The Role of the Extracellullar Calcium-Sensing Receptor in Health and Disease

 

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Abstract

The calcium-sensing receptor has a key role in calcium homeostasis, it is involved in the regulation of the serum calcium level within minutes via the secretion and action of parathyroid and the excretion of calcium in the kidney in a negative feedback manner. Mutations of the calcium sensing receptor gene leads to inactivating and activating mutations resulting in diseases with hypercalcaemia and hypocalcaemia. The loss of function mutations are associated with familial benign hypocalciuric hypercalcaemia (FHH), an autosomal dominant disease characterised by lifelong mild hypercalcaemia, low urinary calcium excretion, and inappropriate high parathyroid hormone levels, sometimes difficult to distinguish from mild asymptomatic primary hyperparathyroidism. Patients with FHH did not profit from parathyroidectomy, a calcium lowering therapy is not necessary. The gain of function mutations of the calcium-sensing receptor are associated with autosomal dominant hypocalcaemia (ADH), a disease characterised by a generally asymptomatic hypocalcaemia, inappropriately high urinary calcium excretion and normal PTH levels. A therapy to raise the serum calcium concentration has to be done carefully and is only indicated in symptomatic patients, because of enhancement of hypercalciuria with the risk of nephrocalcinosis and nephrolithiasis. Molecular genetic analysis of the calcium sensing receptor gene facilitates the sometimes difficult diagnosis. The development of compounds modulating the calcium sensing receptor function and thereby the section of PTH may become an important role in treatment of diseases of calcium metabolism.

References

• 1 Adams GB, Chabner KT, Alley IR, Olson DP, Szczepiorkowski ZM, Poznansky MC, Kos CH, Pollak MR, Brown EM, Scadden DT. Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor.  Nature. 2006;  439 599-603
  CrossrefPubMedGoogle Scholar
• 2 Aida K, Koishi S, Inoue M, Nakazato M, Tawata M, Onaya T. Familial hypocalciuric hypercalcemia associated with mutation in the human Ca(2+)-sensing receptor gene.  J Clin Endocrinol Metab. 1995a;  80 2594-2598
  CrossrefPubMedGoogle Scholar
• 3 Aida K, Koishi S, Tawata M, Onaya T. Molecular cloning of a putative Ca(2+)-sensing receptor cDNA from human kidney.  Biochem Biophys Res Commun. 1995b;  214 524-529
  CrossrefPubMedGoogle Scholar
• 4 Andrade SC, Kohara SK, D'Souza-Li L. A Novel Mutation in the Calcium-Sensing Receptor in Familiar Hypocalciuric Hypercalcemia and Neonatal Severe Hyperparathyroidism.  2004;  , ASBMR 26th Annual Meeting of the American Society for Bone and Mineral Research, Abstract SA 542
  PubMedGoogle Scholar
• 5 Bai M, Pearce SHS, Kifor O, Trivedi S, Stauffer UG, Thakker RV, Brown EM, Steinmann B. In vivo and in vitro characterization of neonatal hyperparathyroidism resulting from a de novo, heterozygous mutation in the Ca2+-sensing receptor gene: Normal maternal calcium homeostasis as a cause of secondary hyperparathyroidism in familial benign hypocalciuric hypercalcemia.  J Clin Invest. 1997a;  99 88-96
  PubMedGoogle Scholar
• 6 Bai M, Janicic N, Trivedi S, Quinn SJ, Cole DE, Brown EM, Handy GN. Markedly reduced activity of mutant calcium-sensing receptor with an inserted Alu element from a kindred with familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.  J Clin Invest. 1997b;  99 1917-1925
