* 601199

CALCIUM-SENSING RECEPTOR; CASR


Alternative titles; symbols

PARATHYROID CA(2+)-SENSING RECEPTOR 1; PCAR1


HGNC Approved Gene Symbol: CASR

Cytogenetic location: 3q13.33-q21.1     Genomic coordinates (GRCh38): 3:122,183,668-122,291,629 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
3q13.33-q21.1 {?Epilepsy idiopathic generalized, susceptibility to, 8} 612899 AD 3
Hyperparathyroidism, neonatal 239200 AD, AR 3
Hypocalcemia, autosomal dominant 601198 AD 3
Hypocalcemia, autosomal dominant, with Bartter syndrome 601198 AD 3
Hypocalciuric hypercalcemia, type I 145980 AD 3

TEXT

Description

CASR is a plasma membrane G protein-coupled receptor that is expressed in the parathyroid hormone-producing chief cells of the parathyroid gland and the cells lining the kidney tubule. By virtue of its ability to sense small changes in circulating calcium concentration and to couple this information to intracellular signaling pathways that modify PTH secretion or renal cation handling, CASR plays an essential role in maintaining mineral ion homeostasis (Hendy et al., 2000).


Cloning and Expression

Parathyroid cells respond to decreases in extracellular calcium concentration by means of the calcium-sensing receptor, a cell surface receptor that alters phosphatidylinositol turnover and intracellular calcium, ultimately effecting an increase in parathyroid hormone (PTH; 168450) secretion. The 'set point' of parathyroid cells is defined as that calcium concentration at which PTH secretion is half-maximal. Parathyroid glands from familial hypocalciuric hypercalcemia (HHC1; 145980) patients have an increase in this set point, and in vitro studies of parathyroid tissue from neonatal severe hyperparathyroidism (NSHPT; 239200) patients show a still greater increase in this set point. Calcium handling by the kidney is also abnormal in individuals with HHC, who fail to show a hypercalciuric response to hypercalcemia. Brown et al. (1993) identified a putative bovine parathyroid cell Ca(2+)-sensing receptor cDNA by expression cloning in Xenopus laevis oocytes. The cDNA encoded a predicted 120-kD polypeptide containing a large extracellular domain and 7-membrane-spanning regions characteristic of G protein-coupled cell surface receptors. In addition to parathyroid tissue, the receptor was also expressed in regions of the kidney involved in Ca(2+)-regulated Ca(2+) and Mg(2+) reabsorption.

By screening a human adenoma cDNA library with bovine Casr, Garrett et al. (1995) cloned 2 CASR variants that differed at their 5-prime and 3-prime UTRs. The 1,078-amino acid protein has a large extracellular N-terminal domain, a central region of 7 transmembrane domains, and a long intracellular C-terminal domain. It contains 11 potential N-glycosylation sites in the extracellular domain, several sites for phosphorylation in the intracellular domain and the intracellular loop, and 20 conserved cysteines. Pidasheva et al. (2005) stated that the first 19 amino acids of CASR encode a signal peptide that is predicted to direct the nascent polypeptide chain into the endoplasmic reticulum (ER). Garrett et al. (1995) also identified a rare variant that encodes a protein with a 10-amino acid insertion in the extracellular domain close to the transmembrane region. Northern blot analysis of adenomatous parathyroid detected a major CASR transcript of about 5.4 kb and minor transcripts of about 10, 4.8, and 4.2 kb.


Gene Structure

The human calcium-sensing receptor is encoded by 6 exons that span more than 20 kb (Pollak et al., 1993). Chikatsu et al. (2000) identified alternatively spliced CASR exons 1a and 1b that are noncoding and provide alternative promoters. The upstream promoter has TATA and CAAT boxes, and the downstream promoter is GC-rich.


Gene Function

By expression in Xenopus oocytes, Garrett et al. (1995) demonstrated that CASR responded to extracellular application of physiologically relevant concentrations of Ca(2+) and other CASR agonists. The rank order of potency of CASR agonists displayed by the native receptor was maintained by the expressed receptor.

Using reporter gene constructs, Chikatsu et al. (2000) demonstrated that the CASR gene contains 2 functional promoters and that expression from only the upstream promoter was reduced in parathyroid adenomas compared with normal glands.

Canaff and Hendy (2002) demonstrated that Casr mRNA levels increased in rat parathyroid, thyroid, and kidney after intraperitoneal injection of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Cultured human thyroid C-cells and kidney proximal tubule cells also increased CASR mRNA in response to 1,25(OH)2D3. In kidney cells, transcriptional activity of the P1 promoter and P2 promoter were increased 11-fold and 33-fold by 1,25(OH)2D3, respectively. In both promoters, Canaff and Hendy (2002) identified vitamin D response elements (VDREs) in which 6-bp half-sites are separated by 3 nucleotides. These VDREs conferred 1,25(OH)2D3 responsiveness to a heterologous promoter, and responsiveness was lost when the VDREs were mutated.

Kapoor et al. (2008) found CASR expression in the cerebral cortex, hypothalamus, hippocampus, whole adult brain, and fetal brain. Western blot analysis found an immunoreactive CASR protein in temporal, frontal, and parietal lobes, hippocampus, and cerebellum.

Stepanchick et al. (2010) stated that wildtype CASR assembles in the ER as a covalent disulfide-linked dimer. They identified an arginine-rich region in the proximal C terminus of human CASR (residues R890 to R898) that indirectly contributed to dimer formation by retaining nascent CASR in the ER, delaying its targeting to the plasma membrane. Patient mutations in this arginine-rich region enhanced targeting of CASR to the plasma membrane, and some mutations, including R898Q (601199.0050) enhanced calcium-stimulated ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) phosphorylation. Phosphorylation of S899, a protein kinase A (see 188830) site, negatively regulated CASR retention in the ER by facilitating transient interaction of 14-3-3 proteins (see 113508) with the arginine-rich motif.

