{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T14:48:48Z","timestamp":1789051728253,"version":"build-2803163510"},"reference-count":26,"publisher":"The Endocrine Society","issue":"5","license":[{"start":{"date-parts":[[2024,6,26]],"date-time":"2024-06-26T00:00:00Z","timestamp":1719360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100013286","name":"Research Fund at Rigshospitalet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013286","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Beckett Foundation"},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Candy Foundation"},{"DOI":"10.13039\/501100011958","name":"Independent Research Fund Denmark","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011958","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context and Objectives<\/jats:title>\n                  <jats:p>To date, only 4 loss-of-function variants in the GNA11 gene encoding the G protein subunit \u03b111 (G\u03b111) leading to familial hypocalciuric hypercalcemia (FHH) 2 have been characterized. G\u03b111 is involved in calcium-sensing receptor (CaSR) signaling, and loss-of-function variants in GNA11 lead to reduced agonist potency at CaSR and an FHH phenotype.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Design and participants<\/jats:title>\n                  <jats:p>We have identified a family with a heterozygous GNA11 Thr347Ala variant and characterized its impact on calcium homeostasis in FHH2 patients and the signaling properties of CaSR through the G\u03b111-Thr347Ala variant in vitro.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Main Outcome Measures<\/jats:title>\n                  <jats:p>The index patient and her family had clinical, biochemical, and genetic analyses performed. The expression levels of G\u03b111 and the cell-surface expression levels of CaSR in human embryonic kidney 293A Gq\/11 knockout cells (\u0394Gq\/11-HEK293A) cotransfected with CaSR and G\u03b111 [wild type (WT) or Thr347Ala] were determined, and the functional properties exhibited by calcium at CaSR were characterized in an inositol monophosphate (IP1) accumulation assay.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Heterozygous carriers of the GNA11 Thr347Ala variant had mild asymptomatic hypercalcemia, hypocalciuria, and inappropriately high normal PTH levels considering their elevated serum calcium levels. Whereas the variant did not impact G\u03b111 expression or CaSR cell surface expression levels, calcium displayed a moderately but significantly lower agonist potency at CaSR\/G\u03b111-Thr347Ala-transfected cells compared with CaSR\/G\u03b111-WT-transfected cells in the IP1 accumulation assay (EC50 values of 5.67 mM and 4.38 mM, respectively).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>This identification of a novel GNA11 variant causing FHH2 substantiates the important role of G\u03b111 for CaSR signaling and Ca2+ homeostasis.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/clinem\/dgae440","type":"journal-article","created":{"date-parts":[[2024,6,25]],"date-time":"2024-06-25T05:53:16Z","timestamp":1719294796000},"page":"1342-1349","source":"Crossref","is-referenced-by-count":4,"title":["Loss-of-function Thr347Ala Variant in the G Protein Subunit-\u039111 Causes Familial Hypocalciuric Hypercalcemia 2"],"prefix":"10.1210","volume":"110","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2401-2877","authenticated-orcid":false,"given":"Ida Marie","family":"Boisen","sequence":"first","affiliation":[{"name":"Division of Translational Endocrinology, Department of Endocrinology and Internal Medicine, University Hospital Copenhagen , DK-2730 Herlev ,","place":["Denmark"]},{"name":"Department of Growth and Reproduction, Copenhagen University Hospital\u2014Rigshospitalet , DK-2100 Copenhagen ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , DK-2100 Copenhagen ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0534-4350","authenticated-orcid":false,"given":"Anders","family":"Juul","sequence":"additional","affiliation":[{"name":"Department of Growth and Reproduction, Copenhagen University Hospital\u2014Rigshospitalet , DK-2100 Copenhagen ,","place":["Denmark"]},{"name":"International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, Copenhagen University Hospital\u2014Rigshospitalet , DK-2100 Copenhagen ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9495-7388","authenticated-orcid":false,"given":"Hans","family":"Br\u00e4uner-Osborne","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , DK-2100 Copenhagen ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7927-5052","authenticated-orcid":false,"given":"Anders A","family":"Jensen","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , DK-2100 Copenhagen ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3800-4253","authenticated-orcid":false,"given":"Martin","family":"Blomberg