  PubMedGoogle Scholar
• 7 Baron J, Winer KK, Yanovski JA, Cunningham AW, Laue L, Zimmermann D, Cutler GB. Mutations in the Ca(2+)-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism.  Hum Mol Genet. 1996;  5 601-606
  CrossrefPubMedGoogle Scholar
• 8 Block G, Martin K, de Francisco A, Turner S, Avram M, Suranyi M, Hercz G, Cunningham J, Abu-Alfa A, Messa P, Coyne D, Locatelli F, Cohen R, Evenepoel P, Moe S, Fournier A, Braun J, McCary L, Zani V, Olson K, Drueke T, Goodman W. Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis.  N Engl J Med. 2004;  350 1516-1525
  CrossrefPubMedGoogle Scholar
• 9 Boonstra CE, Jackson CE. Serum calcium survey for hyperparathyroidism.  Am J Clin Pathol. 1971;  55 523-525
  PubMedGoogle Scholar
• 10 Brown EM, Mclead RJ. Extracellular calcium-sensing and extracellular calcium signalling.  Physiol Rev. 2001;  81 239-297
  Google Scholar
• 11 Brown EM. Mutant extracellular calcium-sensing receptors and severity of disease.  J Clin Endocrinol Metab. 2005;  90 1246-1248
  PubMedGoogle Scholar
• 12 Burski K, Torjussen B, Paulsen AQ, Boman H, Bollerslev J. Parathyroid adenoma in a subject with familial hypocalciuric hypercalcemia: coincidence or causality?.  J Clin Endocrinol Metab. 2002;  87 1015-1016
  CrossrefPubMedGoogle Scholar
• 13 Carling T, Szabo E, Gustavsson P, Westin G, Hellman P, Akerstrom G, Dahl N, Rastad J. Mutation in the calcium-sensing receptor gene in autosomal dominant hypercalcemia with hypercalciuria.  , 80th Annual Meeting of The Endocrine Society, 1998; 
  PubMedGoogle Scholar
• 14 Cetani F, Pardi E, Borsari S, Tonacchera M, Morabito E, Pinchera A, Marcocci C, Dipollina G. Two Italian kindreds with familial hypocalciuric hypercalcaemia caused by loss-of-function mutations in the calcium-sensing receptor (CaR) gene: functional characterization of a novel CaR missense mutation.  Clin Endocrinol (Oxf). 2003;  58 199-206 , Erratum in: Clin Endocrinol (Oxf) 2003; 58: 671
  CrossrefPubMedGoogle Scholar
• 15 Chikatsu N, Fukumoto S, Suzawa M, Tanaka Y, Takeuchi Y, Takeda S, Tamura Y, Matsumoto T, Fujita T. An adult patient with severe hypercalcaemia and hypocalciuria due to a novel homzoygous inactivating mutation of calcium-sensing receptor.  Clinical Endocrinology. 1999;  50 537-543
  CrossrefPubMedGoogle Scholar
• 16 Chou YH, Pollak MR, Brandi ML, Toss G, Arnquist H, Atkinson AB, Papapoulos SE, Marx S, Brown EM, Seidman JG. Mutations in the human Ca(2+)-sensing-receptor gene that cause familial hypocalciuric hypercalcemia.  Am J Hum Genet. 1995;  56 1075-1079
  PubMedGoogle Scholar
• 17 Cole DEC, Janicic N, Salisbury SR, Handy GN. Neonatal severe hyperparathyroidism, secondary hyperparathyroidism, and familial hypocalciuric hypercalcemia: multiple different phenotypes associated with an inactivation ALU insertion mutation of the calcium-sensing receptor gene.  Am J Med Genet. 1997;  71 202-210
  CrossrefPubMedGoogle Scholar
• 18 Cole D, Peltekova V, Rubin L, Hawker G, Vieth R, Liew C, Hwang D, Evrovski J, Hendy G. A986S polymorphism of the calcium-sensing receptor and circulating calcium concentrations.  Lancet. 1998;  353 112-115
  PubMedGoogle Scholar
• 19 Cole D, Vieth R, Trang H, Wong B, Hendy G, Rubin L. Association between total serum calcium and the A986S polymorphism of the calcium-sensing receptor gene.  Mol Gen Metab. 2001;  72 168-174
