FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 335:1115-1122 October 10, 1996 Number 15 Next

Abstract PDF Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background The calcium-sensing receptor regulates the secretion of parathyroid hormone in response to changes in extracellular calcium concentrations, and mutations that result in a loss of function of the receptor are associated with familial hypocalciuric hypercalcemia. Mutations involving a gain of function have been associated with hypocalcemia in two kindreds. We examined the possibility that the latter type of mutation may result in a phenotype of familial hypocalcemia with hypercalciuria.

Methods We studied six kindreds given a diagnosis of autosomal dominant hypoparathyroidism on the basis of their hypocalcemia and normal serum parathyroid hormone concentrations, a combination that suggested a defect of the calcium-sensing receptor. The hypocalcemia was associated with hypercalciuria, and treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment. Mutations in the calcium-sensing–receptor gene were identified by DNA-sequence analysis and expressed in human embryonic kidney cells (HEK-293).

Results Five heterozygous missense mutations (Asn118Lys, Phe128Leu, Thr151Met, Glu191Lys, and Phe612Ser) were detected in the extracellular domain of the calcium-sensing–receptor gene and shown to cosegregate with the disease. Analysis of the functional expression of three of the mutant receptors in HEK-293 cells demonstrated shifts in the dose–response curves so that the extracellular calcium concentrations needed to produce half-maximal increases in total inositol phosphate in the cells were significantly (P = 0.02 to P<0.001) lower than those required for the wild-type receptor.

Conclusions Gain-of-function mutations in the calcium-sensing receptor are associated with a familial syndrome of hypocalcemia with hypercalciuria that needs to be distinguished from hypoparathyroidism.

The calcium-sensing–receptor gene is located on chromosome 3q13.3–q21 and encodes a cell-surface protein of 1078 amino acids that is expressed in the parathyroid glands and kidneys and belongs to the family of G-protein–coupled receptors.^13,14,15 This receptor regulates the secretion of parathyroid hormone and the reabsorption of calcium by the renal tubules in response to alterations in serum calcium concentrations.^15,16 Mutations in this calcium receptor involving a loss of function cause familial benign hypercalcemia, also known as familial hypocalciuric hypercalcemia; persons with this autosomal dominant disorder, who are generally asymptomatic, have lifelong elevations of serum calcium concentrations together with a low urinary excretion of calcium.^{17,18,19,20,21,22} The association of two mutations of the calcium-sensing–receptor gene with hypocalcemia led us to postulate that the phenotype of gain-of-function mutations may be hypocalcemia with hypercalciuria. We therefore investigated six kindreds with autosomal dominant hypocalcemia and hypercalciuria for mutations involving the calcium-sensing–receptor gene.

Methods

Patients

We studied six kindreds with hypocalcemia in which isolated hypoparathyroidism had been diagnosed but in which hypocalcemia was associated with normal serum parathyroid hormone concentrations.^1,7 Clinical and biochemical studies revealed 20 affected (Table 1) and 17 unaffected family members. Biochemical measurements were performed as described previously,²³ and statistical analyses were performed with Student's t-test and analysis of variance.

View this table: [in this window] [in a new window]   Table 1. Clinical and Biochemical Features of 20 Affected Members of Six Families with Hypocalcemic Hypercalciuria.

 
Preparation of Genomic DNA and Characterization of Mutations in the Calcium-Sensing–Receptor Gene

Samples of venous blood were obtained from the 20 affected and 17 unaffected members of the six families. DNA was extracted from leukocytes²⁴ and amplified with 12 pairs of oligonucleotide primers specific for the calcium-sensing–receptor gene to examine the 6 coding exons and 9 of the 12 splice sites by the polymerase chain reaction (PCR), as previously described.^17,20 DNA-sequence analysis of the resulting PCR products with a semiautomated laser detection system (Sequencer 373a, Applied Biosystems, Foster City, Calif.) was performed for the proband of each family, and the results were compared with the normal DNA sequence (GenBank number X81086), as previously described.²⁰ The DNA-sequence abnormalities in the probands were confirmed either by restriction-endonuclease analysis or by hybridization to sequence-specific oligonucleotides, as previously described.²⁰ In addition, each abnormality was demonstrated to cosegregate with the disorder and to be absent, and therefore not a neutral polymorphism, in the DNA obtained from 55 unrelated normal subjects.

Analysis of Single-Strand Conformational Polymorphisms

Genomic DNA obtained from the probands in whom mutations had been identified and 10 unrelated normal subjects was amplified by PCR with appropriate primers,^17,20 and the products were subjected to analysis of single-strand conformational polymorphisms (SSCPs) with the Phast electrophoresis system (Pharmacia LKB, Uppsala, Sweden), as previously described.²⁰ In order to detect mutations in exon 3 (Asn118Lys, Phe128Leu, and Thr151Met), we used a temperature of 10°C and a run length of 240 volt-hours. The results were scored by two observers who were unaware of the identity of the samples.

Expression of Wild-Type and Mutant Calcium-Sensing Receptors

Restriction fragments of complementary DNA (cDNA) from the wild-type human calcium-sensing–receptor gene (HuPCaR4.0)¹⁴ were ligated into pBluescript SK(-) (Stratagene, La Jolla, Calif.), and three mutations (Phe128Leu, Thr151Met, and Glu191Lys) were successfully produced by site-directed mutagenesis.²⁵ The Phe612Ser mutation could not be produced because it was too close to the 3' end of one of the restriction fragments used for site-directed mutagenesis, and the Asn118Lys mutation was not studied. Mutant clones, which were verified by DNA sequencing of both strands, were ligated into the construct of the full-length receptor cDNA in the mammalian expression vector pcDNA3 (Invitrogen, San Diego, Calif.). One microgram of the wild-type or mutant calcium-sensing–receptor cDNA was bound to lipofectamine (Gibco BRL, Gaithersburg, Md.) and transfected into human embryonic kidney cells (HEK-293, American Type Culture Collection number CRL-1573) that had been grown to 90 percent confluence in Dulbecco's modified Eagle's medium (GIBCO BRL) supplemented with 10 percent heat-inactivated fetal-calf serum (Hyclone, Logan, Utah). Forty-eight hours after transfection, the cells were labeled for 18 hours with 30 µCi of [³H]inositol per milliliter (New England Nuclear, Boston), washed, and incubated for 30 minutes in Dulbecco's modified Eagle's medium (free of bicarbonate, calcium, and magnesium), supplemented with 20 mM HEPES buffer (pH 7.45), 0.2 percent bovine serum albumin, 10 mM lithium chloride, 0.5 mM magnesium chloride, and various concentrations of calcium chloride (0.5, 1.0, 1.5, 2.0, 3.0, and 5 mM).²⁶ Each calcium concentration was studied in a total of four transfection experiments performed independently on two days, and the total cellular inositol phosphate that accumulated (i.e., IP + IP₂ +IP₃ + IP₄) was measured by ion-exchange chromatography,²⁷ with the value normalized on the basis of cellular protein by measurement of the total protein content (micro BCA protein assay, Pierce, Rockford, Ill.). Inositol phosphate values are reported as means ±SE. The effective extracellular calcium concentration required for a half-maximal inositol phosphate response for each clone was derived from the mean of the four transfection experiments.