Lee et al. (2012) showed that the murine CASR activates the NLRP3 (606416) inflammasome, mediated by increased intracellular calcium and decreased cellular cAMP. Calcium or other CASR agonists activate the NLRP3 inflammasome in the absence of exogenous ATP, whereas knockdown of CASR reduces inflammasome activation in response to known NLRP3 activators. CASR activates the NLRP3 inflammasome through phospholipase C (see 607120), which catalyzes inositol-1,4,5-trisphosphate production and thereby induces release of calcium from endoplasmic reticulum stores. The increased cytoplasmic ionized calcium promotes the assembly of inflammasome components, and intracellular calcium is required for spontaneous inflammasome activity in cells from patients with cryopyrin-associated periodic syndromes (CAPS). CASR stimulation also results in reduced intracellular cAMP, which independently activates the NLRP3 inflammasome. Cyclic AMP binds to NLRP3 directly to inhibit inflammasome assembly, and downregulation of cAMP relieves this inhibition. The binding affinity of cAMP for CAPS-associated mutant NLRP3 is substantially lower than for wildtype NLRP3, and the uncontrolled mature IL1-beta (147720) production from these patients' peripheral blood mononuclear cells is attenuated by increasing cAMP. Lee et al. (2012) concluded that, taken together, their findings indicated that ionized calcium and cAMP are 2 key molecular regulators of the NLRP3 inflammasome and have critical roles in the molecular pathogenesis of cryopyrin-associated periodic syndromes.


Mapping

By Southern analysis of hamster-human hybrid cell DNAs containing only human chromosome 3, Pollak et al. (1993) demonstrated that the human homolog of the bovine Casr gene is located on chromosome 3. Janicic et al. (1995) mapped the CASR gene to 3q13.3-q21 by fluorescence in situ hybridization. The localization to chromosome 3 was confirmed by somatic cell hybrid analysis. By interspecific backcross analysis, they found that the Casr gene segregated with D16Mit4 on mouse chromosome 16. The corresponding gene was found to be on rat chromosome 11.


Molecular Genetics

Hypocalciuric Hypercalcemia and Neonatal Severe Hyperparathyroidism

Pollak et al. (1993) demonstrated that mutations in the human Ca(2+)-sensing receptor gene cause both familial hypocalciuric hypercalcemia (HHC1; 145980) and neonatal severe hyperparathyroidism (NSHPT; 239200). They discovered 3 nonconservative missense mutations, 2 in the extracellular N-terminal domain of the receptor (601199.0002 and 601199.0003) and 1 in the final intracellular loop (601199.0001). The wildtype receptor expressed in Xenopus laevis oocytes elicited large inward currents in response to perfused polyvalent cations; in contrast, a markedly attenuated response was observed with the protein expressed by one of the mutations.

In affected members of a Japanese family with HHC, Aida et al. (1995) identified a mutation (601199.0021) in the CASR gene by PCR and SSCP. The proband was homozygous and the consanguineous parents were heterozygous for the mutation. The parents showed borderline elevations of serum calcium.

Chou et al. (1995) reported 5 novel mutations (601199.0022-601199.0025) in affected members of unrelated families with HHC or NSHPT. On the basis of their data and previous analyses, Chou et al. (1995) suggested that these disorders may be caused by a wide range of mutations.

Pearce et al. (1995) analyzed the CASR gene in 9 unrelated kindreds with a total of 39 affected members with familial benign hypercalcemia and in 3 unrelated children with sporadic NSHPT. In 6 of 9 HHC kindreds, heterozygosity for a novel mutation (1 missense and 5 missense) was found; in the 3 children with NSHPT, 2 de novo heterozygous missense mutations and 1 homozygous frameshift mutation were identified (see 601199.0006, 601199.0007, and 601199.0008). SSCP analysis was found by the authors to be a sensitive and specific mutational screening method that detected more than 85% of these CASR gene mutations. Pearce et al. (1995) noted that the identification of CASR mutations may help distinguish HHC from mild primary hyperparathyroidism, which otherwise can be clinically difficult. These results indicated that NSHPT is not exclusively the result of homozygosity for a mutation that causes familial benign hypercalcemia in the heterozygous state, but rather can be due to heterozygosity for mutations at the CASR locus. Indeed, the parents and sibs of the 3 children with NSHPT were normocalcemic. All 3 children with NSHPT presented with neonatal hypercalcemia that was associated with marked bony undermineralization. Parathyroidectomy and histologic examination revealed T-cell hyperplasia of all 4 parathyroid glands in the 3 NSHPT children, who all became hypocalcemic and required vitamin D replacement postoperatively. The clinical features of 2 of the cases had previously been reported by Dezateux et al. (1984) and Meeran et al. (1994).

Nissen et al. (2007) studied the mutation spectrum of the CASR gene in a Danish HHC population and investigated genotype-phenotype relationships regarding the different mutations. A total of 213 subjects clinically suspected to have HHC and 121 subjects enrolled as part of a family-screening program were studied. They identified 22 different mutations in 39 HHC families; 19 of these mutations were novel.

