{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T23:08:33Z","timestamp":1785798513457,"version":"3.56.0"},"reference-count":32,"publisher":"The Endocrine Society","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective:<\/jats:title>\n                    <jats:p>Activating mutations in the calcium-sensing receptor (CASR) gene cause autosomal dominant hypoparathyroidism, and heterozygous inactivating CASR mutations cause familial hypocalciuric hypercalcemia. Recently, there has been a focus on the use of allosteric modulators to restore the functional activity of mutant CASRs. In this study, the effect of allosteric modulators NPS R-568 and NPS 2143 on CASR mutants was studied in vitro.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>DNA sequence analysis of the CASR gene was undertaken in autosomal dominant hypoparathyroidism and familial hypocalciuric hypercalcemia Japanese patients, and the functional consequences for the Gi-MAPK pathway and cell surface expression of CASR were determined. Furthermore, we studied the effect of NPS R-568 and NPS 2143 on the signal transduction activity and cell surface expression of each mutant CASR.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>We identified 3 activating mutations (S122C, P569H, and I839T) and 2 inactivating mutations (A110T and R172G) in patients. The activating and inactivating mutations caused leftward and rightward shifts, respectively, in the dose-response curves of the signaling pathway. NPS R-568 rescued the signal transduction capacity of 2 inactivating mutants without increasing cell surface expression levels. NPS 2143 suppressed the enhanced activity of the activating mutants without altering cell surface expression levels, although A843E, which is a constitutively active mutant, was suppressed to a lesser degree.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>We have identified 4 novel mutations of CASR. Moreover, our results indicate that allosteric modulators can restore the activity of the loss- and gain-of-function mutant CASRs, identified in this study.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/jc.2013-1974","type":"journal-article","created":{"date-parts":[[2013,8,22]],"date-time":"2013-08-22T00:01:27Z","timestamp":1377129687000},"page":"E1692-E1701","source":"Crossref","is-referenced-by-count":18,"title":["Loss-of-Function and Gain-of-Function Mutations of Calcium-Sensing Receptor: Functional Analysis and the Effect of Allosteric Modulators NPS R-568 and NPS 2143"],"prefix":"10.1210","volume":"98","author":[{"given":"Akie","family":"Nakamura","sequence":"first","affiliation":[{"name":"Department of Pediatrics (A.N., K.I., T.T.), Hokkaido University School of Medicine, Sapporo 060-8635, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Hotsubo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (T.H.), NTT East Japan Sapporo Hospital, Sapporo 060-0061, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiji","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (K.K.), Nishisaitama-chuo National Hospital, Saitama 359-1151, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Mochizuki","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism (H.M.), Saitama Children's Medical Center, Saitama, Japan 339-8551"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsura","family":"Ishizu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (A.N., K.I., T.T.), Hokkaido University School of Medicine, Sapporo 060-8635, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihiro","family":"Tajima","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (A.N., K.I., T.T.), Hokkaido University School of Medicine, Sapporo 060-8635, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071615264999100_B1","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/366575a0","article-title":"Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid","volume":"366","author":"Brown","year":"1993","journal-title":"Nature"},{"key":"2020071615264999100_B2","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.berh.2007.11.006","article-title":"Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations","volume":"22","author":"Egbuna","year":"2008","journal-title":"Best Pract Res Clin Rheumatol"},{"key":"2020071615264999100_B3","doi-asserted-by":"crossref","first-page":"F485","DOI":"10.1152\/ajprenal.00608.2009","article-title":"Physiology and pathophysiology of the calcium-sensing receptor in the kidney","volume":"298","author":"Riccardi","year":"2010","journal-title":"Am J Physiol Renal Physiol"},{"key":"2020071615264999100_B4","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/978-1-4020-6191-2_6","article-title":"The calcium-sensing receptor: physiology, pathophysiology and CaR-based therapeutics","volume":"45","author":"Brown","year":"2007","journal-title":"Subcell Biochem"},{"key":"2020071615264999100_B5","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1111\/j.1582-4934.2007.00096.x","article-title":"Structure and function of the human calcium-sensing receptor: insights from natural and engineered mutations and allosteric modulators","volume":"11","author":"Hu","year":"2007","journal-title":"J Cell Mol Med"},{"key":"2020071615264999100_B6","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1016\/0092-8674(93)90617-Y","article-title":"Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism","volume":"75","author":"Pollak","year":"1993","journal-title":"Cell"},{"key":"2020071615264999100_B7","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/ng1194-303","article-title":"Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation","volume":"8","author":"Pollak","year":"1994","journal-title":"Nat Genet"},{"key":"2020071615264999100_B8","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1056\/NEJM199610103351505","article-title":"A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor","volume":"335","author":"Pearce","year":"1996","journal-title":"N Engl J Med"},{"key":"2020071615264999100_B9","doi-asserted-by":"crossref","first-page":"4040","DOI":"10.1073\/pnas.95.7.4040","article-title":"Calcimimetics with potent and selective activity on the parathyroid calcium receptor","volume":"95","author":"Nemeth","year":"1998","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071615264999100_B10","first-page":"323","article-title":"Calcilytic compounds: potent and selective Ca2+ receptor antagonists that stimulate secretion of parathyroid hormone","volume":"299","author":"Nemeth","year":"2001","journal-title":"J Pharmacol Exp Ther"},{"key":"2020071615264999100_B11","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1111\/j.1476-5381.2011.01511.x","article-title":"New concepts in calcium-sensing receptor pharmacology and signaling","volume":"165","author":"Ward","year":"2012","journal-title":"Br J Pharmacol"},{"key":"2020071615264999100_B12","doi-asserted-by":"crossref","first-page":"18990","DOI":"10.1074\/jbc.M400724200","article-title":"Positive and negative allosteric modulators of the Ca2+-sensing receptor interact within overlapping but not identical binding sites in the transmembrane domain","volume":"279","author":"Petrel","year":"2004","journal-title":"J Biol 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Med"},{"key":"2020071615264999100_B16","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1111\/j.1365-2796.2006.01684.x","article-title":"Normalization of serum calcium by cinacalcet in a patient with hypercalcaemia due to a de novo inactivating mutation of the calcium-sensing receptor","volume":"260","author":"Timmers","year":"2006","journal-title":"J Intern Med"},{"key":"2020071615264999100_B17","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1111\/j.1365-2265.2007.03027.x","article-title":"Correction of hypercalcaemia by cinacalcet in familial hypocalciuric hypercalcaemia","volume":"68","author":"Festen-Spanjer","year":"2008","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2020071615264999100_B18","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1007\/s00467-010-1547-5","article-title":"Beneficial effect of cinacalcet in a child with familial hypocalciuric hypercalcemia","volume":"25","author":"Alon","year":"2010","journal-title":"Pediatr 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AXT914","volume":"78","author":"Park","year":"2013","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2020071615264999100_B22","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1210\/jc.87.3.1309","article-title":"Identification and functional characterization of novel calcium-sensing receptor mutations in familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia","volume":"87","author":"D'Souza-Li","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071615264999100_B23","first-page":"13","article-title":"A novel mutation in the calcium-sensing receptor gene in a Chinese subject with persistent hypercalcemia and hypocalciuria","volume":"86","author":"Jap","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071615264999100_B24","doi-asserted-by":"crossref","first-page":"4372","DOI":"10.1210\/jc.2008-2484","article-title":"A novel loss-of-function mutation, Gln459Arg, of the calcium-sensing receptor gene associated with apparent 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