Search tips
Search criteria 


Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. 1995 December; 96(6): 2683–2692.
PMCID: PMC185975

Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism.


Familial benign hypercalcemia (FBH) and neonatal hyperparathyroidism (NHPT) are disorders of calcium homeostasis that are associated with missense mutations of the calcium-sensing receptor (CaR). We have undertaken studies to characterize such CaR mutations in FBH and NHPT and to explore methods for their more rapid detection. Nine unrelated kindreds (39 affected, 32 unaffected members) with FBH and three unrelated children with sporadic NHPT were investigated for mutations in the 3,234-bp coding region of the CaR gene by DNA sequencing. Six novel heterozygous (one nonsense and five missense) mutations were identified in six of the nine FBH kindreds, and two de novo heterozygous missense mutations and one homozygous frame-shift mutation were identified in the three children with NHPT. Our results expand the phenotypes associated with CaR mutations to include sporadic NHPT. Single-stranded conformational polymorphism analysis was found to be a sensitive and specific mutational screening method that detected > 85% of these CaR gene mutations. The single-stranded conformational polymorphism identification of CaR mutations may help in the distinction of FBH from mild primary hyperparathyroidism which can be clinically difficult. Thus, the results of our study will help to supplement the clinical evaluation of some hypercalcemic patients and to elucidate further the structure-function relationships of the CaR.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.0M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A, Hediger MA, Lytton J, Hebert SC. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature. 1993 Dec 9;366(6455):575–580. [PubMed]
  • Pollak MR, Brown EM, Chou YH, Hebert SC, Marx SJ, Steinmann B, Levi T, Seidman CE, Seidman JG. Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell. 1993 Dec 31;75(7):1297–1303. [PubMed]
  • 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 Apr;56(4):880–886. [PubMed]
  • Chou YH, Pollak MR, Brandi ML, Toss G, Arnqvist H, Atkinson AB, Papapoulos SE, Marx S, Brown EM, Seidman JG, et al. Mutations in the human Ca(2+)-sensing-receptor gene that cause familial hypocalciuric hypercalcemia. Am J Hum Genet. 1995 May;56(5):1075–1079. [PubMed]
  • Pollak MR, Brown EM, Estep HL, McLaine PN, Kifor O, Park J, Hebert SC, Seidman CE, Seidman JG. Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation. Nat Genet. 1994 Nov;8(3):303–307. [PubMed]
  • Marx SJ, Attie MF, Levine MA, Spiegel AM, Downs RW, Jr, Lasker RD. The hypocalciuric or benign variant of familial hypercalcemia: clinical and biochemical features in fifteen kindreds. Medicine (Baltimore) 1981 Nov;60(6):397–412. [PubMed]
  • Law WM, Jr, Heath H., 3rd Familial benign hypercalcemia (hypocalciuric hypercalcemia). Clinical and pathogenetic studies in 21 families. Ann Intern Med. 1985 Apr;102(4):511–519. [PubMed]
  • Paterson CR, Gunn A. Familial benign hypercalcaemia. Lancet. 1981 Jul 11;2(8237):61–63. [PubMed]
  • Sopwith AM, Burns C, Grant DB, Taylor GW, Wolf E, Besser GM. Familial hypocalciuric hypercalcaemia: association with neonatal primary hyperparathyroidism, and possible linkage with HLA haplotype. Clin Endocrinol (Oxf) 1984 Jul;21(1):57–64. [PubMed]
  • Heath H., 3rd Familial benign (hypocalciuric) hypercalcemia. A troublesome mimic of mild primary hyperparathyroidism. Endocrinol Metab Clin North Am. 1989 Sep;18(3):723–740. [PubMed]
  • Spiegel AM, Harrison HE, Marx SJ, Brown EM, Aurbach GD. Neonatal primary hyperparathyroidism with autosomal dominant inheritance. J Pediatr. 1977 Feb;90(2):269–272. [PubMed]
  • Marx SJ, Attie MF, Spiegel AM, Levine MA, Lasker RD, Fox M. An association between neonatal severe primary hyperparathyroidism and familial hypocalciuric hypercalcemia in three kindreds. N Engl J Med. 1982 Feb 4;306(5):257–264. [PubMed]
  • Page LA, Haddow JE. Self-limited neonatal hyperparathyroidism in familial hypocalciuric hypercalcemia. J Pediatr. 1987 Aug;111(2):261–264. [PubMed]
  • Wilkinson H, James J. Self limiting neonatal primary hyperparathyroidism associated with familial hypocalciuric hypercalcaemia. Arch Dis Child. 1993 Sep;69(3 Spec No):319–321. [PMC free article] [PubMed]
  • Nishiyama S, Tomoeda S, Inoue F, Ohta T, Matsuda I. Self-limited neonatal familial hyperparathyroidism associated with hypercalciuria and renal tubular acidosis in three siblings. Pediatrics. 1990 Sep;86(3):421–427. [PubMed]