Hypocalcemia, Autosomal Dominant 1, with or without Bartter Syndrome

In addition to familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism, mutation in the CASR gene can cause an autosomal dominant form of hypocalcemia (HYPOC1; 601198). Pollak et al. (1994) hypothesized that, in contrast to familial hypocalciuric hypercalcemia in which mild hypercalcemia is caused by mutations that reduce the activity of the Ca(2+)-sensing receptor, mild hypocalcemia might be caused by a mutation that inappropriately activates the receptor at subnormal Ca(2+) levels. Such activating mutations have been described in other G protein-coupled receptors. In 1 of 2 probands with hypocalcemia, they indeed found a missense mutation (E128A; see 601199.0004) in the CASR gene, which they symbolized PCAR1. Pollak et al. (1994) discussed the effects of mutant gene dosage on the observed hypocalcemia phenotype.

Finegold et al. (1994) presented evidence for linkage of a form of autosomal dominant hypoparathyroidism to a region of 3q13 flanking marker D3S1303 and suggested that the disorder in this family may be caused by an activating mutation in the Ca(2+)-sensing receptor that suppresses PTH secretion and lowers the set point for serum calcium levels. Baron et al. (1996) identified 2 families with autosomal dominant hypoparathyroidism with heterozygous mutations in the CASR gene (601199.0009, 601199.0010). They also identified a de novo CASR missense mutation (601199.0011) in an infant with severe hypoparathyroidism. These mutations were not found in normal controls.

Lienhardt et al. (2001) identified activating CASR mutations in 8 (42%) of 19 unrelated probands with isolated hypoparathyroidism. The severity of hypocalcemic symptoms at diagnosis was independent of age, mutation type, or mode of inheritance but was related to the degree of hypocalcemia. Hypocalcemia segregated with the CASR mutation, but no phenotype-genotype relationships were identified. The authors concluded that mutational analysis of the CASR gene should be considered early in the work-up of isolated hypoparathyroidism and that the risk of nephrocalcinosis during treatment can be minimized by carefully monitoring urinary calcium excretion.

Bartter syndrome (see 241200) is a genetically heterogeneous disorder characterized by deficient renal reabsorption of sodium and chloride, and hypokalemic metabolic alkalosis with hyperreninemia and hyperaldosteronemia. Watanabe et al. (2002) described 2 hypocalcemic patients with deficient parathyroid hormone secretion, characteristics of Bartter syndrome, and activating mutations of the CASR gene (601199.0034 and 601199.0035). The authors noted that in rats it has been shown that activation of this calcium-sensing receptor by higher concentrations of extracellular calcium ions inhibits the activity of the renal outer-medullary potassium channel (KCNJ1; 600359) (see Brown and MacLeod, 2001); the KCNJ1 gene is mutated in type 2 Bartter syndrome.

In a boy with severe autosomal dominant hypocalcemia associated with Bartter syndrome-like features, who was negative for mutation in the CLCNKB gene (602023), Vargas-Poussou et al. (2002) identified a de novo missense mutation in the CASR gene (L125P; 601199.0037). Functional analysis in transfected HEK293 cells revealed that the L125P mutation was more potent than any previously reported gain-of-function mutation, with an EC50 value approximately one-third that of wildtype; Vargas-Poussou et al. (2002) proposed that mutant L125P CASR may reduce NaCl reabsorption in the cortical thick ascending limb of the loop of Henle sufficiently to result in renal loss of NaCl with secondary hyperaldosteronism and hypokalemia.

Hu et al. (2004) described monozygotic twin sisters of Italian origin with severe symptomatic hypocalcemia in whom they identified a heterozygous de novo gain-of-function missense mutation (K29E; 601199.0053). In a follow-up study, Vezzoli et al. (2006) reported that the twins developed Bartter syndrome-like features at 22 years of age, with mild hypokalemia, mild hyperreninemia and hyperaldosteronism, but no alkalosis; the authors designated the disorder 'type 5 Bartter syndrome.' Vezzoli et al. (2006) noted that all 4 CASR mutations causing hypocalcemia associated with Bartter syndrome-like features were highly activating, with EC50 values less than 1.5 mmol/L, whereas the EC50 values for other CASR mutations causing autosomal dominant hypocalcemia but not Bartter syndrome ranged between 1.5 and 3 mmol/L.

Serum Level of Calcium

Scillitani et al. (2004) evaluated the frequency of the ala986-to-ser (A986S; 601199.0040) and 2 neighboring CASR polymorphisms (R90G and Q1011E) and their association with ionized serum calcium in 377 unrelated healthy adults recruited from a blood donor clinic. Their study confirmed the association of increased serum ionized calcium with the 986S variant and also suggested that the 2 neighboring loci are also predictive.

Scillitani et al. (2007) examined the 3 SNPs in exon 7 of the CASR gene (A986S, R90G, and Q1011E) in 237 patients with sporadic primary hyperparathyroidism (see 145000) and 433 healthy controls and found significant association of the AGQ haplotype with kidney stones (p = 0.0007) within this patient population.

Idiopathic Generalized Epilepsy 8

By genomewide linkage analysis and candidate gene sequencing of a large Indian family with idiopathic generalized epilepsy (EIG8; 612899) mapping to chromosome 3q13.3-q21, Kapoor et al. (2008) identified a heterozygous mutation in the CASR gene (R898Q; 601199.0050) that segregated with the disorder in affected family members. The mutation occurred in a highly conserved residue and was not found in 504 control chromosomes. Four additional possibly pathogenic variants in the CASR gene were identified in 5 of 96 unrelated patients with juvenile myoclonic epilepsy from southern India. None of the patients had electrolyte abnormalities. Kapoor et al. (2008) postulated a role for calcium signaling abnormalities that may affect neuronal excitability in this form of epilepsy.