Jensen","sequence":"additional","affiliation":[{"name":"Division of Translational Endocrinology, Department of Endocrinology and Internal Medicine, University Hospital Copenhagen , DK-2730 Herlev ,","place":["Denmark"]},{"name":"Department of Clinical Medicine, University of Copenhagen , DK-2100 Copenhagen ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2024,6,26]]},"reference":[{"issue":"7","key":"2025042208270291400_dgae440-B1","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1016\/0092-8674(93)90617-Y","article-title":"Mutations in the human Ca2+-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism","volume":"75","author":"Pollak","year":"1993","journal-title":"Cell"},{"issue":"1","key":"2025042208270291400_dgae440-B2","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/ng.2492","article-title":"Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3","volume":"45","author":"Nesbit","year":"2013","journal-title":"Nat Genet"},{"issue":"8","key":"2025042208270291400_dgae440-B3","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1038\/emboj.2012.49","article-title":"Claudin-14 regulates renal Ca++ transport in response to CaSR signalling via a novel microRNA pathway","volume":"31","author":"Gong","year":"2012","journal-title":"EMBO J"},{"issue":"6","key":"2025042208270291400_dgae440-B4","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1002\/jbmr.4803","article-title":"GNA11 variants identified in patients with hypercalcemia or hypocalcemia","volume":"38","author":"Howles","year":"2023","journal-title":"J. Bone Miner. Res"},{"issue":"6","key":"2025042208270291400_dgae440-B5","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1002\/jbmr.2778","article-title":"A G-protein subunit-\u03b111 loss-of-function mutation, Thr54Met, causes familial hypocalciuric hypercalcemia type 2 (FHH2)","volume":"31","author":"Gorvin","year":"2016","journal-title":"J. Bone Miner. Res"},{"issue":"26","key":"2025042208270291400_dgae440-B6","doi-asserted-by":"crossref","first-page":"2476","DOI":"10.1056\/NEJMoa1300253","article-title":"Mutations affecting G-protein subunit \u03b111 in hypercalcemia and hypocalcemia","volume":"368","author":"Nesbit","year":"2013","journal-title":"N Engl J Med"},{"issue":"1","key":"2025042208270291400_dgae440-B7","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1002\/jbmr.3241","article-title":"Cinacalcet rectifies hypercalcemia in a patient with familial hypocalciuric hypercalcemia type 2 (FHH2) caused by a germline loss-of-function G\u03b111 mutation","volume":"33","author":"Gorvin","year":"2018","journal-title":"J. Bone Miner. Res"},{"issue":"3","key":"2025042208270291400_dgae440-B8","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1016\/S0021-9258(18)46018-8","article-title":"Activation of phospholipase C by the alpha subunits of the gq and G11 proteins in transfected Cos-7 cells","volume":"267","author":"Wu","year":"1992","journal-title":"J Biol Chem"},{"issue":"405","key":"2025042208270291400_dgae440-B9","doi-asserted-by":"crossref","first-page":"ra123","DOI":"10.1126\/scisignal.aab4068","article-title":"Distinct profiles of functional discrimination among G proteins determine the actions of G protein\u2013coupled receptors","volume":"8","author":"Masuho","year":"2015","journal-title":"Sci Signal"},{"issue":"1","key":"2025042208270291400_dgae440-B10","doi-asserted-by":"crossref","first-page":"10156","DOI":"10.1038\/ncomms10156","article-title":"The experimental power of FR900359 to study Gq-regulated biological processes","volume":"6","author":"Schrage","year":"2015","journal-title":"Nat Commun"},{"issue":"40","key":"2025042208270291400_dgae440-B11","doi-asserted-by":"crossref","first-page":"13850","DOI":"10.1074\/jbc.RA120.013002","article-title":"Delineation of molecular determinants for FR900359 inhibition of Gq\/11 unlocks inhibition of G\u03b1s","volume":"295","author":"Boesgaard","year":"2020","journal-title":"J Biol Chem"},{"issue":"4","key":"2025042208270291400_dgae440-B12","doi-asserted-by":"crossref","first-page":"e1322","DOI":"10.1210\/clinem\/dgz205","article-title":"Heterozygous mutation (Q459R) in the calcium-sensing receptor gene causes familial hypocalciuric hypercalcemia 1 (FHH1)","volume":"105","author":"Boisen","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2025042208270291400_dgae440-B13","doi-asserted-by":"crossref","first-page":"46355","DOI":"10.1038\/srep46355","article-title":"Investigating the molecular mechanism of positive and negative allosteric modulators in the calcium-sensing receptor dimer","volume":"7","author":"Jacobsen","year":"2017","journal-title":"Sci Rep"},{"issue":"6426","key":"2025042208270291400_dgae440-B14","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/363274a0","article-title":"Substitution of three amino acids switches receptor specificity of Gq\u03b1 to that of