","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2390-657X","authenticated-orcid":false,"given":"Afiya","family":"Andrews","sequence":"first","affiliation":[{"name":"Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University London , London , United 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Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University London , London , United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1289-6671","authenticated-orcid":false,"given":"Jack","family":"Williams","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University London , London , United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8667-0296","authenticated-orcid":false,"given":"Katharina","family":"Schilbach","sequence":"additional","affiliation":[{"name":"Endocrine Laboratory, Medizinische Klinik und Poliklinik IV, Klinikum der Universit\u00e4t M\u00fcnchen , Munich , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0849-3191","authenticated-orcid":false,"given":"Lena R","family":"Kaisinger","sequence":"additional","affiliation":[{"name":"MRC Epidemiology Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine , Cambridge CB2 0QQ , United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6483-3771","authenticated-orcid":false,"given":"John R B","family":"Perry","sequence":"additional","affiliation":[{"name":"MRC Epidemiology Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine , Cambridge CB2 0QQ , United Kingdom"},{"name":"Metabolic Research Laboratory, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine , Cambridge CB2 0QQ , United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0530-3524","authenticated-orcid":false,"given":"Louise A","family":"Metherell","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University London , London , United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2225-5181","authenticated-orcid":false,"given":"Peter J","family":"McCormick","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University London , London , United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9963-1931","authenticated-orcid":false,"given":"Helen L","family":"Storr","sequence":"additional","affiliation":[{"name":"Centre for 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