Reviews

Hendy et al. (2000) reviewed mutations in the CASR gene.

Purroy and Spurr (2002) reviewed the cell biology and molecular genetics of calcium sensing in bone cells.

Pidasheva et al. (2004) described a CASR mutation database. They stated that 112 naturally occurring mutations in the human CASR gene had been reported, of which 80 were unique and 32 recurrent.

Hannan and Thakker (2013) provided a review of CASR mutations and associated disorders.

Exclusion Studies

Using direct sequencing in a mutation screen of the CASR gene in 20 sporadic parathyroid adenomas, Cetani et al. (1999) found no mutations. A polymorphism that encoded a single amino acid change (ala826 to thr) was identified in 4 parathyroid adenomas and in 8 of 50 normal unrelated subjects. Loss of heterozygosity (LOH) studies performed on 3q, where the CASR gene is located, demonstrated no allelic loss.

Hannan et al. (2012) demonstrated that the CASR glu250-to lys (E250K) variant, previously believed to be a recurrent mutation found in patients with hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, or autosomal dominant hypocalcemia, is a functionally neutral polymorphism. They found that the variant was present in 0.3% of the approximately 5,400 samples in the NHLBI Exome Sequencing Project database.


Genotype/Phenotype Correlations

Pearce et al. (1996) demonstrated that 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. They studied 6 kindreds with a diagnosis of autosomal dominant hypoparathyroidism. Treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment. Mutations in the CASR gene were identified by restriction enzyme or DNA sequence analysis and were expressed in human embryonic kidney cells. Heterozygosity for 5 missense mutations was identified (see 601199.0013 through 601199.0017). All mutations were in the extracellular domain of the CASR gene and were shown to cosegregate with the disease. Analysis of the functional expression of 3 of the mutated receptors in embryonic kidney cells demonstrated negative shifts in the dose-response curves of the mutant receptor for extracellular calcium. Pearce et al. (1996) stated that this disorder is the mirror image of familial benign hypercalcemia (145980). The authors concluded that, depending on the site of the mutation in the CASR gene, it is possible to modify the response of the calcium-sensing receptor so that the serum calcium concentrations that inhibit the secretion of parathyroid hormone are either higher or lower than normal; the result, respectively, is hypercalcemia or hypocalcemia. Although the receptor is expressed in many tissues, the only obvious consequences of the abnormal receptor function in patients with these conditions have been changes in serum calcium, phosphate, and magnesium concentrations and in the renal handling of these ions.

In a large Swedish family in which 20 members had hypercalcemia, including 3 who were hypocalciuric and 7 who were hypercalciuric, Carling et al. (2000) identified heterozygosity for a missense mutation (F881L; 601199.0031) in the CASR gene, representing the first identified point mutation located within the cytoplasmic tail of the calcium-sensing receptor. The authors noted that some clinical characteristics displayed by affected individuals were atypical of familial benign hypocalciuric hypercalcemia (see 145980) and familial hyperparathyroidism (145000).

Nagase et al. (2002) reported a novel activating mutation (601199.0038) in the CASR gene in a Japanese family with autosomal dominant hypocalcemia. The proband, a 15-year-old boy, and 5 other patients in 3 generations were asymptomatic, except for the proband's grandmother, who had a history of seizures. They showed mild hypocalcemia with normal urinary calcium excretion and low normal serum PTH levels. Their serum magnesium concentrations were below normal in 3 adults and within the normal range in 3 teenagers. There was a significant positive correlation between the serum calcium and magnesium concentrations of 6 affected members. The positive correlation between serum calcium and magnesium levels observed in this family may support the concept that renal CASR acts as a magnesium sensor as well as a calcium sensor.

In 66 HHC patients Nissen et al. (2007) evaluated data on circulating calcium and PTH for 11 different mutations, representing a spectrum of clinical phenotypes ranging from calcium concentrations moderately above the upper reference limit to calcium levels more than 20% above the upper reference limit. The mean plasma PTH concentration was within the normal range in 8 of 11 studied mutations, but mild to moderately elevated in families with the mutations C582Y (601199.0007), C582F (601199.0047), and G553R (601199.0048).

Hannan et al. (2012) analyzed the CASR gene in 294 unrelated probands, of whom 228 were hypercalcemic and 66 were hypocalcemic; 71 different CASR sequence abnormalities were detected in 86 (29%) of the patients, of which 59 variants were found in the 228 hypercalcemia patients (26% detection rate) and 27 in the 66 hypocalcemia patients (41% detection rate). The majority of these and previously reported CASR mutations associated with hyper- and hypocalcemic disorders were located in the extracellular domain. Mutations identified in patients with neonatal severe hyperparathyroidism, both in this report and in previous reports, were significantly more likely to be truncating than those found in patients with hypocalciuric hypercalcemia. Hannan et al. (2012) noted that the phenotypic features of familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia in patients with CASR mutations were similar to those patients without CASR mutations, indicating that phenotypic features alone are unlikely to be useful predictors for the presence or absence of a CASR mutation. In addition, different missense mutations at 2 so-called 'toggle' codons were found to be associated with either hyper- or hypocalcemia, respectively; e.g., at codon 221, P221Q (601199.0051) and P221L (601199.0052) were associated with familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia, respectively. Similarly, at codon 173 in CASR, an L173F mutation was identified in a patient with autosomal dominant hypocalcemia, whereas an L173P mutation had previously been reported by Felderbauer et al. (2003) in a patient with hypocalciuric hypercalcemia and chronic pancreatitis (167800), who also carried a mutation in the SPINK1 gene (167790). Functional characterization of these CASR variants confirmed that P221Q and L173P caused a loss of function, whereas P221L and L173F resulted in a gain of function.