  • Meeran K, Husain M, Puccini M, Scott H, Dionisi-Vici C, Harvey DR, Lynn J, Thakker RV. Neonatal primary hyperparathyroidism masked by vitamin D deficiency. Clin Endocrinol (Oxf) 1994 Oct;41(4):531–534. [PubMed]
  • Marx SJ, Stock JL, Attie MF, Downs RW, Jr, Gardner DG, Brown EM, Spiegel AM, Doppman JL, Brennan MF. Familial hypocalciuric hypercalcemia: recognition among patients referred after unsuccessful parathyroid exploration. Ann Intern Med. 1980 Mar;92(3):351–356. [PubMed]
  • Almahroos GM, Docherty K, Fletcher JA, Webb T, Heath DA. Studies of the parathyroid hormone gene in normal subjects, and in subjects with primary hyperparathyroidism and familial benign hypercalcaemia. J Endocrinol. 1987 Oct;115(1):183–186. [PubMed]
  • Mackintosh P, Almarhoos G, Heath DA. HLA linkage with familial vesicoureteral reflux and familial pelvi-ureteric junction obstruction. Tissue Antigens. 1989 Sep;34(3):185–189. [PubMed]
  • Dezateux CA, Hyde JC, Hoey HM, O'Riordan JL, Spitz L, Taylor GW, Grant DB. Neonatal hyperparathyroidism. Eur J Pediatr. 1984 Jun;142(2):135–136. [PubMed]
  • Thakker RV, Pook MA, Wooding C, Boscaro M, Scanarini M, Clayton RN. Association of somatotrophinomas with loss of alleles on chromosome 11 and with gsp mutations. J Clin Invest. 1993 Jun;91(6):2815–2821. [PMC free article] [PubMed]
  • Thakker RV, Davies KE, Whyte MP, Wooding C, O'Riordan JL. Mapping the gene causing X-linked recessive idiopathic hypoparathyroidism to Xq26-Xq27 by linkage studies. J Clin Invest. 1990 Jul;86(1):40–45. [PMC free article] [PubMed]
  • Trump D, Whyte MP, Wooding C, Pang JT, Pearce SH, Kocher DB, Thakker RV. Linkage studies in a kindred from Oklahoma, with familial benign (hypocalciuric) hypercalcaemia (FBH) and developmental elevations in serum parathyroid hormone levels, indicate a third locus for FBH. Hum Genet. 1995 Aug;96(2):183–187. [PubMed]
  • Scheinman SJ, Pook MA, Wooding C, Pang JT, Frymoyer PA, Thakker RV. Mapping the gene causing X-linked recessive nephrolithiasis to Xp11.22 by linkage studies. J Clin Invest. 1993 Jun;91(6):2351–2357. [PMC free article] [PubMed]
  • Parkinson DB, Thakker RV. A donor splice site mutation in the parathyroid hormone gene is associated with autosomal recessive hypoparathyroidism. Nat Genet. 1992 May;1(2):149–152. [PubMed]
  • Grompe M. The rapid detection of unknown mutations in nucleic acids. Nat Genet. 1993 Oct;5(2):111–117. [PubMed]
  • Garrett JE, Capuano IV, Hammerland LG, Hung BC, Brown EM, Hebert SC, Nemeth EF, Fuller F. Molecular cloning and functional expression of human parathyroid calcium receptor cDNAs. J Biol Chem. 1995 May 26;270(21):12919–12925. [PubMed]
  • Riccardi D, Park J, Lee WS, Gamba G, Brown EM, Hebert SC. Cloning and functional expression of a rat kidney extracellular calcium/polyvalent cation-sensing receptor. Proc Natl Acad Sci U S A. 1995 Jan 3;92(1):131–135. [PubMed]
  • Herskowitz I. Functional inactivation of genes by dominant negative mutations. Nature. 1987 Sep 17;329(6136):219–222. [PubMed]
  • Maggio R, Vogel Z, Wess J. Coexpression studies with mutant muscarinic/adrenergic receptors provide evidence for intermolecular "cross-talk" between G-protein-linked receptors. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):3103–3107. [PubMed]
  • Dejager S, Mietus-Snyder M, Friera A, Pitas RE. Dominant negative mutations of the scavenger receptor. Native receptor inactivation by expression of truncated variants. J Clin Invest. 1993 Aug;92(2):894–902. [PMC free article] [PubMed]
  • Chou YH, Brown EM, Levi T, Crowe G, Atkinson AB, Arnqvist HJ, Toss G, Fuleihan GE, Seidman JG, Seidman CE. The gene responsible for familial hypocalciuric hypercalcemia maps to chromosome 3q in four unrelated families. Nat Genet. 1992 Jul;1(4):295–300. [PubMed]
  • Heath H, 3rd, Jackson CE, Otterud B, Leppert MF. Genetic linkage analysis in familial benign (hypocalciuric) hypercalcemia: evidence for locus heterogeneity. Am J Hum Genet. 1993 Jul;53(1):193–200. [PubMed]
  • McMurtry CT, Schranck FW, Walkenhorst DA, Murphy WA, Kocher DB, Teitelbaum SL, Rupich RC, Whyte MP. Significant developmental elevation in serum parathyroid hormone levels in a large kindred with familial benign (hypocalciuric) hypercalcemia. Am J Med. 1992 Sep;93(3):247–258. [PubMed]
  • Pollak MR, Chou YH, Marx SJ, Steinmann B, Cole DE, Brandi ML, Papapoulos SE, Menko FH, Hendy GN, Brown EM, et al. Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Effects of mutant gene dosage on phenotype. J Clin Invest. 1994 Mar;93(3):1108–1112. [PMC free article] [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation