{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T02:22:18Z","timestamp":1791598938112,"version":"4.3.4"},"reference-count":0,"publisher":"Bioscientifica","issue":"2","content-domain":{"domain":["jme.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,8]]},"abstract":"<jats:p>\n                    Twenty-five years have elapsed since the calcium-sensing receptor (CaSR) was first identified in bovine parathyroid and the receptor is now recognized as a fundamental contributor to extracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    (Ca\n                    <jats:sup>2+<\/jats:sup>\n                    <jats:sub>e<\/jats:sub>\n                    ) homeostasis, regulating parathyroid hormone release and urinary calcium excretion. The CaSR is a class C G-protein-coupled receptor (GPCR) that is functionally active as a homodimer and couples to multiple G-protein subtypes to activate intracellular signalling pathways. The importance of the CaSR in the regulation of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    <jats:sub>e<\/jats:sub>\n                    has been highlighted by the identification of &gt;400 different germline loss- and gain-of-function CaSR mutations that give rise to disorders of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    <jats:sub>e<\/jats:sub>\n                    homeostasis. CaSR-inactivating mutations cause neonatal severe hyperparathyroidism, characterised by marked hypercalcaemia, skeletal demineralisation and failure to thrive in early infancy; and familial hypocalciuric hypercalcaemia, an often asymptomatic disorder associated with mild-moderately elevated serum calcium concentrations. Activating mutations are associated with autosomal dominant hypocalcaemia, which is occasionally associated with a Bartter\u2019s-like phenotype. Recent elucidation of the CaSR extracellular domain structure enabled the locations of CaSR mutations to be mapped and has revealed clustering in locations important for structural integrity, receptor dimerisation and ligand binding. Moreover, the study of disease-causing mutations has demonstrated that CaSR signals in a biased manner and have revealed specific residues important for receptor activation. This review presents the current understanding of the genetic landscape of CaSR mutations by summarising findings from clinical and functional studies of disease-associated mutations. It concludes with reflections on how recently uncovered signalling pathways may expand the understanding of calcium homeostasis disorders.\n                  <\/jats:p>","DOI":"10.1530\/jme-19-0104","type":"journal-article","created":{"date-parts":[[2019,6,11]],"date-time":"2019-06-11T10:55:39Z","timestamp":1560250539000},"page":"R1-R16","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":59,"title":["Molecular and clinical insights from studies of calcium-sensing receptor mutations"],"prefix":"10.1530","volume":"63","author":[{"given":"Caroline M","family":"Gorvin","sequence":"first","affiliation":[{"name":"1Institute of Metabolism and Systems Research (IMSR)University of Birmingham, Birmingham, UK"},{"name":"2Centre of Membrane Proteins and Receptors (COMPARE)University of Birmingham, Birmingham, UK"},{"name":"3Centre for EndocrinologyDiabetes and Metabolism (CEDAM), Birmingham Health Partners, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","container-title":["Journal of Molecular Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/jme.bioscientifica.com\/view\/journals\/jme\/63\/2\/JME-19-0104.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/jme.bioscientifica.com\/downloadpdf\/journals\/jme\/63\/2\/JME-19-0104.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T13:53:45Z","timestamp":1784555625000},"score":1,"resource":{"primary":{"URL":"http:\/\/journals.bioscientifica.com\/jme\/article\/63\/2\/R1-R16\/14350"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8]]},"references-count":0,"journal-issue":{"issue":"2"},"URL":"https:\/\/doi.org\/10.1530\/jme-19-0104","relation":{},"ISSN":["0952-5041","1479-6813"],"issn-type":[{"value":"0952-5041","type":"print"},{"value":"1479-6813","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,8]]}}}