In a 68-year-old man with hypercalcemia, hypercalciuria, and recurrent nephrolithiasis, Mastromatteo et al. (2014) identified heterozygosity for a missense mutation in the CASR gene (T972M; 601199.0055). Screening of his 3 asymptomatic sons revealed 1 carrier, a 41-year-old man with an ionized calcium level at the upper limit of normal and normal PTH and urinary calcium levels. Functional evaluation demonstrated strong impairment of signaling activity of the mutant receptor compared to wildtype. The authors concluded that T972M represents an inactivating mutation of the CASR gene causing an atypical presentation of FHH with hypercalciuria.


Animal Model

To examine the role of CASR in calcium homeostasis and elucidate the mechanism by which inherited human CASR gene defects cause disease, Ho et al. (1995) created mice in which the Casr gene was disrupted by standard methods of homologous recombination. They found that the phenotype of heterozygous mice mimicked familial hypocalciuric hypercalcemia and that homozygous deficient mice exhibited the phenotype of neonatal severe hyperparathyroidism. The authors suggested that human CASR mutations cause these disorders by reducing the number of functional receptor molecules on the cell surface.

Tu et al. (2003) observed that most homozygous Casr-deficient mice died by the end of the first week after birth, and none survived for more than 6 weeks. These mice showed hypocalciuric hyperparathyroidism and rickets/osteomalacia. In order to remove the confounding effects of elevated PTH and assess the independent function of Casr in bone and cartilage, Tu et al. (2003) generated double-homozygous Casr- and Gcm2 (603716)-deficient mice. Superimposed Gcm2 deficiency rescued the lethality of Casr deficiency, and correction of the severe hyperparathyroidism prevented the rickets and osteomalacia, but it did not rescue the hypocalciuria. Analysis of the skeletons of homozygous Casr- and Gcm2-deficient mice failed to identify any essential, nonredundant role for Casr in regulating growth-plate and bone mineralization. Tu et al. (2003) concluded that low urinary calcium is mediated by the absence of Casr in the kidney, but the defective mineralization of bone and cartilage is due to metabolic abnormalities associated with hyperparathyroidism rather than the absence of skeletal Casr.

Kos et al. (2003) generated Casr-null mice on a Pth-null background. Genetic ablation of Pth was sufficient to rescue the lethal Casr-null phenotype. Double-mutant mice survived to adulthood with no obvious difference in size and appearance relative to Pth-null littermates. Histologic examination of most organs revealed no abnormalities, but female double-mutant mice had elevated bone mineral density in the spine. Double-mutant mice exhibited a wider range of values for serum calcium and renal calcium excretion than was observed in control littermates, despite the absence of circulating Pth. Kos et al. (2003) concluded that CASR is necessary for the fine regulation of serum calcium levels and renal calcium excretion independent of its effect on PTH secretion.

Hough et al. (2004) described a mouse model for an activating mutation of the calcium-sensing receptor gene, named Nuf, originally identified by having opaque flecks in the nucleus of the lens in a screen for eye mutants. Nuf mice also displayed ectopic calcification, hypocalcemia, hyperphosphatemia, cataracts, and inappropriately reduced levels of plasma parathyroid hormone. These features are similar to those observed in patients with an autosomal dominant form of hypocalcemia (601198). Inheritance studies of Nuf mice revealed that the trait was transmitted in an autosomal dominant manner, and mapping studies located the locus to mouse chromosome 16, in the vicinity of the gene for the calcium-sensing receptor Gprc2a, which is the mouse ortholog of human CASR. DNA analysis identified a leu723-to-gln (L723Q) substitution in the Gprc2a gene. Transient expression of wildtype and mutant CASRs in human embryonic kidney (HEK293) cells demonstrated that the mutation resulted in a gain of function of the receptor, which had a significantly lower EC(50) value. Ectopic calcification and cataract formation tended to be milder in the heterozygous Nuf mice, indicating that an evaluation for such abnormalities in autosomal dominant hypocalcemia patients who have activating CASR mutations is required.

Adams et al. (2006) showed that through the calcium-sensing receptor, the simple ionic mineral content of the niche may dictate the preferential localization of adult mammalian hematopoiesis in bone. Antenatal mice deficient in calcium-sensing receptor had primitive hematopoietic cells in the circulation and spleen, whereas few were found in bone marrow. Calcium-sensing receptor-null hematopoietic stem cells from fetal liver were normal in number, in proliferative and differentiative function, and in migration and homing to the bone marrow. function, and in migration and homing to the bone marrow. Yet they were highly defective in localizing anatomically to the endosteal niche, behavior that correlated with defective adhesion to the extracellular matrix protein, collagen I (see 120150). Adams et al. (2006) concluded that calcium-sensing receptor has a function in retaining hematopoietic stem cells in close physical proximity to the endosteal surface and the regulatory niche components associated with it.


ALLELIC VARIANTS ( 55 Selected Examples):

.0001 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, ARG796TRP
  
RCV000008810...

In a family (family J) with hypocalciuric hypercalcemia type I (HHC1; 145980) shown by Pollak et al. (1994) to map to 3q2, Pollak et al. (1993) found that one allele of the parathyroid Ca(2+)-sensing receptor gene had a change in codon 796 from CGG (arg) to TGG (trp). To detect the mutation, DNA derived from 2 affected members of the family were screened using RNase A protection assays.


.0002 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

HYPERPARATHYROIDISM, NEONATAL SEVERE, INCLUDED
CASR, GLU297LYS
  
RCV000008811...