  PubMedGoogle Scholar
• 20 Cole DR, Soule S, Raizis A, George P. Hypocalcemia and a novel calcium sensing receptor activating mutation.  , The Royal Australasian College of Physicians Annual Scientific Meeting 2005; 
  PubMedGoogle Scholar
• 21 Conley YP, Finegold DN, Peters DG, Oppenheim JS, Ferrel RE. Three novel activating mutations in the calcium-sensing receptor responsible for autosomal dominant hypocalcemia.  Molecular Genetics and Metabolism. 2000;  71 591-598
  CrossrefPubMedGoogle Scholar
• 22 De Luca F, Mancilla RK, Fan GF, Winer KK, Gore P, Spiegel AM, Baron J. Sporadic hypoparathyroidism caused by de novo gain-of-function mutations of the Ca2+-sensing receptor.  J Clin Endocrinol Metab. 1997;  82 2710-2715
  CrossrefPubMedGoogle Scholar
• 23 Dreimane D, Hendy G, Alon U, Geffner M. Normalization of Serum Calcium, Phosphorus and Magnesium with homeopathic PTH in a child with Hypocalcemic Hypercalciuria (HCHC) and a mutation of the Calcium-Sensing Receptor Gene.  , 83rd Annual Meeting of the Endocrine Society 2001; 
  PubMedGoogle Scholar
• 24 D'Souza-Li L, Canaff L, Janicic N, Cole DE, Hendy GN. An acceptor splice site mutation in the calcium-sensing receptor (CASR) gene in familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.  Hum Mutat. 2001;  18 411-421
  CrossrefPubMedGoogle Scholar
• 25 D'Souza-Li L, Yang B, Canaff L, Bai M, Hanley DA, Bastepe M, Salisbury SR, Brown EM, Cole DE, Hendy GN. Identification and functional characterization of novel calcium-sensing receptor mutations in familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia.  J Clin Endocrinol Metab. 2002;  87 1309-1318
  CrossrefPubMedGoogle Scholar
• 26 Felderbauer P, Hoffmann P, Klein W, Bulut K, Ansorge N, Epplen JT, Schmitz F, Schmidt WE. Identification of a novel calcium-sensing receptor gene mutation causing familial hypocalciuric hypercalcemia by single-strand conformation polymorphism analysis.  Exp Clin Endocrinol Diabetes. 2005;  113 31-34
  Article in Thieme ConnectPubMedGoogle Scholar
• 27 Fukumoto S, Chikatsu N, Okazaki R, Takeuchi Y, Tamura Y, Murakami T, Obara T, Fujita T. Inactivating mutations of calcium-sensing receptor results in parathyroid lipohyperplasia.  Diagn Mol Pathol. 2001;  10 242-247
  CrossrefPubMedGoogle Scholar
• 28 Fuleihan GH. Familial benign hypocalciuric hypercalcemia.  J Bone Miner Res. 2002;  17 N51-56
  PubMedGoogle Scholar
• 29 Haag C, Schulze E, Lorenz A, Frank-Raue K, Raue F. Novel Mutations of the Calcium-Sensing Receptor in Familial Hypocalciuric Hypercalcemia and Autosomal Dominant Hypocalcemia.  , 87th Annual Meeting of The Endocrine Society 2005; 
  PubMedGoogle Scholar
• 30 Heath III H. Familial benign (hypocalciuric) hypercalcemia. A troublesome mimic of hyperparathyroidism.  Endocrinol Metab Clin North Am. 1989;  18 723-740
  CrossrefPubMedGoogle Scholar
• 31 Heath III H, Jackson CE, Otterud B, Leppert MF. Genetic linkage analysis in familial benign (hypocaliuric) hypercalcemia: evidence for locus heterogeneity.  Am J Hum Genet. 1993;  53 193-200
  PubMedGoogle Scholar
• 32 Heath H, Odelberg S, Jackson CE, Teh BT, Hayward N, Larsson C, Buist NR, Krapcho KJ, Hung BC, Capuano IV, Garrett JE, Leppert MF. Clustered inactivating mutations and benign polymorphisms of the calcium receptor gene in familial benign hypocalciuric hypercalcemia suggest receptor functional domains.  J Clin Endocrinol Metab. 1996;  81 1312-1317
  CrossrefPubMedGoogle Scholar
