{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T22:01:40Z","timestamp":1790114500383,"version":"4.0.1"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T00:00:00Z","timestamp":1733788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK079970"],"award-info":[{"award-number":["DK079970"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006458","name":"Children\u2019s Hospital of Philadelphia","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100006458","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Academy of Medical Sciences Springboard Award","award":["SBF004|1034"],"award-info":[{"award-number":["SBF004|1034"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,2,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Autosomal dominant hypocalcemia (ADH) is due to enhanced calcium-dependent signaling caused by heterozygous gain-of-function (GOF) variants in the CASR gene (ADH1) or in the GNA11 gene, encoding G\u03b111 (ADH2). Both ADH1 and ADH2 are associated with hypocalcemia and normal or inappropriately low levels of circulating PTH. ADH1 patients typically manifest hypercalciuria, while ADH2 is associated with short stature in approximately 42% of cases. We evaluated a 10-yr-old boy with hypoparathyroidism and short stature. Biochemical analyses revealed hypocalcemia, hyperphosphatemia, and inconsistent hypercalciuria. Genetic analyses revealed a de novo heterozygous p.Leu723Arg variant in CASR. We characterized the expression of recombinant WT and Leu723Arg calcium-sensing receptor (CaSR) proteins in HEK293 cells and assessed G protein activation in vitro by CaSR using bioluminescence resonance energy transfer. Transient expression studies showed the Leu723Arg variant was normally expressed but resulted in a significantly lower EC50 for extracellular calcium activation of G11 but not other G proteins (ie, Gi, Gq, Gs). The Leu723Arg substitution has a novel GOF phenotype that leads to biased CaSR activation of G11 signaling, suggesting that residue 723 specifies activation of G11 but not other G proteins. Similar studies of a previously described CaSR variant associated with hypoparathyroidism and short stature, Leu616Val, showed no changes in any G protein pathways, indicating it is likely to be a benign variant. Given the preferential activation of G11 by the Leu723Arg CaSR variant, we propose that the patient\u2019s short stature shares a similar basis to that in patients with ADH2 due to GOF variants in GNA11.<\/jats:p>","DOI":"10.1093\/jbmr\/zjae199","type":"journal-article","created":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T02:02:51Z","timestamp":1733882571000},"page":"270-282","source":"Crossref","is-referenced-by-count":5,"title":["An activating calcium-sensing receptor variant with biased signaling reveals a critical residue for G\u03b111 coupling"],"prefix":"10.1093","volume":"40","author":[{"given":"Matthew R","family":"Benson","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Diabetes & Metabolism, Nemours Children\u2019s Health , Jacksonville, FL 32207 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael A","family":"Wyatt","sequence":"additional","affiliation":[{"name":"Institute of Metabolism and Systems Research (IMSR) and Centre for Diabetes, Endocrinology and Metabolism (CEDAM), University of Birmingham , Birmingham , B15 2TT,","place":["United Kingdom"]},{"name":"Centre for Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham , Birmingham , B15 2TT,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0036-7809","authenticated-orcid":false,"given":"Michael A","family":"Levine","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Diabetes, Department of Pediatrics, Center for Bone Health, The Children\u2019s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1361-9174","authenticated-orcid":false,"given":"Caroline M","family":"Gorvin","sequence":"additional","affiliation":[{"name":"Institute of Metabolism and Systems Research (IMSR) and Centre for Diabetes, Endocrinology and Metabolism (CEDAM), University of Birmingham , Birmingham , B15 2TT,","place":["United Kingdom"]},{"name":"Centre for Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham , Birmingham , B15 2TT,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,12,10]]},"reference":[{"issue":"2","key":"2025020314510577100_ref1","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1530\/JME-21-0058","article-title":"Heterogeneity of G protein activation by the calcium-sensing receptor","volume":"67","author":"Abid","year":"2021","journal-title":"J Mol 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