Steinmann et al. (1984) described a boy who had both neonatal severe primary hyperparathyroidism (NSHPT; 239200) and alkaptonuria (203500). Both parents, who were related, had familial hypocalciuric hypercalcemia (HHC1; 145980). By the RNase A protection method, Pollak et al. (1993) detected an abnormality in exon 3 of the CASR gene, referred to as PCAR1 by them. In the male with both NSPH and alkaptonuria, Pollak et al. (1993) found that the wildtype GAG sequence of codon 298 was replaced by AAG in all clones, predicting that the normal glutamic acid residue would be replaced by a lysine residue (E298K) with concurrent loss of an MnII site. Thus, the boy was homozygous as predicted; both his parents, related as first cousins, were heterozygous.

In a 16-year-old boy of Turkish origin with familial hypocalciuric hypercalcemia and a parathyroid adenoma, Brachet et al. (2009) identified heterozygosity for a missense mutation in exon 4 of the CASR gene, which they stated was a glu297-to-lys (E297K) substitution. The proband's affected father and paternal grandmother were also heterozygous for the mutation, and the grandmother also had a parathyroid adenoma; the mutation status of the proband's affected brother and sister was not reported. The authors stated that this was the same mutation that had been identified in homozygosity in a patient with NSHPT and in heterozygosity in patients with HHC (Pollak et al., 1993; Woo et al., 2006).


.0003 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

HYPERPARATHYROIDISM, NEONATAL SEVERE, INCLUDED
CASR, ARG185GLN
  
RCV000008813...

In a large kindred (family N) with hypocalciuric hypercalcemia (HCC1; 145980) described previously by Marx et al. (1982) as family A, Pollak et al. (1993) found by RNase A protection assay that affected individuals were heterozygous for a mutation in exon 3 of the CASR gene: a G-to-A transition, predicting an arginine-to-glutamic acid change at amino acid residue 186 (ARG186GLU). Brown et al. (1995) pointed out in their legend to Figure 2 that Pollak et al. (1993) used the amino acid numbering based on the bovine receptor sequence and that the mutation was inadvertently reported as arg to glu instead of arg to gln; the correct designation of the mutation is therefore arg185 to gln or R185Q.

Bai et al. (1997) reported a de novo arg185-to-gln mutation in a female infant with neonatal hyperparathyroidism (NSHPT; 239200). The authors stated that the mutation may exert a strong dominant-negative effect on the function of the normal CASR, resulting in NHPT and unusually severe hypercalcemia. The severity of the initial clinical presentation was due to the secondary hyperparathyroidism brought on by gestation of a fetus with abnormal parathyroid set point for Ca(2+)-regulated PTH in a mother with normal calcium homeostasis.


.0004 HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, GLU128ALA
  
RCV000008815...

In a family in which at least 16 members of 4 generations had autosomal dominant hypocalcemia-1 (HYPOC1; 601198), Pollak et al. (1994) found a glu128-to-ala (E128A) mutation in the CASR gene. Xenopus oocytes expressing the mutant receptor exhibited a larger increase in inositol 1,4,5-triphosphate in response to Ca(2+) than did oocytes expressing the wildtype receptor. Parathyroid hormone levels were normal in affected individuals. Serum phosphate levels were normal or mildly elevated. Affected family members did not exhibit the usual signs and symptoms of hypocalcemia, with the exception of one who experienced intermittent overt tetany. Bone films of this patient were normal. Target organ responsiveness to PTH was also normal.


.0005 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

HYPERPARATHYROIDISM, NEONATAL SEVERE, INCLUDED
CASR, ALU INS, CODON 877
   RCV000008816...

Janicic et al. (1995) studied family members of a Nova Scotian deme in which both familial hypocalciuric hypercalcemia (HCC1; 145980) and neonatal severe hyperparathyroidism (NSHPT; 239200) were segregating and found, by PCR amplification of CASR exons, that HCC1 individuals were heterozygous and NSHPT individuals were homozygous for an abnormally long exon 7. This was due to an insertion at codon 877 of an Alu-repetitive element of the predicted-variant/human-specific-1 subfamily. The Alu insertion was in the opposite orientation to the PCAR1 gene and contained an exceptionally long poly(A) tract. Stop signals were found in all reading frames within the Alu sequence, leading to a predicted shortening of the Ca(2+)-sensing receptor protein. Janicic et al. (1995) observed that the loss of most of the C-terminal intracellular domain of the protein would dramatically impair its signal transduction capability. Identification of the specific mutation in this community will allow rapid testing of at-risk individuals. Clinical features of affected members of the kindred had previously been reported by Pratt et al. (1947), Goldbloom et al. (1972), and Cole et al. (1990). This was a common ancestry that dated back at least 11 generations to settlement of the area by New England fishing families in the mid-1700s.

Bai et al. (1997) demonstrated that insertion of the Alu-repetitive element documented by Janicic et al. (1995) resulted in the production of a nonfunctional protein 30 kD less than wildtype with decreased cell surface expression. They also showed that transcription of the Alu-containing CASR produced both a full-length product and a product that was truncated due to stalling at the poly(T) tract. Subsequent in vitro translation produced 3 truncated proteins due to termination in all reading frames as predicted.


.0006 HYPERPARATHYROIDISM, NEONATAL SEVERE

CASR, ARG227LEU
  
RCV000008818...

In a sporadic case of neonatal hyperparathyroidism (NSHPT; 239200), Pearce et al. (1995) found a heterozygous CGA-to-CTA transversion in codon 227 of exon 4, resulting in an amino acid substitution of leucine for arginine (R227L).