• 33 Hendy GN, D'Souza-Li L, Yang B, Canaff L, Cole DE. Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia.  Hum Mutat. 2000;  16 281-296
  CrossrefPubMedGoogle Scholar
• 34 Hendy GN, Minutti C, Canaff L, Pidasheva S, Yang B, Nouhi Z, Zimmerman D, Wei C, Cole DE. Recurrent familial hypocalcemia due to germline mosaicism for an activating mutation of the calcium-sensing receptor gene.  J Clin Endocrinol Metab. 2003;  88 3674-3681
  CrossrefPubMedGoogle Scholar
• 35 Hinnie J, Bell E, McKillop E, Gallacher S. The prevalence of familial hypocalciuric hypercalcemia.  Calcif Tissue Int. 2001;  68 216-218
  PubMedGoogle Scholar
• 36 Hirai H, Nakajima S, Miyauchi A, Nishimura K, Shimizu N, Shima M, Michigami T, Ozono K, Okada S. A novel activating mutation (C129S) in the calcium-sensing receptor gene in a Japanese family with autosomal dominant hypocalcemia.  J Hum Genet. 2001;  46 41-44
  CrossrefPubMedGoogle Scholar
• 37 Hu J, Mora S, Colussi G, Proverbio MC, Jones KA, Bolzoni L, De Ferrari ME, Civati G, Spiegel AM. Autosomal dominant hypocalcemia caused by a novel mutation in the loop 2 region of the human calcium receptor extracellular domain.  J Bone Miner Res. 2002;  17 1461-1469
  CrossrefPubMedGoogle Scholar
• 38 Hu J, Spiegel AM. Naturally occurring mutations in the extracellular Ca²⁺-sensing receptor, implications for its structure and function.  Trends Endocrinol Metab. 2003;  14 282-288
  PubMedGoogle Scholar
• 39 Hu J, Mora S, Weber G, Zamproni I, Proverbio MC, Spiegel AM. Autosomal dominant hypocalcemia in monozygotic twins caused by a de novo germline mutation near the amino-terminus of the human calcium receptor.  J Bone Miner Res. 2004;  19 578-586
  CrossrefPubMedGoogle Scholar
• 40 Hu J, McLarnon SJ, Mora S, Jiang J, Thomas C, Jacobson KA, Spiegel AM. A region in the seven-transmembrane domain of the human Ca2+ receptor critical for response to Ca2+.  J Biol Chem. 2005;  280 5113-5120
  PubMedGoogle Scholar
• 41 Inoue D, Saika M, Ikeda Y, MatsumotoT. Successful treatment of hypoparathyroidism caused by a novel calcium-sensing receptor mutation with thiazide diuretics and low dose alfacalcidol.  Bone. 1998;  23 382
  PubMedGoogle Scholar
• 42 Janicic N, Pausova Z, Cole DE, Hendy GN. Insertion of an Alu sequence in the Ca(2+)-sensing receptor gene in familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.  Am J Hum Genet. 1995;  56 880-886
  PubMedGoogle Scholar
• 43 Jap T, Wu Y, Jenq S, Won G. A novel mutation in the calcium-sensing receptor gene in a Chinese subject with persistent hypercalcemia and hypocalciuria.  J Clin Endocrinol Metab. 2001;  86 13-15
  CrossrefPubMedGoogle Scholar
• 44 Kifor O, Moore FD, Delaney M, Garber J, Hendy GN, Butters RR, Gao P, Couter TL, Kifor I, Brown EM, Wysolmerki J. A syndrome of hypocalciuric hypercalcemia caused by auto-antibodies directed at the calcium-sensing receptor.  J Clin Endocrinol Metab. 2003;  88 60-72
  CrossrefPubMedGoogle Scholar
• 45 Kobayashi M, Tanaka H, Tsuzuki K, Tsuyuki M, Igaki H, Ichinose Y, Aya K, Nishioka N, Seino Y. Two novel missense mutations in calcium-sensing receptor gene associated with neonatal severe hyperparathyroidism.  J Clin Endocrinol Metab. 1997;  82 2716-2719
  CrossrefPubMedGoogle Scholar
• 46 Konrad M, Weber S. Recent advances in molecular genetics of hereditary magnesium-losing disorders.  J Am Soc Nephrol. 2003;  14 249-253
  CrossrefPubMedGoogle Scholar