Results

Clinical and Biochemical Studies

Twenty of the 37 family members studied had hypocalcemia, of whom 11 had carpopedal spasm or childhood seizures. Two subjects, Subject I-2 in Family 1 and Subject I-2 in Family 2, had calcification of basal ganglia and seizures, and in Subject I-2 in Family 1, the seizures continued into adult life. The remaining 9 affected subjects had asymptomatic hypocalcemia, and 16 subjects also had hypomagnesemia (Table 1). In addition, urinary calcium excretion was either inappropriately within the normal range or high at the time of the initial diagnosis. The mean (±SE) ratio of urinary calcium to urinary creatinine (expressed as milligrams of calcium per milligram of creatinine [and as millimoles of calcium per millimole of creatinine]) before treatment in the 11 affected subjects in whom it was measured was significantly higher than that reported in 10 untreated subjects with idiopathic or postoperative hypoparathyroidism²⁸ (0.16±0.02 vs. 0.07±0.02 [0.5±0.1 vs. 0.2±0.1], P = 0.004), despite the presence of similar levels of hypocalcemia (6.8±0.2 vs. 6.9±0.4 mg per deciliter [1.7±0.04 vs. 1.7±0.1 mmol per liter]).²⁸

Nineteen subjects were treated with oral preparations of vitamin D; serum parathyroid hormone concentrations became low or undetectable in 16, and 9 had hypercalciuria (ratio of urinary calcium to urinary creatinine before treatment, 0.17±0.03 [0.5±0.1]; during treatment, 0.44±0.09 [1.2±0.2]; P = 0.005). Renal calcification developed in eight of these nine subjects, and renal impairment in seven (Table 1). Renal calcification and renal impairment also developed in seven other subjects during vitamin D therapy; in three of these subjects the ratios of urinary calcium to urinary creatinine were in the high-normal range (0.19 to 0.22 [0.5 to 0.6]; normal, <0.25 [<0.7]).^29,30 Urinary measurements were not done in the remaining four subjects.

The bone mineral density of the lumbar spine, as assessed by dual-emission x-ray absorptiometry, was normal in four affected subjects (Subjects II-2 and III-1 in Family 4 and Subjects II-1 and II-2 in Family 1), but increased (2.4 to 9.0 SD above the age-adjusted normal mean values) in three others (Subjects I-2, II-5, and II-7 in Family 2) (Table 1).

Analysis of Mutations

An analysis of the DNA sequence of the entire 3234-bp coding region of the calcium-sensing–receptor gene from each proband revealed heterozygous missense mutations involving the extracellular domain of the receptor in five of the six families (Table 2). Three of these mutations predicted the substitution of leucine (Leu) for phenylalanine (Phe) at codon 128 (TTC to CTC) in Family 2 (Figure 1A, Figure 1B, and Figure 1C), the substitution of methionine (Met) for threonine (Thr) at codon 151 (ACG to ATG) in Family 3, and the substitution of serine (Ser) for phenylalanine (Phe) at codon 612 (TTT to TCT) in Family 5. These three mutations were associated with the alteration of a restriction-enzyme site (Table 2), which allowed the demonstration of the cosegregation of the mutations with hypocalcemia in these families (Figure 1A, Figure 1B, and Figure 1C).

View this table: [in this window] [in a new window]   Table 2. Mutations Identified in Five Families with Hypocalcemic Hypercalciuria.

 

View larger version (9K): [in this window] [in a new window]   Figure 1. Missense Mutation in Exon 3 of the Calcium-Sensing–Receptor Gene in Family 2. Analysis of the DNA sequence of Subject III-3 revealed the substitution of C for T at codon 128 (Panel A). Panel B shows the pedigree. Squares denote male family members, circles female family members, symbols with a slash deceased family members, symbols with a solid lower right quadrant subjects with hypocalcemia, symbols with a solid upper right quadrant subjects with renal impairment, symbols with a solid upper left quadrant subjects with nephrocalcinosis or nephrolithiasis, and symbols with a solid lower left quadrant subjects with seizures. The proband is indicated by the arrow. Panel C shows the restriction-enzyme map of the PCR product. Restriction-enzyme analysis was used to demonstrate cosegregation of this mutation with hypocalcemia. At codon 128 the wild-type sequence is TTC, encoding a phenylalanine residue, whereas the mutant sequence is CTC, encoding a leucine. This missense mutation resulted in the formation of an AluI restriction-enzyme site (A) (AG/CT). Amplification with the PCR and digestion with AluI result in one product of 356 bp from the normal (wild type) sequence but two products of 220 bp and 136 bp from the mutant sequence. The cosegregation of this Phe128Leu mutation with hypocalcemia and its heterozygosity in affected members are revealed by the analysis, and the absence of this mutation in 110 alleles from 55 unrelated subjects with normocalcemia (N1, N2, and N3 are shown) indicates that it is not a common DNA-sequence polymorphism. M denotes the DNA size markers.

 
The other two mutations predicted the substitution of lysine (Lys) for asparagine (Asn) at codon 118 (AAC to AAA) in Family 1 and the substitution of lysine (Lys) for glutamate (Glu) at codon 191 (GAG to AAG) in Family 4 (Figure 2A and Figure 2B). These two mutations were not associated with altered restriction-enzyme sites, and the technique of sequence-specific oligonucleotide hybridization²⁰ was therefore used to confirm their cosegregation with hypocalcemia. Each of the five mutations was absent in 110 alleles from 55 unrelated subjects with normal serum calcium concentrations, thereby demonstrating that it was not a neutral polymorphism occurring in more than 1 percent of the population.

View larger version (11K): [in this window] [in a new window]   Figure 2. Missense Mutation in Exon 4 of the Calcium-Sensing–Receptor Gene in Family 4. The DNA sequences from codons 189 to 192 of Subject II-2 and a normal subject are shown in Panel A. The replacement of the wild-type G with A in one allele at the first position of codon 191 results in a change from glutamate to lysine. Panel B shows the pedigree and the results of sequence-specific oligonucleotide analysis of dot blots. The symbols used for the pedigree members are as indicated in Figure 1, and the proband is indicated by the arrow. The cosegregation of the mutation (Glu191Lys) with hypocalcemia in Family 4 and its absence in 55 subjects with normocalcemia (N1, N2, and N3 are shown) were demonstrated by sequence-specific oligonucleotide hybridization analysis13 because it was not associated with an alteration of a restriction-enzyme site. Thus, the unrelated normal subjects and the unaffected Subjects II-3 and III-2 were homozygous for the wild-type sequence. However, all the affected family members had both the wild-type and the mutant sequence.

 
All five mutations found by direct DNA-sequence analysis were correctly identified by SSCP analysis. Similar analysis of 244 individual PCR products of the calcium-sensing–receptor gene did not consistently detect any other abnormal bands,²⁰ thereby indicating an absence of false positive results. Thus, SSCP analysis reliably detected all mutations, a result consistent with our experience in the detection of calcium-sensing–receptor mutations in familial benign hypercalcemia.²⁰

Functional Characterization of Mutant Calcium-Sensing Receptors

Functional expression of the wild-type calcium-sensing–receptor cDNA in HEK-293 cells, assessed in terms of the inositol phosphate response, was maximal at an extracellular calcium concentration of 5.0 mM (Figure 3). In contrast, in cells transfected with the mutant receptors (Phe128Leu, Thr151Met, and Glu191Lys), the responses were maximal at extracellular calcium concentrations between 1.5 and 2.0 mM (Figure 3). The inositol phosphate concentrations were significantly higher at one or more calcium concentrations in cells transfected with the mutant receptors than in cells transfected with the wild-type receptors. The half-maximal responses of the mutant receptors were also decreased (1.3 mM for the Phe128Leu mutation, 1.2 mM for the Thr151Met mutation, and <1.0 mM for the Glu191Lys mutation), as compared with the response of 2.9 mM for the wild-type receptor (the latter may be an underestimate, because the effects of higher extracellular calcium concentrations were not tested). These results demonstrate a leftward shift in the dose–response curve for extracellular-calcium–activated accumulation of inositol phosphate in cells transfected with mutant calcium-sensing receptors. Thus, these mutant receptors are active at lower extracellular calcium concentrations than the wild-type receptor, which is consistent with their gain of function and the hypocalcemia in affected family members.

View larger version (3K): [in this window] [in a new window]   Figure 3. Functional Expression in HEK-293 Cells of the Wild-Type Calcium-Sensing Receptor and Three Mutant Receptors — Phe128Leu, Thr151Met, and Glu191Lys — Involving a Gain of Function. The accumulation of total tritiated inositol phosphates (adjusted for the total cellular protein) in cells transfected with the wild-type receptor and each of the mutant receptors was measured after the transfected cells were incubated in medium containing various extracellular calcium concentrations. The results are the mean (±SE) values from four separate transfection experiments. The maximal inositol phosphate response in the cells transfected with the wild-type receptor occurred at a calcium concentration of 5.0 mM, whereas the maximal responses in the cells transfected with the three mutant receptors occurred at concentrations ranging from 1.5 to 2.0 mM. In each case the P value is for the comparison with the wild-type receptor.

 
Discussion

We have identified five novel mutations of the calcium-sensing–receptor gene in families with hypocalcemia and hypercalciuria, thereby providing evidence of the role of abnormal calcium receptors in the cause of this syndrome. The five missense mutations, which result in structurally important changes in amino acids, were confined to the extracellular domain of the receptor, whereas in subjects with familial benign hypercalcemia, mutations have been detected in both the extracellular and transmembrane domains of the receptor.^{17,19,20,21,22} Activating mutations of other G-protein–coupled receptors — for example, the thyrotropin or luteinizing hormone receptors, which result in follicular thyroid adenomas³¹ and familial precocious male puberty,³² respectively — involve mutations in the transmembrane domains that render these receptors constitutively hyperactive. In one family (Family 6), no DNA-sequence abnormalities were detected, a finding similar to that in a previous report of a family with autosomal dominant hypocalcemia.^10,33 These families may have a mutation within the promoter region of the receptor, or there may be genetic heterogeneity, as found in familial benign hypercalcemia.^34,35

The hypocalcemia in the families with hypocalcemia and hypercalciuria was initially attributed to hypoparathyroidism^1,7 because it was associated with serum parathyroid hormone concentrations in the low-normal range.^36,37 However, it is important to differentiate patients with familial hypocalcemic hypercalciuria from those with hypoparathyroidism,^{1,4,5,6,7,8,9} because treatment with vitamin D to correct the hypocalcemia in the former may lead to hypercalciuria, nephrocalcinosis, and renal impairment. We suggest that asymptomatic patients with familial hypocalcemic hypercalciuria should not routinely receive vitamin D; such treatment should be reserved for symptomatic patients and given to them with the aim not of restoring normocalcemia, but of maintaining a serum calcium concentration just sufficient to alleviate the symptoms.

Familial hypocalcemic hypercalciuria may be difficult to distinguish from hypoparathyroidism on the basis of measurements of serum parathyroid hormone and urinary calcium. However, the identification of mutations in the calcium-sensing–receptor gene will help in making this distinction and in facilitating early recognition of patients with hypocalcemic hypercalciuria, but the mutational diversity of the gene^{17,18,19,20,21,22} makes screening for the disorder arduous and time consuming. The use of the SSCP technique for rapid molecular genetic screening has so far allowed detection of all the mutations in the extracellular domain of the calcium-sensing receptor, suggesting that SSCP analysis should be helpful in differentiating familial hypocalcemic hypercalciuria from other causes of hypocalcemia. Thus, a finding of hypocalcemia that is not associated with an undetectable or very low serum parathyroid hormone concentration and markedly reduced urinary calcium excretion should suggest a diagnosis of hypocalcemic hypercalciuria, which can be confirmed by analysis of mutations in the calcium-sensing–receptor gene.

Studies of the expression of three of the mutant calcium-sensing receptors associated with hypocalcemia revealed a gain of function that led to a leftward shift in calcium-activated stimulation of inositol phosphate accumulation. This is consistent with activation of the calcium-sensing receptors, which may be due to either an increased affinity for calcium or a greater basal activity of the receptor.¹⁰ This, in turn, would suppress the secretion of parathyroid hormone and increase renal calcium excretion at inappropriately low levels of serum calcium, thereby leading to stable hypocalcemia; this situation is the converse of that in familial benign hypercalcemia, in which the parathyroid glands and kidney are "resistant" to the elevations in serum calcium and thereby increase the secretion of parathyroid hormone and decrease the excretion of urinary calcium, respectively, at any extracellular calcium concentration. However, the underlying mechanism responsible for the hypercalciuria and nephrocalcinosis that occur during vitamin D therapy in patients with hypocalcemic hypercalciuria is not known. It may be due to a decrease in renal calcium reabsorption due to the inhibition of parathyroid hormone secretion when the serum calcium concentration is increased by vitamin D therapy. Alternatively, it may reflect a greater degree of activation of the mutant calcium-sensing receptors in the distal tubules that are involved in regulating renal calcium reabsorption^15,38 than that which occurs in patients with hypoparathyroidism when their serum calcium concentrations are increased. This situation contrasts with that in familial benign hypercalcemia, in which the mutant calcium-sensing receptors have decreased function, so that hypercalcemia-induced increases in urinary calcium excretion are markedly reduced, even after total parathyroidectomy.^39,40 In addition, polyuria and polydipsia develop at normal serum calcium concentrations in some subjects with hypocalcemic hypercalciuria, perhaps due to increased activity of the mutant receptors in the collecting duct; this also contrasts with familial benign hypercalcemia, in which hypercalcemia does not impair urinary concentrating ability.⁴¹ Thus, the combined effects of hypercalciuria and dehydration may make subjects with hypocalcemic hypercalciuria particularly susceptible to nephrocalcinosis and renal impairment.

Supported by the Medical Research Council, United Kingdom (Drs. Pearce, Williamson, and Thakker); the Clinical Endocrinology Trust (United Kingdom) and the Samuel Leonard Simpson Fellowship of the Royal College of Physicians, London (Dr. Pearce); grants from the U.S. Public Health Service (DK41415, DK44588, DK48330, and DK46422); N.P.S. Pharmaceuticals; and the St. Giles Foundation (Drs. Kifor, Bai, and Brown).

We are indebted to Dr. F. Jewkes for referral of one family and to Dr. J.M.S. Pearce and Prof. O.M. Wrong for their critical reading of the manuscript.

Source Information

From the Medical Research Council Molecular Endocrinology Group, Royal Postgraduate Medical School, London (S.H.S.P., C.W., R.V.T.); the Endocrine–Hypertension Division, Brigham and Women's Hospital, Boston (S.H.S.P., O.K., M.B., E.M.B.); the Paediatric (M.G.C.) and Endocrine (P.K.-T.) Units, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom; the Department of Medicine, Manchester Royal Infirmary, Manchester, United Kingdom (M.D.); the Department of Medicine, University of Otago, Dunedin, New Zealand (N.L.-B.); and the Royal Children's Hospital, Melbourne, Victoria, Australia (D.M., H.P.).

Address reprint requests to Dr. Thakker at the MRC Molecular Endocrinology Group, MRC Clinical Sciences Centre, Collier Bldg., Royal Postgraduate Medical School, Hammersmith Hospital, DuCane Rd., London W12 0NN, United Kingdom.

References

1. Thakker RV. Molecular genetics of hypoparathyroidism. In: Bilezikian JP, Marcus R, Levine MA, eds. The parathyroids: basic and clinical concepts. New York: Raven press, 1994:765-79. 
2. Aaltonen J, Bjorses P, Sandkuijl L, Perheentupa J, Peltonen L. An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type 1 assigned to chromosome 21. Nat Genet 1994;8:83-87. [CrossRef][Medline]
3. Carey AH, Kelly D, Halford S, et al. Molecular genetic study of the frequency of monosomy 22q11 in DiGeorge syndrome. Am J Hum Genet 1992;51:964-970. [Medline]
4. 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;86:40-45.
5. Arnold A, Horst SA, Gardella TJ, Baba H, Levine MA, Kronenberg HM. Mutations of the signal peptide-encoding region of the preproparathyroid hormone gene in familial isolated hypoparathyroidism. J Clin Invest 1990;86:1084-1087.
6. Parkinson DB, Thakker RV. A donor splice site mutation in the parathyroid hormone gene is associated with autosomal recessive hypoparathyroidism. Nat Genet 1992;1:149-152. [CrossRef][Medline]
7. Ahn TG, Antonarakis SE, Kronenberg HM, Igarashi T, Levine MA. Familial isolated hypoparathyroidism: a molecular genetic analysis of 8 families with 23 affected persons. Medicine (Baltimore) 1986;65:73-81. [Medline]
8. Bilous RW, Murty G, Parkinson DB, et al. Autosomal dominant familial hypoparathyroidism, sensorineural deafness, and renal dysplasia. N Engl J Med 1992;327:1069-1074. [Medline]
9. Parkinson DB, Shaw NJ, Himsworth RL, Thakker RV. Parathyroid hormone gene analysis in autosomal hypoparathyroidism using an intragenic tetranucleotide (AAAT)n polymorphism. Hum Genet 1993;91:281-284. [Medline]
10. Pollak MR, Brown EM, Estep HL, et al. Autosomal dominant hypocalcaemia caused by a Ca²+-sensing receptor gene mutation. Nat Genet 1994;8:303-307. [CrossRef][Medline]
11. Finegold DN, Armitage MM, Galiani M, et al. Preliminary localization of a gene for autosomal dominant hypoparathyroidism to chromosome 3q13. Pediatr Res 1994;36:414-417. [Medline]
12. Perry YM, Finegold DN, Armitage MM, Ferrell RE. A missense mutation in the Ca-sensing receptor gene causes familial autosomal dominant hypoparathyroidism. Am J Hum Genet 1994;55:Suppl:A17-A17.abstract 
13. Brown EM, Gamba G, Riccardi D, et al. Cloning and characterization of an extracellular Ca²+-sensing receptor from bovine parathyroid. Nature 1993;366:575-580. [CrossRef][Medline]
14. Garrett JE, Capuano IV, Hammerland LG, et al. Molecular cloning and functional expression of human parathyroid calcium receptor cDNAs. J Biol Chem 1995;270:12919-12925. [Free Full Text]
15. Brown EM, Pollak M, Seidman CE, et al. Calcium-ion-sensing cell-surface receptors. N Engl J Med 1995;333:234-240. [Free Full Text]
16. Brown EM. Extracellular Ca²+ sensing, regulation of parathyroid cell function, and role of Ca²+ and other ions as extracellular (first) messengers. Physiol Rev 1991;71:371-411. [Free Full Text]
17. Pollak MR, Brown EM, Chou YH, et al. Mutations in the human Ca²+-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 1993;75:1297-1303. [CrossRef][Medline]
18. Janicic N, Pausova Z, Cole DEC, Hendy GN. Insertion of an Alu sequence in the Ca²+-sensing receptor gene in familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Am J Hum Genet 1995;56:880-886. [Medline]
19. Chou YH, Pollak MR, Brandi ML, et al. Mutations in the human Ca²+-sensing-receptor gene that cause familial hypocalcemia. Am J Hum Genet 1995;56:1075-1079. [Medline]
20. Pearce SHS, Trump D, Wooding C, et al. Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism. J Clin Invest 1995;96:2683-2692.
21. Aida K, Koishi S, Inoue M, Nakazato M, Tawata M, Onaya T. Familial hypocalciuric hypercalcemia associated with mutation in the human Ca²+-sensing receptor gene. J Clin Endocrinol Metab 1995;80:2594-2598. [Abstract]
22. Heath H III, Odelberg S, Jackson CE, et al. 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. [Abstract]
23. Thakker RV, Fraher LJ, Adami S, Karmali R, O'Riordan JLH. Circulating concentrations of 1,25-dihydroxyvitamin D₃ in patients with primary hyperparathyroidism. Bone Miner 1986;1:137-144. [Medline]
24. Thakker RV, Bouloux P, Wooding C, et al. Association of parathyroid tumors in multiple endocrine neoplasia type 1 with loss of alleles on chromosome 11. N Engl J Med 1989;321:218-224. [Abstract]
25. Kunkel TA. Rapid and efficient site-specific mutagenesis without phenotypic selection. Proc Natl Acad Sci U S A 1985;82:488-492. [Free Full Text]
26. Brown E, Enyedi P, LeBoff M, Rotberg J, Preston J, Chen C. High extracellular Ca²+ and Mg²+ stimulate accumulation of inositol phosphates in bovine parathyroid cells. FEBS Lett 1987;218:113-118. [CrossRef][Medline]
27. Kifor O, Kifor I, Brown EM. Effects of high extracellular calcium concentrations on phosphoinositide turnover and inositol phosphate metabolism in dispersed bovine parathyroid cells. J Bone Miner Res 1992;7:1327-1336. [Medline]
28. Markowitz ME, Rosen JF, Smith C, DeLuca HF. 1,25-dihydroxyvitamin D₃-treated hypoparathyroidism: 35 patient years in 10 children. J Clin Endocrinol Metab 1982;55:727-733. [Free Full Text]
29. Ghazali S, Barratt TM. Urinary excretion of calcium and magnesium in children. Arch Dis Child 1974;49:97-101. [Free Full Text]
30. Moore ES, Coe FL, McMann BJ, Favus MJ. Idiopathic hypercalciuria in children: prevalence and metabolic characteristics. J Pediatr 1978;92:906-910. [CrossRef][Medline]
31. Parma J, Duprez L, Van Sande J, et al. Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 1993;365:649-651. [CrossRef][Medline]
32. Shenker A, Laue L, Kosugi S, Merendino JJ Jr, Minegishi T, Cutler GB Jr. A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. Nature 1993;365:652-654. [CrossRef][Medline]
33. Hunter AGW, Heick H, Poznanski WJ, McLaine PN. Autosomal dominant hypoparathyroidism: a proband with concurrent nephrogenic diabetes insipidus. J Med Genet 1981;18:431-435. [Free Full Text]
34. Heath H III, Jackson CE, Otterud B, Leppert MF. Genetic linkage analysis in familial benign (hypocalciuric) hypercalcemia: evidence for locus heterogeneity. Am J Hum Genet 1993;53:193-200. [Medline]
35. Trump D, Whyte MP, Wooding C, et al. 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;96:183-187. [CrossRef][Medline]
36. Nussbaum SR, Zahradnik RJ, Lavigne RJ, et al. Highly sensitive two-site immunoradiometric assay of parathyrin, and its clinical utility in evaluating patients with hypercalcemia. Clin Chem 1987;33:1364-1367. [Free Full Text]
37. Nussbaum SR, Potts JT. Advances in immunoassays for parathyroid hormone: clinical applications to skeletal disorders of bone and mineral metabolism. In: Bilezikian JP, Marcus R, Levine MA, eds. The parathyroids: basic and clinical concepts. New York: Raven press, 1994:157-69.
38. Brown EM, Pollak M, Hebert SC. Sensing of extracellular Ca²+ by parathyroid and kidney cells: cloning and characterization of an extracellular Ca²+-sensing receptor. Am J Kidney Dis 1995;25:506-513. [Medline]
39. Attie MF, Gill JR Jr, Stock JL, et al. Urinary calcium excretion in familial hypocalciuric hypercalcemia: persistence of relative hypocalciuria after induction of hypoparathyroidism. J Clin Invest 1983;72:667-676.
40. Davies M, Adams PH, Lumb GA, Berry JL, Loveridge N. Familial hypocalciuric hypercalcaemia: evidence for continued enhanced renal tubular reabsorption of calcium following total parathyroidectomy. Acta Endocrinol Suppl (Copenh) 1984;106:499-504. 
41. Marx SJ, Attie MF, Stock JL, Spiegel AM, Levine MA. Maximal urine-concentrating ability: familial hypocalciuric hypercalcemia versus typical primary hyperparathyroidism. J Clin Endocrinol Metab 1981;52:736-740. [Free Full Text]

Abstract PDF Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

This article has been cited by other articles:

• Cole, D. E C, Yun, F. H J, Wong, B. Y L, Shuen, A. Y, Booth, R. A, Scillitani, A., Pidasheva, S., Zhou, X., Canaff, L., Hendy, G. N (2009). Calcium-sensing receptor mutations and denaturing high performance liquid chromatography. J Mol Endocrinol 42: 331-339 [Abstract] [Full Text]  
• Drueke, T. B., Ritz, E. (2009). Treatment of Secondary Hyperparathyroidism in CKD Patients with Cinacalcet and/or Vitamin D Derivatives. CJASN 4: 234-241 [Abstract] [Full Text]  
• Phillips, C. G., Harnett, M. T., Chen, W., Smith, S. M. (2008). Calcium-Sensing Receptor Activation Depresses Synaptic Transmission. J. Neurosci. 28: 12062-12070 [Abstract] [Full Text]  
• Mannstadt, M., Bertrand, G., Muresan, M., Weryha, G., Leheup, B., Pulusani, S. R., Grandchamp, B., Juppner, H., Silve, C. (2008). Dominant-Negative GCMB Mutations Cause an Autosomal Dominant Form of Hypoparathyroidism. J. Clin. Endocrinol. Metab. 93: 3568-3576 [Abstract] [Full Text]  
• Maret, A., Ding, C., Kornfield, S. L., Levine, M. A. (2008). Analysis of the GCM2 Gene in Isolated Hypoparathyroidism: A Molecular and Biochemical Study. J. Clin. Endocrinol. Metab. 93: 1426-1432 [Abstract] [Full Text]  
• Mittelman, S. D., Hendy, G. N., Fefferman, R. A., Canaff, L., Mosesova, I., Cole, D. E. C., Burkett, L., Geffner, M. E. (2006). A Hypocalcemic Child with a Novel Activating Mutation of the Calcium-Sensing Receptor Gene: Successful Treatment with Recombinant Human Parathyroid Hormone. J. Clin. Endocrinol. Metab. 91: 2474-2479 [Abstract] [Full Text]  
• Ding, Z., Kim, S., Kunapuli, S. P. (2006). Identification of a Potent Inverse Agonist at a Constitutively Active Mutant of Human P2Y12 Receptor. Mol. Pharmacol. 69: 338-345 [Abstract] [Full Text]  
• Moe, O. W., Bonny, O. (2005). Genetic Hypercalciuria. J. Am. Soc. Nephrol. 16: 729-745 [Abstract] [Full Text]  
• Hoenderop, J. G.J., Bindels, R. J.M. (2005). Epithelial Ca2+ and Mg2+ Channels in Health and Disease. J. Am. Soc. Nephrol. 16: 15-26 [Abstract] [Full Text]  
• Miyashiro, K., Kunii, I., Manna, T. D., de Menezes Filho, H. C., Damiani, D., Setian, N., Hauache, O. M. (2004). Severe Hypercalcemia in a 9-Year-Old Brazilian Girl Due to a Novel Inactivating Mutation of the Calcium-Sensing Receptor. J. Clin. Endocrinol. Metab. 89: 5936-5941 [Abstract] [Full Text]  
• Hough, T. A., Bogani, D., Cheeseman, M. T., Favor, J., Nesbit, M. A., Thakker, R. V., Lyon, M. F. (2004). Activating calcium-sensing receptor mutation in the mouse is associated with cataracts and ectopic calcification. Proc. Natl. Acad. Sci. USA 101: 13566-13571 [Abstract] [Full Text]  
• Konrad, M., Schlingmann, K. P., Gudermann, T. (2004). Insights into the molecular nature of magnesium homeostasis. Am. J. Physiol. Renal Physiol. 286: F599-F605 [Abstract] [Full Text]  
• Kifor, O., McElduff, A., LeBoff, M. S., Moore, F. D. Jr., Butters, R., Gao, P., Cantor, T. L., Kifor, I., Brown, E. M. (2004). Activating Antibodies to the Calcium-Sensing Receptor in Two Patients with Autoimmune Hypoparathyroidism. J. Clin. Endocrinol. Metab. 89: 548-556 [Abstract] [Full Text]  
• Ba, J., Brown, D., Friedman, P. A. (2003). Calcium-sensing receptor regulation of PTH-inhibitable proximal tubule phosphate transport. Am. J. Physiol. Renal Physiol. 285: F1233-F1243 [Abstract] [Full Text]  
• Hendy, G. N., Minutti, C., Canaff, L., Pidasheva, S., Yang, B., Nouhi, Z., Zimmerman, D., Wei, C., Cole, D. E. C. (2003). Recurrent Familial Hypocalcemia Due to Germline Mosaicism for an Activating Mutation of the Calcium-Sensing Receptor Gene. J. Clin. Endocrinol. Metab. 88: 3674-3681 [Abstract] [Full Text]  
• Singh, J, Moghal, N, Pearce, S H S, Cheetham, T (2003). The investigation of hypocalcaemia and rickets. Arch. Dis. Child. 88: 403-407 [Abstract] [Full Text]  
• Frick, K. K., Bushinsky, D. A. (2003). Molecular Mechanisms of Primary Hypercalciuria. J. Am. Soc. Nephrol. 14: 1082-1095 [Full Text]  
• Tan, Y. M., Cardinal, J., Franks, A. H., Mun, H.-C., Lewis, N., Harris, L. B., Prins, J. B., Conigrave, A. D. (2003). Autosomal Dominant Hypocalcemia: A Novel Activating Mutation (E604K) in the Cysteine-Rich Domain of the Calcium-Sensing Receptor. J. Clin. Endocrinol. Metab. 88: 605-610 [Abstract] [Full Text]  
• Kifor, O., Moore, F. D. Jr., Delaney, M., Garber, J., Hendy, G. N., Butters, R., Gao, P., Cantor, T. L., Kifor, I., Brown, E. M., Wysolmerski, J. (2003). A Syndrome of Hypocalciuric Hypercalcemia Caused by Autoantibodies Directed at the Calcium-Sensing Receptor. J. Clin. Endocrinol. Metab. 88: 60-72 [Abstract] [Full Text]  
• Konrad, M., Weber, S. (2003). Recent Advances in Molecular Genetics of Hereditary Magnesium-Losing Disorders. J. Am. Soc. Nephrol. 14: 249-260 [Abstract] [Full Text]  