Wystrychowski et al. (2005) performed a functional analysis comparing the R227L and R227Q mutations (see 601199.0049).


.0007 HYPERPARATHYROIDISM, NEONATAL SEVERE

CASR, CYS582TYR
  
RCV000008819...

In a sporadic case of neonatal hyperparathyroidism (NSHPT; 239200), Pearce et al. (1995) described a heterozygous TGT-to-TAT transition in codon 582 of exon 7, resulting in a cys-to-tyr amino acid change (C582Y).


.0008 HYPERPARATHYROIDISM, NEONATAL SEVERE

CASR, 2-BP DEL/1-BP INS, CCC747TC
  
RCV000008820

In a sporadic case of neonatal hyperparathyroidism (NSHPT; 239200), Pearce et al. (1995) detected a change in codon 747 in exon 7 from CCC to TC. The mutation resulted in a frameshift with a 28-amino acid stretch of missense peptide in which a stop signal (TGA) occurred at codon 776. The mutation was associated with the loss of an HhaI site, which was used to confirm that the proband was homozygous for the mutation and that the normocalcemic parents were heterozygous. Although the parents denied consanguinity, it is likely that they share a common ancestor.


.0009 HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, GLU681HIS
  
RCV000008821

In 5 affected members of a 3-generation family (family N) with autosomal dominant hypocalcemia (HYPOC1; 601198), Baron et al. (1996) identified a heterozygous 2043G-T transversion in the CASR gene that resulted in a glu681-to-his (Q681H) substitution. Affected members of family N had low serum calcium concentrations, elevated serum phosphate concentrations, and low serum levels of parathyroid hormone; most presented in childhood with seizures or tetany.


.0010 HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, ALA116THR
  
RCV000008822...

In affected members of a family with autosomal dominant hypocalcemia-1 (HYPOC1; 601198), Baron et al. (1996) identified 2 mutations in the CASR gene: a T-to-A transversion at position 2550 that resulted in a substitution of serine for cysteine at residue 851 (C851S), and a G-to-A transition at position 346 that resulted in a substitution of threonine for alanine at residue 116 (A116T). Since the former mutation was also present in unaffected members of this family, Baron et al. (1996) suggested that the C851S mutation was a rare polymorphism.


.0011 HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, PHE806SER
  
RCV000008823...

In an infant with severe hypocalcemia (HYPOC1; 601198), Baron et al. (1996) identified a T-to-C transition at position 2415 that resulted in a substitution of serine for phenylalanine at residue 806 (F806S). No other affected members of the family were known; hence, Baron et al. (1996) referred to the disorder as sporadic severe hypoparathyroidism.


.0012 HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, THR151MET
  
RCV000008824...

In affected members of a large Norwegian family with isolated autosomal dominant hypocalcemia (HYPOC1; 601198), Lovlie et al. (1996) identified a C-to-T transition in exon 2 (cDNA position 452) of the CASR gene, predicting a thr151-to-met (T151M) substitution. A StyI restriction site created by the nucleotide substitution was used to confirm the mutation in all affected individuals, as well as to exclude it in 100 normal alleles from blood donors. The T151M mutation is located in the extracellular N-terminal domain of CASR, which belongs to the superfamily of G protein-coupled receptors. Lovlie et al. (1996) suggested that this is a gain-of-function mutation that increases the sensitivity of the receptor to calcium ion, thereby decreasing the calcium set point.

In a family with hypercalciuric hypocalcemia, Pearce et al. (1996) identified heterozygosity for the T151M mutation in the CASR gene.


.0013 HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, ASN118LYS
  
RCV000008825

Pearce et al. (1996) identified heterozygosity for an asn118-to-lys (N118K) mutation of the CASR gene in a family with hypercalciuric hypocalcemia (HYPOC1; 601198).

De Luca et al. (1997) described a patient with sporadic hypoparathyroidism who was severely symptomatic from infancy and was heterozygous for the N118K mutation affecting the N-terminal, extracellular domain of CASR. The proband's parents did not carry the mutation, indicating that the mutation, although potentially familial, arose de novo.


.0014 HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, PHE128LEU
  
RCV000008827

In a family with hypercalciuric hypocalcemia (HYPOC1; 601198), Pearce et al. (1996) identified heterozygosity for a phe128-to-leu (F128L) mutation of the CASR gene.


.0015 REMOVED FROM DATABASE


.0016 HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, GLU191LYS
  
RCV000008828

In a family with hypercalciuric hypocalcemia (HYPOC1; 601198), Pearce et al. (1996) identified heterozygosity for a glu191-to-lys mutation (E191K) of the CASR gene.


.0017 HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, PHE612SER
  
RCV000008829

In a family with hypercalciuric hypocalcemia (HYPOC1; 601198), Pearce et al. (1996) identified heterozygosity for a phe612-to-ser mutation (F612S) of the CASR gene.


.0018 MOVED TO 601199.0036


.0019 HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, LEU773ARG
  
RCV000008830

De Luca et al. (1997) described a patient with sporadic hypoparathyroidism (HYPOC1; 601198), who presented with mild symptoms at age 18 years. The patient was heterozygous for a leu773-to-arg (L773R) mutation in the CASR gene that involved the fifth transmembrane domain. The proband's parents lacked the corresponding mutation, indicating that the mutation arose de novo.


.0020 HYPERPARATHYROIDISM, NEONATAL SEVERE

CASR, GLY670GLU
  
RCV000008831

Kobayashi et al. (1997) reported a Japanese child with severe neonatal hyperparathyroidism (NSHPT; 239200). The child was a genetic compound for codon 185 (CGA to TGA/R185X; 601199.0036) and codon 670 (GGG-to-GAG/G670E) mutations located in exons 4 and 7, respectively. The R185X mutation was also present in samples from the proband's unaffected father and paternal grandmother. The G670E mutation was also found in the sample from the proband's unaffected mother of Philippine origin.


