{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T02:09:16Z","timestamp":1791857356582,"version":"4.3.4"},"reference-count":36,"publisher":"The Endocrine Society","issue":"4","funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Context<\/jats:title>\n                    <jats:p>The \u03b1 subunit of the stimulatory G protein (G\u03b1s) links numerous receptors to adenylyl cyclase. G\u03b1s, encoded by GNAS, is expressed predominantly from the maternal allele in certain tissues. Thus, maternal heterozygous loss-of-function mutations cause hormonal resistance, as in pseudohypoparathyroidism type Ia, whereas somatic gain-of-function mutations cause hormone-independent endocrine stimulation, as in McCune-Albright syndrome.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>We report two unrelated boys presenting with a new combination of clinical findings that suggest both gain and loss of G\u03b1s function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design and Setting<\/jats:title>\n                    <jats:p>Clinical features were studied and sequencing of GNAS was performed. Signaling capacities of wild-type and mutant G\u03b1s were determined in the presence of different G protein\u2013coupled receptors (GPCRs) under basal and agonist-stimulated conditions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Both unrelated patients presented with unexplained hyponatremia in infancy, followed by severe early onset gonadotrophin-independent precocious puberty and skeletal abnormalities. An identical heterozygous de novo variant (c.1136T&amp;gt;G; p.F376V) was found on the maternal GNAS allele in both patients; this resulted in a clinical phenotype that differed from known G\u03b1s-related diseases and suggested gain of function at the vasopressin 2 receptor (V2R) and lutropin\/choriogonadotropin receptor (LHCGR), yet increased serum PTH concentrations indicative of impaired proximal tubular PTH1 receptor (PTH1R) function. In vitro studies demonstrated that G\u03b1s-F376V enhanced ligand-independent signaling at the PTH1R, LHCGR, and V2R and, at the same time, blunted ligand-dependent responses. Structural homology modeling suggested mutation-induced modifications at the C-terminal \u03b15 helix of G\u03b1s that are relevant for interaction with GPCRs and signal transduction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The G\u03b1s p.F376V mutation causes a previously unrecognized multisystem disorder.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/jc.2018-01250","type":"journal-article","created":{"date-parts":[[2018,10,11]],"date-time":"2018-10-11T14:03:20Z","timestamp":1539266600000},"page":"1079-1089","source":"Crossref","is-referenced-by-count":21,"title":["A New Multisystem Disorder Caused by the G\n                    <i>\u03b1<\/i>\n                    s Mutation p.F376V"],"prefix":"10.1210","volume":"104","author":[{"given":"Heike","family":"Biebermann","sequence":"first","affiliation":[{"name":"Institute of Experimental Pediatric Endocrinology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2131-671X","authenticated-orcid":false,"given":"Gunnar","family":"Kleinau","sequence":"additional","affiliation":[{"name":"Institute of Experimental Pediatric Endocrinology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, Berlin, Germany"},{"name":"Institut f\u00fcr Medizinische Physik und Biophysik, Group Protein X-ray Crystallography and Signal Transduction, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, Berlin, 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Clinical Genetics, Great Ormond Street Hospital for Children, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Tully","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, University Hospital of Wales, Cardiff, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Kiff","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology, Great Ormond Street Hospital for Children, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Scheerer","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Medizinische Physik und Biophysik, Group Protein X-ray Crystallography and Signal Transduction, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Reyes","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Zschunke","sequence":"additional","affiliation":[{"name":"Institute of Experimental Pediatric Endocrinology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W","family":"Gregory","sequence":"additional","affiliation":[{"name":"Division of Population Medicine, School of Medicine, Cardiff University, Cardiff, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Allgrove","sequence":"additional","affiliation":[{"name":"Department of Pediatric 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