• Vezzoli, G., Tanini, A., Ferrucci, L., Soldati, L., Bianchin, C., Franceschelli, F., Malentacchi, C., Porfirio, B., Adamo, D., Terranegra, A., Falchetti, A., Cusi, D., Bianchi, G., Brandi, M. L. (2002). Influence of Calcium-Sensing Receptor Gene on Urinary Calcium Excretion in Stone-Forming Patients. J. Am. Soc. Nephrol. 13: 2517-2523 [Abstract] [Full Text]  
• Canaff, L., Hendy, G. N. (2002). Human Calcium-sensing Receptor Gene. VITAMIN D RESPONSE ELEMENTS IN PROMOTERS P1 AND P2 CONFER TRANSCRIPTIONAL RESPONSIVENESS TO 1,25-DIHYDROXYVITAMIN D. J. Biol. Chem. 277: 30337-30350 [Abstract] [Full Text]  
• Sato, K., Hasegawa, Y., Nakae, J., Nanao, K., Takahashi, I., Tajima, T., Shinohara, N., Fujieda, K. (2002). Hydrochlorothiazide Effectively Reduces Urinary Calcium Excretion in Two Japanese Patients with Gain-of-Function Mutations of the Calcium-Sensing Receptor Gene. J. Clin. Endocrinol. Metab. 87: 3068-3073 [Abstract] [Full Text]  
• 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. (2002). A Family of Autosomal Dominant Hypocalcemia with a Positive Correlation between Serum Calcium and Magnesium: Identification of a Novel Gain of Function Mutation (Ser820Phe) in the Calcium-Sensing Receptor. J. Clin. Endocrinol. Metab. 87: 2681-2687 [Abstract] [Full Text]  
• Sherrard, D. J. (2002). Manipulating the Calcium Receptor. J. Am. Soc. Nephrol. 13: 1124-1125 [Full Text]  
• D'Souza-Li, L., Yang, B., Canaff, L., Bai, M., Hanley, D. A., Bastepe, M., Salisbury, S. R., Brown, E. M., Cole, D. E. C., Hendy, G. N. (2002). Identification and Functional Characterization of Novel Calcium-Sensing Receptor Mutations in Familial Hypocalciuric Hypercalcemia and Autosomal Dominant Hypocalcemia. J. Clin. Endocrinol. Metab. 87: 1309-1318 [Abstract] [Full Text]  
• Lerolle, N., Coulet, F., Lantz, B., Paillard, F., Houillier, P., Soubrier, F., Gattegno, B., Jeunemaitre, X., Ronco, P., Rondeau, E. (2001). No evidence for point mutations of the calcium-sensing receptor in familial idiopathic hypercalciuria. Nephrol Dial Transplant 16: 2317-2322 [Abstract] [Full Text]  
• Lienhardt, A., Bai, M., Lagarde, J.-P., Rigaud, M., Zhang, Z., Jiang, Y., Kottler, M.-L., Brown, E. M., Garabedian, M. (2001). Activating Mutations of the Calcium-Sensing Receptor: Management of Hypocalcemia. J. Clin. Endocrinol. Metab. 86: 5313-5323 [Abstract] [Full Text]  
• Dai, L.-J., Ritchie, G., Kerstan, D., Kang, H. S., Cole, D. E. C., Quamme, G. A. (2001). Magnesium Transport in the Renal Distal Convoluted Tubule. Physiol. Rev. 81: 51-84 [Abstract] [Full Text]  
• Brown, E. M., MacLeod, R. J. (2001). Extracellular Calcium Sensing and Extracellular Calcium Signaling. Physiol. Rev. 81: 239-297 [Abstract] [Full Text]  
• Marx, S. J. (2000). Hyperparathyroid and Hypoparathyroid Disorders. NEJM 343: 1863-1875 [Full Text]  
• Yamamoto, M., Akatsu, T., Nagase, T., Ogata, E. (2000). Comparison of Hypocalcemic Hypercalciuria between Patients with Idiopathic Hypoparathyroidism and Those with Gain-of-Function Mutations in the Calcium-Sensing Receptor: Is It Possible to Differentiate the Two Disorders?. J. Clin. Endocrinol. Metab. 85: 4583-4591 [Abstract] [Full Text]  
• Hauache, O. M., Hu, J., Ray, K., Xie, R., Jacobson, K. A., Spiegel, A. M. (2000). Effects of a Calcimimetic Compound and Naturally Activating Mutations on the Human Ca2+ Receptor and on Ca2+ Receptor/Metabotropic Glutamate Chimeric Receptors. Endocrinology 141: 4156-4163 [Abstract] [Full Text]  
• COLE, D. E. C., QUAMME, G. A. (2000). Inherited Disorders of Renal Magnesium Handling. J. Am. Soc. Nephrol. 11: 1937-1947 [Abstract] [Full Text]  
• YAMAMOTO, K., COX, J. P. D. T., FRIEDRICH, T., CHRISTIE, P. T., BALD, M., HOUTMAN, P. N., LAPSLEY, M. J., PATZER, L., TSIMARATOS, M., VAN'T HOFF, W. G, YAMAOKA, K., JENTSCH, T. J., THAKKER, R. V. (2000). Characterization of Renal Chloride Channel (CLCN5) Mutations in Dent's Disease. J. Am. Soc. Nephrol. 11: 1460-1468 [Abstract] [Full Text]  
• Larsson, C. (2000). Editorial: Dissecting the Genetics of Hyperparathyroidism--New Clues from an Old Friend. J. Clin. Endocrinol. Metab. 85: 1752-1754 [Full Text]  
• Carling, T., Szabo, E., Bai, M., Ridefelt, P., Westin, G., Gustavsson, P., Trivedi, S., Hellman, P., Brown, E. M., Dahl, N., Rastad, J. (2000). Familial Hypercalcemia and Hypercalciuria Caused by a Novel Mutation in the Cytoplasmic Tail of the Calcium Receptor. J. Clin. Endocrinol. Metab. 85: 2042-2047 [Abstract] [Full Text]  
• Lienhardt, A., Garabédian, M., Bai, M., Sinding, C., Zhang, Z., Lagarde, J.-P., Boulesteix, J., Rigaud, M., Brown, E. M., Kottler, M.-L. (2000). 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. 85: 1695-1702 [Abstract] [Full Text]  
• Stock, J. L., Brown, R. S., Baron, J., Coderre, J. A., Mancilla, E., De Luca, F., Ray, K., Mericq, M. V. (1999). Autosomal Dominant Hypoparathyroidism Associated with Short Stature and Premature Osteoarthritis. J. Clin. Endocrinol. Metab. 84: 3036-3040 [Abstract] [Full Text]  