• 47 Lam CW, Lee KF, Chan AO, Poon PM, Law TY, Tong SF. Novel missense mutation in the CASR gene in a Chinese family with familial hypocalciuric hypercalcemia.  Clin Chim Acta. 2005;  360 167-172
  CrossrefPubMedGoogle Scholar
• 48 Law Jr WM, Heath III H. Familial benign hypercalcemia (hypocalciuric hypercalcemia) - clinical and pathogenetic studies in 21 families.  Ann Intern Med. 1985;  102 511-519
  CrossrefPubMedGoogle Scholar
• 49 Li Y, Song YH, Rais N, Connar E, Schatz D, Mair A, Maclaren N. Autoantibodies to the extracellular domain of the calcium sensing receptor in patients with acquired hypoparathyroidism.  J Clin Invest. 1996;  97 910-914
  CrossrefPubMedGoogle Scholar
• 50 Lienhardt A, Garabedian M, Bai M, Sinding C, Zhang Z, Lagarde J, Boulesteix J, Rigaud M, Brown EM, Kottler M. A large homozygous or heterozygous in-frame deletion within the calcium-sensing receptor's carboxylterminal cytoplasmic tail that causes autosomal dominant hypocalcemia.  J Clin Endocrinol Metab. 2000;  85 1695-1702
  CrossrefPubMedGoogle Scholar
• 51 Lienhardt A, Bai M, Lagarde JP, Rigaud M, Zhang Z, Jiang Y, Kottler ML, Brown EM, Garabedian M. Activating mutations of the calcium-sensing receptor: management of hypocalcemia.  J Clin Endocrinol Metab. 2001;  86 5313-5323
  CrossrefPubMedGoogle Scholar
• 52 Lovlie R, Eiken HG, Sorheim JI, Boman H. The Ca(2+)-sensing receptor gene (PCAR1) mutation T151 M in isolated autosomal dominant hypoparathyroidism.  Hum Genet. 1996;  98 129-133
  PubMedGoogle Scholar
• 53 Lloyd SE, Pannett AAJ, Dixon PH, Whyle MP, Thakker RV. Localisation of familial benign hypercalcemia Oklahoma variant (FBH_OK) to chromosome 19q13.  Am J Hum Genet. 1999;  64 189-195
  CrossrefPubMedGoogle Scholar
• 54 Marcocci C, Cetani F, Borsari B, Pardi E, Dipollina G, Ambrogini E, Cianferotti L, Viccica G, Pinchera A. Hypercalcemia in a Women with Breast Cancer Misdiagnosed as Hypercalcemia of Malignancy: An Unusual Presentation of Familial Hypocalciuric Hypercalcemia.  , ASBMR 25th Annual Meeting of the American Society for Bone and Mineral Research 2003;  , Abstract SU 456
  PubMedGoogle Scholar
• 55 Marx SJ, Attie MF, Levine MA, Spiegel AM, Downs RW, Lasker RD. The hypocalciuric or benign variant of familial hypercalcemia: clinical and biochemical features in fifteen kindreds.  Medicine (Baltimore). 1981;  60 397-412
  CrossrefPubMedGoogle Scholar
• 56 Miyashiro K, Kasamatsu TS, Steinmetz L, de Menezes Filho HC, Damiani D, Setian N, Hauache OM. Identification and functional analysis of a novel inactivating mutation (A804D) of the calcium-sensing receptor gene.  Clin Endocrinol (Oxf). 2004a;  61 780-782
  CrossrefPubMedGoogle Scholar
• 57 Miyashiro K, Kunii I, Manna TD, de Menezes Filho HC, Damiani D, Setian N, Hauache OM. Severe hypercalcemia in a 9-year-old Brazilian girl due to a novel inactivating mutation of the calcium-sensing receptor.  J Clin Endocrinol Metab. 2004b;  89 5936-5941
  CrossrefPubMedGoogle Scholar
• 58 Nagase T, Murakami T, Tsukada T, Kitamura R, Chikatsu N, Takeo H, Takata N, Yasuda H, Fukumoto S, Tanaka Y, Nagata N, Yamaguchi K, Akatsu T, Yamamoto M. A family of autosomal dominant hypocalcemia with a positive correlation between serum calcium and magnesium: identification of a novel gain of function mutation (Ser[820]Phe) in the calcium-sensing receptor.  J Clin Endocrinol Metab. 2002;  87 2681-2687
  CrossrefPubMedGoogle Scholar