Gi\u03b1","volume":"363","author":"Conklin","year":"1993","journal-title":"Nature"},{"issue":"34","key":"2025042208270291400_dgae440-B15","doi-asserted-by":"crossref","first-page":"17929","DOI":"10.1074\/jbc.M116.735720","article-title":"Structural elements in the G\u03b1s and G\u03b1q C termini that mediate selective G protein-coupled receptor (GPCR) signaling","volume":"291","author":"Semack","year":"2016","journal-title":"J Biol Chem"},{"issue":"3","key":"2025042208270291400_dgae440-B16","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1152\/physrev.00021.2020","article-title":"G protein-coupled receptor-G protein interactions: a single-molecule perspective","volume":"101","author":"Calebiro","year":"2021","journal-title":"Physiol Rev"},{"issue":"2","key":"2025042208270291400_dgae440-B17","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1530\/EJE-16-0842","article-title":"AP2S1 and GNA11 mutations\u2014not a common cause of familial hypocalciuric hypercalcemia","volume":"176","author":"Hovden","year":"2017","journal-title":"Eur J Endocrinol"},{"issue":"20","key":"2025042208270291400_dgae440-B18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1172\/jci.insight.96540","article-title":"Cinacalcet corrects hypercalcemia in mice with an inactivating G\u03b111 mutation","volume":"2","author":"Howles","year":"2017","journal-title":"JCI Insight"},{"issue":"2","key":"2025042208270291400_dgae440-B19","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.cellsig.2005.08.004","article-title":"Cell signalling diversity of the Gq\u03b1 family of heterotrimeric G proteins","volume":"18","author":"Hubbard","year":"2006","journal-title":"Cell Signal"},{"issue":"1","key":"2025042208270291400_dgae440-B20","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1210\/me.2006-0110","article-title":"Parathyroid-Specific double knockout of Gq and G11 \u03b1-subunits leads to a phenotype resembling germline knockout of the extracellular Ca2+-sensing receptor","volume":"21","author":"Wettschureck","year":"2007","journal-title":"Mol Endocrinol"},{"issue":"4","key":"2025042208270291400_dgae440-B21","doi-asserted-by":"crossref","first-page":"e1775","DOI":"10.1210\/clinem\/dgaa937","article-title":"The calcium-sensing receptor is essential for calcium and bicarbonate sensitivity in human spermatozoa","volume":"106","author":"Boisen","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"2025042208270291400_dgae440-B22","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1530\/JOE-20-0321","article-title":"Calcium transport in male reproduction is possibly influenced by vitamin D and CaSR","volume":"251","author":"Boisen","year":"2021","journal-title":"J Endocrinol"},{"issue":"11","key":"2025042208270291400_dgae440-B23","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1002\/cmdc.201700155","article-title":"Structure-Activity relationship studies of the cyclic depsipeptide natural product YM-254890, targeting the G q protein","volume":"12","author":"Zhang","year":"2017","journal-title":"ChemMedChem"},{"issue":"9","key":"2025042208270291400_dgae440-B24","doi-asserted-by":"crossref","first-page":"3138","DOI":"10.1210\/jc.2012-1429","article-title":"The importance of measuring ionized calcium in characterizing calcium status and diagnosing primary hyperparathyroidism","volume":"97","author":"Ong","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"2025042208270291400_dgae440-B25","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1210\/jc.2013-3593","article-title":"A homozygous CaSR mutation causing a FHH phenotype completely masked by vitamin D deficiency presenting as rickets","volume":"99","author":"Szczawinska","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"2025042208270291400_dgae440-B26","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1016\/j.ajhg.2020.04.006","article-title":"Familial hypocalciuric hypercalcemia type 1 and autosomal-dominant hypocalcemia type 1: prevalence in a large healthcare population","volume":"106","author":"Dershem","year":"2020","journal-title":"Am J Hum Genet"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jcem\/advance-article-pdf\/doi\/10.1210\/clinem\/dgae440\/58464700\/dgae440.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/110\/5\/1342\/58464700\/dgae440.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/110\/5\/1342\/58464700\/dgae440.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,22]],"date-time":"2025-04-22T12:27:14Z","timestamp":1745324834000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/110\/5\/1342\/7699409"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,26]]},"references-count":26,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,6,26]]},"published-print":{"date-parts":[[2025,4,22]]}},"URL":"https:\/\/doi.org\/10.1210\/clinem\/dgae440","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,5]]},"published":{"date-parts":[[2024,6,26]]}}}