{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T05:16:43Z","timestamp":1788931003238,"version":"build-2803163510"},"reference-count":45,"publisher":"The Endocrine Society","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2007,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Context: Familial hypocalciuric hypercalcemia (FHH) is a benign condition associated with heterogeneous inactivating mutations in the calcium-sensing receptor (CASR) gene.<\/jats:p><jats:p>Objective: The objective of the study was to identify and characterize a CASR mutation in a moderately hypercalcemic, hyperparathyroid individual and his family and assess the influence of vitamin D status on the clinical expression of the defect.<\/jats:p><jats:p>Subjects: We studied a kindred with FHH, in which the proband (a 34-yr-old male) was initially diagnosed with primary hyperparathyroidism due to frankly elevated serum PTH levels.<\/jats:p><jats:p>Methods: CASR gene mutation analysis was performed on genomic DNA of the proband and family members. The mutant CASR was functionally characterized by transient transfection studies in kidney cells in vitro.<\/jats:p><jats:p>Results: A novel heterozygous mutation (F180C, TTC&amp;gt;TGC) in exon 4 of the CASR gene was identified. Although the mutant receptor was expressed normally at the cell surface, it was unresponsive with respect to intracellular signaling (MAPK activation) to increases in extracellular calcium concentrations. The baby daughter of the proband presented with neonatal hyperparathyroidism with markedly elevated PTH. Vitamin D supplementation of both the proband and the baby resulted in reduction of serum PTH levels to the normal range. The serum calcium level remained at a constant and moderately elevated level.<\/jats:p><jats:p>Conclusion: The identification of a novel CASR gene mutation established the basis of the hypercalcemia in the kindred. Concomitant vitamin D deficiency modulates the severity of the presentation of FHH.<\/jats:p>","DOI":"10.1210\/jc.2007-0123","type":"journal-article","created":{"date-parts":[[2007,5,2]],"date-time":"2007-05-02T14:37:32Z","timestamp":1178116652000},"page":"2616-2623","source":"Crossref","is-referenced-by-count":54,"title":["Identification and Functional Characterization of a Novel Mutation in the Calcium-Sensing Receptor Gene in Familial Hypocalciuric Hypercalcemia: Modulation of Clinical Severity by Vitamin D Status"],"prefix":"10.1210","volume":"92","author":[{"given":"Katerina","family":"Zajickova","sequence":"first","affiliation":[{"name":"Institute of Endocrinology (K.Z., J.V.), Prague 1, 116 94, Czech Republic"},{"name":"Departments of Medicine, Physiology, and Human Genetics (K.Z., L.C., D.G., G.N.H.), McGill University, and Calcium Research Laboratory, Royal Victoria Hospital, Montre\u0301al, Que\u0301bec, Canada H3A 1A1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Vrbikova","sequence":"additional","affiliation":[{"name":"Institute of Endocrinology (K.Z., J.V.), Prague 1, 116 94, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"Canaff","sequence":"additional","affiliation":[{"name":"Departments of Medicine, Physiology, and Human Genetics (K.Z., L.C., D.G., G.N.H.), McGill University, and Calcium Research Laboratory, Royal Victoria Hospital, Montre\u0301al, Que\u0301bec, Canada H3A 1A1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter D.","family":"Pawelek","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry (P.D.P.), Concordia University, Montre\u0301al, Que\u0301bec, Canada H4B 1R6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Goltzman","sequence":"additional","affiliation":[{"name":"Departments of Medicine, Physiology, and Human Genetics (K.Z., L.C., D.G., G.N.H.), McGill University, and Calcium Research Laboratory, Royal Victoria Hospital, Montre\u0301al, Que\u0301bec, Canada H3A 1A1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey N.","family":"Hendy","sequence":"additional","affiliation":[{"name":"Departments of Medicine, Physiology, and Human Genetics (K.Z., L.C., D.G., G.N.H.), McGill University, and Calcium Research Laboratory, Royal Victoria Hospital, Montre\u0301al, Que\u0301bec, Canada H3A 1A1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071613451637700_R1","doi-asserted-by":"crossref","first-page":"511","DOI":"10.7326\/0003-4819-102-4-511","article-title":"Familial benign hypercalcemia (hypocalciuric hypercalcemia). 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chromosome 3q13.3\u201321 by fluorescence in situ hybridization, and localization to rat chromosome 11 and mouse chromosome 16.","volume":"6","author":"Janicic","year":"1995","journal-title":"Mamm Genome"},{"key":"2020071613451637700_R5","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":"2020071613451637700_R6","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1210\/jcem.81.4.8636323","article-title":"Clustered inactivating mutations and benign polymorphisms of the calcium receptor gene in familial benign hypocalciuric hypercalcemia suggest receptor functional domains.","volume":"81","author":"Heath 3rd","year":"1996","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613451637700_R7","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1002\/1098-1004(200010)16:4<281::AID-HUMU1>3.0.CO;2-A","article-title":"Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia.","volume":"16","author":"Hendy","year":"2000","journal-title":"Hum Mutat"},{"key":"2020071613451637700_R8","doi-asserted-by":"crossref","first-page":"2683","DOI":"10.1172\/JCI118335","article-title":"Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism.","volume":"96","author":"Pearce","year":"1995","journal-title":"J Clin Invest"},{"key":"2020071613451637700_R9","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1002\/humu.20067","article-title":"CASRdb: calcium-sensing receptor locus-specific database for mutations causing familial (benign) hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia.","volume":"24","author":"Pidasheva","year":"2004","journal-title":"Hum Mutat"},{"key":"2020071613451637700_R10","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1210\/jcem.87.3.8280","article-title":"Identification and functional characterization of novel calcium-sensing receptor mutations in familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia.","volume":"87","author":"D\u2019Souza-Li","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613451637700_R11","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1002\/humu.1212","article-title":"An acceptor splice site mutation in the calcium-sensing receptor (CASR) gene in familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.","volume":"18","author":"D\u2019Souza-Li","year":"2001","journal-title":"Hum 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modeling.","volume":"18","author":"Guex","year":"1997","journal-title":"Electrophoresis"},{"key":"2020071613451637700_R18","author":"DeLano","year":"2002"},{"key":"2020071613451637700_R19","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1107\/S0108767390010224","article-title":"Improved methods for building protein models in electron density maps and the location of errors in these models.","volume":"47","author":"Jones","year":"1991","journal-title":"Acta Crystallogr"},{"key":"2020071613451637700_R20","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.ceca.2003.10.018","article-title":"Structure-function relationship of the extracellular calcium-sensing receptor.","volume":"35","author":"Bai","year":"2004","journal-title":"Cell Calcium"},{"key":"2020071613451637700_R21","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.ceca.2003.10.012","article-title":"Extracellular Ca2+-sensing receptors\u2014an 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cells.","volume":"125","author":"Kremer","year":"1989","journal-title":"Endocrinology"},{"key":"2020071613451637700_R33","doi-asserted-by":"crossref","first-page":"30337","DOI":"10.1074\/jbc.M201804200","article-title":"Human calcium-sensing receptor gene. 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