• 59 Nakayama T, Minato M, Nakagawa M, Soma M, Tobe H, Aoi N, Kosuge K, Sato M, Ozawa Y, Kanmatsuse K, Kokubun S. A novel mutation in Ca2+-sensing receptor gene in familial hypocalciuric hypercalcemia.  Endocrine. 2001;  15 277-282
  CrossrefPubMedGoogle Scholar
• 60 Nemeth EF, Steffey ME, Hammerland LG, Hung BC, van Wagenen BC, DelMar EG, Balandrin MF. Calcimimetics with potent and selective activity on the parathyroid calcium receptor.  Proc Natl Acad Sci USA. 1998;  95 4040-4045
  CrossrefPubMedGoogle Scholar
• 61 Okazaki R, Chikatsu N, Nakatsu M, Takeuchi Y, Ajima M, Miki J, Fujita T, Ara M, Totsuka Y, Tanaka K, Fukumoto S. A novel activating mutation in calcium-sensing receptor gene associated with a family of autosomal dominant hypocalcemia.  J Clin Endocrinol Metab. 1999;  84 363-366
  CrossrefPubMedGoogle Scholar
• 62 Pallais JC, Kifor O, Chen YB, Slovik D, Brown EM. Acquired hypocalciuric hypercalcemia due to autoantibodies against the calcium-sensing receptor.  N Engl J Med. 2004;  351 362-369
  CrossrefPubMedGoogle Scholar
• 63 Pearce SHS, Trump D, Wooding C, Besser GM, Chew SL, Grant DB, Heath DA, Hughes IA, Paterson CR, Whyle MP, Thakker RV. Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism.  J Clin Invest. 1995;  96 2683-2692
  PubMedGoogle Scholar
• 64 Pearce SHS, Williamson C, Kifor O, Bai M, Coulthard MG, Davies M, Lewis-Barned N, McCredie D, Powell H, Kendall-Taylor P, Brown EM, Thakker RV. A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor.  N Engl J Med. 1996a;  335 1115-1122
  CrossrefPubMedGoogle Scholar
• 65 Pearce SHS, Bai M, Quinn SJ, Kifor O, Brown EM, Thakker RV. Functional characterization of calcium-sensing receptor mutations expressed in human embryonic kidney cells.  J Clin Invest. 1996b;  98 1860-1866
  PubMedGoogle Scholar
• 66 Pearce SHS, Wooding C, Davies M, Tollefsen SE, Whyte MP, Thakker RV. Calcium-sensing receptor mutations in familial hypocalciuric hypercalcaemia with recurrent pancreatitis.  Clin Endocrinol (Oxf). 1996c;  45 675-680
  CrossrefPubMedGoogle Scholar
• 67 Pearce SHS. Clinical disorders of extracellular calcium-sensing and the molecular biology of the calcium-sensing receptor.  Ann Med. 2002;  34 201-206
  PubMedGoogle Scholar
• 68 Pollak MR, Brown EM, Chou YH, Herbert SC, Marx SJ, Steinmann B, Levi T, Seidman CE, Seidman JG. Mutations in the human Ca2+-sensing receptor gene causes familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.  Cell. 1993;  75 1297-1303
  CrossrefPubMedGoogle Scholar
• 69 Pollak MR, Chou YH, Marx SJ, Steinmann B, Cole DE, Brandi ML, Papapoulos SE, Menko FH, Hendy GN, Brown EM, Seidman CE, Seidman JG. Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Effects of mutant gene dosage on phenotype.  J Clin Invest. 1994a;  93 1108-1112
  PubMedGoogle Scholar
• 70 Pollak MR, Brown EM, Estep HL, McLaine PN, Kifor O, Park J, Hebert SC, Seidman CE, Seidman JG. Autosomal dominant hypocalcaemia caused by a Ca2+-sensing receptor gene mutation.  Nat Genet. 1994b;  8 303-307
  CrossrefPubMedGoogle Scholar
• 71 Rajguru M, Bedu A, Magdelaine C, Bai M, Aujuard Y, Lienhardt A. Neonatal primary hyperparathyroidism due to a new calcium sensing receptor mutation.  , Pediatric Academic Societies' 2001 Annual Meeting, Abstract P3-294
  PubMedGoogle Scholar
• 72 Ray K, Hauschild BC, Steinbach PJ, Goldsmith PK, Hauache O, Spiegel AM. Identification of the cysteine residue in the amino-terminal extracellular domain of the human Ca²⁺ receptor critical for dimerization.  J Biol Chem. 1999;  274 27642-27650