• Scheinman, S. J., Guay-Woodford, L. M., Thakker, R. V., Warnock, D. G. (1999). Genetic Disorders of Renal Electrolyte Transport. NEJM 340: 1177-1187 [Full Text]  
• Bai, M., Trivedi, S., Kifor, O., Quinn, S. J., Brown, E. M. (1999). Intermolecular interactions between dimeric calcium-sensing receptor monomers are important for its normal function. Proc. Natl. Acad. Sci. USA 96: 2834-2839 [Abstract] [Full Text]  
• Okazaki, R., Chikatsu, N., Nakatsu, M., Takeuchi, Y., Ajima, M., Miki, J., Fujita, T., Arai, M., Totsuka, Y., Tanaka, K., Fukumoto, S. (1999). A Novel Activating Mutation in Calcium-Sensing Receptor Gene Associated with a Family of Autosomal Dominant Hypocalcemia. J. Clin. Endocrinol. Metab. 84: 363-366 [Abstract] [Full Text]  
• Dixon, P. H., Christie, P. T., Wooding, C., Trump, D., Grieff, M., Holm, I., Gertner, J. M., Schmidtke, J., Shah, B., Shaw, N., Smith, C., Tau, C., Schlessinger, D., Whyte, M. P., Thakker, R. V. (1998). Mutational Analysis of PHEX Gene in X-Linked Hypophosphatemia. J. Clin. Endocrinol. Metab. 83: 3615-3623 [Abstract] [Full Text]  
• Bai, M., Trivedi, S., Brown, E. M. (1998). Dimerization of the Extracellular Calcium-sensing Receptor (CaR) on the Cell Surface of CaR-transfected HEK293 Cells. J. Biol. Chem. 273: 23605-23610 [Abstract] [Full Text]  
• El-Hajj Fuleihan, G., Seifter, J., Scott, J., Brown, E. M. (1998). Calcium-Regulated Renal Calcium Handling in Healthy Men: Relationship to Sodium Handling. J. Clin. Endocrinol. Metab. 83: 2366-2372 [Abstract] [Full Text]  
• Watanabe, T., Bai, M., Lane, C. R., Matsumoto, S., Minamitani, K., Minagawa, M., Niimi, H., Brown, E. M., Yasuda, T. (1998). Familial Hypoparathyroidism: Identification of a Novel Gain of Function Mutation in Transmembrane Domain 5 of the Calcium-Sensing Receptor. J. Clin. Endocrinol. Metab. 83: 2497-2502 [Abstract] [Full Text]  
• Eubanks, P. J., Stabile, B. E. (1998). Osteitis Fibrosa Cystica With Renal Parathyroid Hormone Resistance: A Review of Pseudohypoparathyroidism With Insight Into Calcium Homeostasis. Arch Surg 133: 673-676 [Abstract] [Full Text]  
• Ott, S. M. (1998). Calcimimetics--New Drugs with the Potential To Control Hyperparathyroidism. J. Clin. Endocrinol. Metab. 83: 1080-1082 [Full Text]  
• Collins, M. T., Skarulis, M. C., Bilezikian, J. P., Silverberg, S. J., Spiegel, A. M., Marx, S. J. (1998). Treatment of Hypercalcemia Secondary to Parathyroid Carcinoma with a Novel Calcimimetic Agent. J. Clin. Endocrinol. Metab. 83: 1083-1088 [Abstract] [Full Text]  
• Ray, K., Fan, G.-F., Goldsmith, P. K., Spiegel, A. M. (1997). The Carboxyl Terminus of the Human Calcium Receptor. REQUIREMENTS FOR CELL-SURFACE EXPRESSION AND SIGNAL TRANSDUCTION. J. Biol. Chem. 272: 31355-31361 [Abstract] [Full Text]  
• Farnebo, F., Enberg, U., Grimelius, L., Backdahl, M., Schalling, M., Larsson, C., Farnebo, L.-O. (1997). Tumor-Specific Decreased Expression of Calcium Sensing Receptor Messenger Ribonucleic Acid in Sporadic Primary Hyperparathyroidism. J. Clin. Endocrinol. Metab. 82: 3481-3486 [Abstract] [Full Text]  
• De Luca, F., Ray, K., Mancilla, E. E., Fan, G.-F., Winer, K. K., Gore, P., Spiegel, A. M., Baron, J. (1997). Sporadic Hypoparathyroidism Caused by de Novo Gain- of-Function Mutations of the Ca2+-Sensing Receptor. J. Clin. Endocrinol. Metab. 82: 2710-2715 [Abstract] [Full Text]  
• Kobayashi, M., Tanaka, H., Tsuzuki, K., Tsuyuki, M., Igaki, H., Ichinose, Y., Aya, K., Nishioka, N., Seino, Y. (1997). Two Novel Missense Mutations in Calcium-Sensing Receptor Gene Associated with Neonatal Severe Hyperparathyroidism. J. Clin. Endocrinol. Metab. 82: 2716-2719 [Abstract] [Full Text]  
• Heath, D. (1996). Familial Hypocalcemia -- Not Hypoparathyroidism. NEJM 335: 1144-1145 [Full Text]  
• Quitterer, U., Hoffmann, M., Freichel, M., Lohse, M. J. (2001). Paradoxical Block of Parathormone Secretion Is Mediated by Increased Activity of Galpha Subunits. J. Biol. Chem. 276: 6763-6769 [Abstract] [Full Text]  
• Canaff, L., Petit, J.-L., Kisiel, M., Watson, P. H., Gascon-Barre, M., Hendy, G. N. (2001). Extracellular Calcium-sensing Receptor Is Expressed in Rat Hepatocytes. COUPLING TO INTRACELLULAR CALCIUM MOBILIZATION AND STIMULATION OF BILE FLOW. J. Biol. Chem. 276: 4070-4079 [Abstract] [Full Text]  
• Jensen, A. A., Spalding, T. A., Burstein, E. S., Sheppard, P. O., O'Hara, P. J., Brann, M. R., Krogsgaard-Larsen, P., Brauner-Osborne, H. (2000). Functional Importance of the Ala116-Pro136 Region in the Calcium-sensing Receptor. CONSTITUTIVE ACTIVITY AND INVERSE AGONISM IN A FAMILY C G-PROTEIN-COUPLED RECEPTOR. J. Biol. Chem. 275: 29547-29555 [Abstract] [Full Text]