{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T05:13:26Z","timestamp":1783487606077,"version":"3.55.0"},"reference-count":36,"publisher":"The Endocrine Society","issue":"3","license":[{"start":{"date-parts":[[2019,12,10]],"date-time":"2019-12-10T00:00:00Z","timestamp":1575936000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Wellcome Trust Senior Investigator Award","award":["106995\/Z\/15\/Z"],"award-info":[{"award-number":["106995\/Z\/15\/Z"]}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wellcome Trust Clinical Training Fellowship","award":["205011\/Z\/16\/Z"],"award-info":[{"award-number":["205011\/Z\/16\/Z"]}]},{"name":"NIHR Senior Investigator Award","award":["NF-SI-0514\u201310091"],"award-info":[{"award-number":["NF-SI-0514\u201310091"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>Autosomal dominant hypocalcemia types 1 and 2 (ADH1 and ADH2) are caused by germline gain-of-function mutations of the calcium-sensing receptor (CaSR) and its signaling partner, the G-protein subunit \u03b1\u200a11 (G\u03b1\u200a11), respectively. More than 70 different gain-of-function CaSR mutations, but only 6 different gain-of-function G\u03b1\u200a11 mutations are reported to date.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We ascertained 2 additional ADH families and investigated them for CaSR and G\u03b1\u200a11 mutations. The effects of identified variants on CaSR signaling were evaluated by transiently transfecting wild-type (WT) and variant expression constructs into HEK293 cells stably expressing CaSR (HEK-CaSR), and measuring intracellular calcium (Ca2+i) and MAPK responses following stimulation with extracellular calcium (Ca2+e).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>CaSR variants were not found, but 2 novel heterozygous germline G\u03b1\u200a11 variants, p.Gly66Ser and p.Arg149His, were identified. Homology modeling of these revealed that the Gly66 and Arg149 residues are located at the interface between the G\u03b1\u200a11 helical and GTPase domains, which is involved in guanine nucleotide binding, and this is the site of 3 other reported ADH2 mutations. The Ca2+i and MAPK responses of cells expressing the variant Ser66 or His149 G\u03b1\u200a11 proteins were similar to WT cells at low Ca2+e, but significantly increased in a dose-dependent manner following Ca2+e stimulation, thereby indicating that the p.Gly66Ser and p.Arg149His variants represent pathogenic gain-of-function G\u03b1\u200a11 mutations. Treatment of Ser66- and His149-G\u03b1\u200a11 expressing cells with the CaSR negative allosteric modulator NPS 2143 normalized Ca2+i and MAPK responses.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Two novel ADH2-causing mutations that highlight the G\u03b1\u200a11 interdomain interface as a hotspot for gain-of-function G\u03b1\u200a11 mutations have been identified.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/clinem\/dgz251","type":"journal-article","created":{"date-parts":[[2019,12,10]],"date-time":"2019-12-10T12:37:18Z","timestamp":1575981438000},"page":"952-963","source":"Crossref","is-referenced-by-count":12,"title":["Activating Mutations of the G-protein Subunit \u03b1\u200a11 Interdomain Interface Cause Autosomal Dominant Hypocalcemia Type 2"],"prefix":"10.1210","volume":"105","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1361-9174","authenticated-orcid":false,"given":"Caroline M","family":"Gorvin","sequence":"first","affiliation":[{"name":"Academic Endocrine Unit, Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Oxford, UK"},{"name":"Oxford NIHR Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria J","family":"Stokes","sequence":"additional","affiliation":[{"name":"Academic Endocrine Unit, Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Oxford, UK"},{"name":"Oxford NIHR Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Boon","sequence":"additional","affiliation":[{"name":"Oxford Molecular Genetics Laboratory, Churchill Hospital, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Treena","family":"Cranston","sequence":"additional","affiliation":[{"name":"Oxford Molecular Genetics Laboratory, Churchill Hospital, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna K","family":"Gl\u00fcck","sequence":"additional","affiliation":[{"name":"Academic Endocrine Unit, Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shailini","family":"Bahl","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Ashford and St. Peter\u2019s Hospitals NHS Foundation Trust, Surrey, 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