  CrossrefPubMedGoogle Scholar
• 73 Schwarz P, Larsen NE, Lonborg Friis IM, Lillquist K, Brown EM, Gammeltoft S. Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism associated with mutations in the human Ca2+-sensing receptor gene in three Danish families.  Scand J Clin Lab Invest. 2000;  60 221-227
  PubMedGoogle Scholar
• 74 Scillitani A, Guarnirei V, de Geronimo S, Muscarella LA, Battista C, D'Agruma L, Bertoldo F, Florio C, Minisola S, Hendy G, Cole D. Blood ionized calcium is associated with clustered polymorphisms in the carboxyl-terminal tail of the calcium-sensing receptor.  J Clin Endocrinol Metab. 2004;  89 5634-5638
  CrossrefPubMedGoogle Scholar
• 75 Shiohara M, Mori T, Mei B, Brown EM, Watanabe T, Yasuda T. A novel gain-of-function mutation (F821 L) in the transmembrane domain of calcium-sensing receptor is a cause of severe sporadic hypoparathyroidism.  Eur J Pediatr. 2004;  163 94-98
  CrossrefPubMedGoogle Scholar
• 76 Silver J, Naveh-Many T. Regulation of parathyroid hormone synthesis and secretion.  Semin Nephrol. 1994;  14 175-194
  PubMedGoogle Scholar
• 77 Silverberg SJ, Bone III HG, Mariott TB, Locker FG, Thys-Jacobs S, Dziem G, Kaatz S, Sanguinetti EL, Bilezikian JP. Short-term inhibition of parathyroid hormone secretion by a calcium-receptor agonist in patients with primary hyperparathyroidism.  N Engl J Med. 1997;  337 1506-1511
  CrossrefPubMedGoogle Scholar
• 78 Simonds WF, James-Newton LA, Agarwal SK, Yang BM, Skarulis MC, Hendy GN, Marx SJ. Familial Isolated Hyperparathyroidism: Clinical and Genetic Characteristics of 36 Kindreds.  Medicine. 2002;  81 1-26
  CrossrefPubMedGoogle Scholar
• 79 Stock JL, Brown RS, Baron J, Coderre JA, Mancilla E, De Luca F, Ray K, Mericq MV. Autosomal dominant hypoparathyroidism associated with short stature and premature osteoarthritis.  J Clin Endocrinol Metab. 1999;  84 3036-3040
  CrossrefPubMedGoogle Scholar
• 80 Takacs I, Speer G, Bajnok E, Tabak A, Nagy Z, Horvath C, Kovacs K, Lakatos P. Lack of association between calcium-sensing receptor gene “A986S” polymorphism and bone mineral density in Hungarian postmenopausal women.  Bone. 2002;  30 849-852
  CrossrefPubMedGoogle Scholar
• 81 Thakker RV. Diseases associated with the extracellular calcium-sensing receptor.  Cell Calcium. 2004;  35 275-282
  CrossrefPubMedGoogle Scholar
• 82 Tan YM, Cardinal J, Franks AH, Mun HC, Lewis N, Harris LB, Prins JB, Conigrave AD. Autosomal dominant hypocalcaemia: a novel activating mutation (E604 K) in the cysteine-rich domain of the calcium-sensing receptor.  J Clin Endocrinol Metab. 2003;  88 605-610
  CrossrefPubMedGoogle Scholar
• 83 Uckun-Kitapci A, Underwood LE, Zhang J, Moats-Staats B. A novel mutation (E767 K) in the second extracellular loop of the calcium sensing receptor in a family with autosomal dominant hypocalcemia.  Am J Med Genet. 2005;  132 125-129
  PubMedGoogle Scholar
• 84 Vargas-Poussou R, Huang C, Hulin P, Houillier P, Jeunemaître X, Paillard M, Planelles G, Dechaux M, Miller RT, Antignac C. Functional characterization of a calcium-sensing receptor mutation in severe autosomal dominant hypocalcemia with a Bartter-like syndrome.  J Am Soc Nephrol. 2002;  13 2259-2266
  CrossrefPubMedGoogle Scholar
• 85 Vigouroux C, Bourut C, Guerci B, Ziegler O, Magre J, Capeau J, Meyer L. A new missense mutation in the calcium-sensing receptor in familial benign hypercalcaemia associated with partial lipoatrophy and insulin resistant diabetes.  Clin Endocrinol (Oxf). 2000;  53 393-398
  CrossrefPubMedGoogle Scholar
• 86 Waller S, Kurzawinski T, Spitz L, Thakker R, Cranston T, Pearce S, Cheetham T, van't Hoff WG. Neonatal severe hyperparathyroidism: genotype/phenotype correlation and the use of pamidronate as rescue therapy.  Eur J Pediatr. 2004;  163 589-594
  PubMedGoogle Scholar
• 87 Ward BK, Cameron FJ, Magno AL, McDonnell CM, Stuckey BG, Ratajczak T. A novel homozygous deletion in the calcium-sensing receptor ligand-binding domain associated with neonatal severe hyperparathyroidism.  J Pediatr Endocrinol Metab. 2006;  19 93-100
  PubMedGoogle Scholar
• 88 Ward BK, Stuckey BG, Gutteridge DH, Laing NG, Pullan PT, Ratajczak T. A novel mutation (L174R) in the Ca2+-sensing receptor gene associated with familial hypocalciuric hypercalcemia.  Hum Mutat. 1997;  10 233-235
  CrossrefPubMedGoogle Scholar
• 89 Ward BK, Magno AL, Davis EA, Hanyaloglu AC, Stuckey BG, Burrows M, Eidne KA, Charles AK, Ratajczak T. Functional deletion of the calcium-sensing receptor in a case of neonatal severe hyperparathyroidism.  J Clin Endocrinol Metab. 2004;  89 3721-3730
  CrossrefPubMedGoogle Scholar
• 90 Warner J, Epstein M, Sweet A, Singh D, Burgess J, Stranks S, Hill P, Perry-Keene D, Learoyd D, Robinson B, Birdsey P, Mackenzie E, Teh BT, Prins JB, Cardinal J. Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications.  J Med Genet. 2004;  41 155-160
  CrossrefPubMedGoogle Scholar
• 91 Watanabe T, Bai M, Lane CR, Matsumoto S, Minamitani K, Minagawa M, Niimi H, Brown EM, Yasuda T. Familial hypoparathyroidism: Identification of a novel gain of function mutation in transmembrane domain 5 of the calcium-sensing receptor.  J Clin Endocrinol Metab. 1998;  83 2497-2502
  CrossrefPubMedGoogle Scholar
• 92 Watanabe S, Fukumoto S, Chang H, Takeuchi Y, Hasegawa Y, Okazaki R, Chikatsu N, Fujita T. Association between activating mutations of calcium-sensing receptor and Bartter's syndrome.  Lancet. 2002;  360 692-694
  CrossrefPubMedGoogle Scholar
• 93 Wystrychowski A, Pidasheva S, Canaff L, Chudek J, Kokot F, Wiecek A, Hendy GN. Functional characterization of calcium-sensing receptor codon 227 mutations presenting as either familial (benign) hypocalcrin.  J Clin Endocrin Metab. 2005;  90 864-870
  PubMedGoogle Scholar
• 94 Yamauchi M, SugimotoT, Yamaguchi T, Yano S, Kanzawa M, Kobayashi A, Chihara K. Association of polymorphic alleles of the calcium-sensing receptor gene with the clinical severity of primary hyperparathyroidism.  Clin Endocrinol. 2001;  55 373-379
  CrossrefPubMedGoogle Scholar
• 95 Yano S, Sugimoto T, Kanzawa M, Tsukamoto T, Hattori T, Chihara K. Association of polymorphic alleles of the calcium-sensing receptor gene with parathyroid hormone secretion in hemodialysis patients.  Nephron. 2000;  85 317-323
  CrossrefPubMedGoogle Scholar
• 96 Young R, Wu F, Van de Water N, Ames R, Gamble G, Reid IR. Calcium-sensing receptor gene A986S polymorphism and responsiveness to calcium supplementationinpostmenopausal women.  J Clin Endonol Metab. 2003;  88 697-700
  PubMedGoogle Scholar

Correspondence

Prof. Dr. med. Friedhelm Raue

Endokrinologische Gemeinschaftspraxis

Brückenstr. 21

69120 Heidelberg

Phone: +49/62/21 43 90 90

Fax: +49/62/21 43 90 99

Email: friedhelm.raue@raue-endokrinologie.de