.0021 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, PRO39ALA
  
RCV000008832

In a Japanese family with hypocalciuric hypercalcemia (HHC1; 145980), Aida et al. (1995) identified a mutation in the CASR gene by PCR and SSCP. Nucleotide sequencing showed a G-to-C transversion at nucleotide 118 that resulted in a pro40-to-ala (P40A) amino acid substitution. The proband was homozygous and the consanguineous parents were heterozygous for the mutation. The parents showed borderline elevations of serum calcium. Aida et al. (1995) stated that they designated this mutation 'P40A' based on numbering according to bovine cDNA.


.0022 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, ARG228GLN
  
RCV000008833...

In studies of DNA from 22 unrelated families or individuals with definite or possible familial hypocalciuric hypercalcemia (HHC1; 145980) or neonatal severe hyperparathyroidism (NSHPT; 239200), Chou et al. (1995) found 5 novel mutations in the CASR gene, including an arg228-to-gln (R228Q) substitution. All 5 mutations resulted in a nonconservative amino acid alteration and all were predicted to be in the large extracellular domain of the Ca(2+)-sensing receptor. In the case of the probands from 3 other families with HHC linked to 3q, no mutations were identified in CASR.


.0023 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, THR139MET
  
RCV000008834...

In studies of DNA from 22 unrelated families or individuals with definite or possible familial hypocalciuric hypercalcemia (HHC1; 145980) or neonatal severe hyperparathyroidism (NSHPT; 239200), Chou et al. (1995) found 5 novel mutations in the CASR gene, including a thr139-to-met (T139M) substitution. All 5 mutations resulted in a nonconservative amino acid alteration and all were predicted to be in the large extracellular domain of the Ca(2+)-sensing receptor.


.0024 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, GLY144GLU
  
RCV000008835...

In studies of DNA from 22 unrelated families or individuals with definite or possible familial hypocalciuric hypercalcemia (HHC1; 145980) or neonatal severe hyperparathyroidism (NSHPT; 239200), Chou et al. (1995) found 5 novel mutations in the CASR gene, including a gly144-to-glu (G144E) substitution. All 5 mutations resulted in a nonconservative amino acid alteration and all were predicted to be in the large extracellular domain of the Ca(2+)-sensing receptor.


.0025 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, ARG63MET
  
RCV000008836

In studies of DNA from 22 unrelated families or individuals with definite or possible familial hypocalciuric hypercalcemia (HHC1; 145980) or neonatal severe hyperparathyroidism (NSHPT; 239200), Chou et al. (1995) found 5 novel mutations in the CASR gene, including an arg63-to-met (R63M) substitution. All 5 mutations resulted in a nonconservative amino acid alteration and all were predicted to be in the large extracellular domain of the Ca(2+)-sensing receptor.


.0026 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, ARG67CYS
  
RCV000008837...

For discussion of the arg67-to-cys (R67C) mutation in the CASR gene that was found in compound heterozygous state in studies of DNA from 22 unrelated families or individuals with definite or possible familial hypocalciuric hypercalcemia (HHC1; 145980) by Chou et al. (1995), see 601199.0022.


.0027 HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, PHE788CYS
  
RCV000008838...

In a Japanese family with severe familial hypocalcemia (HYPOC1; 601198), Watanabe et al. (1998) reported a heterozygous missense mutation encoding a phe788-to-cys (F788C) substitution in the fifth transmembrane domain of the CASR gene product. The mutation was absent in DNA from 50 control subjects. The proband presented with a seizure at 6 days of age. Her older brother and mother, who had also experienced seizures and tetany, respectively, likewise had hypoparathyroidism. Some patients in the family did not experience seizures despite their severe hypocalcemia. The authors concluded that the gain-of-function F788C mutation causes severe hypoparathyroidism by rendering the receptor more sensitive than normal to activation by cytosolic calcium.


.0028 HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, LYS47ASN
  
RCV000008839

Okazaki et al. (1999) reported a 41-year-old male who had asymptomatic hypocalcemia (HYPOC1; 601198) with a history of recurrent nephrolithiasis. His father had asymptomatic hypocalcemia, but his mother was normocalcemic. PCR-SSCP and DNA sequencing revealed that both the proband and his father were heterozygous for a CASR mutation that was predicted to encode a lysine-to-asparagine substitution at codon 47 (K47N), which is in the CASR extracellular domain. The authors concluded that the N-terminal portion of CASR is important in extracellular calcium sensing.


.0029 HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, LEU616VAL
  
RCV000008840

Stock et al. (1999) evaluated a 3-generation family segregating autosomal dominant hypocalcemia (HYPOC1; 601198), short stature, and premature osteoarthritis. A 74-year-old female (generation I) presented with hypoparathyroidism, a movement disorder secondary to ectopic calcification of the cerebellum and basal ganglia, and a history of knee and hip replacements for osteoarthritis. Two members of generation II and 1 member of generation III were also documented with hypoparathyroidism, short stature, and premature osteoarthritis evident as early as 11 years of age. Sequencing of PCR-amplified genomic DNA revealed a C-to-G transversion at nucleotide 1846 of the CASR gene, resulting in a leu616-to-val (L616V) substitution in the first transmembrane domain. The mutation cosegregated with the disorder; however, this amino acid sequence change did not affect the total accumulation of inositol phosphates as a function of extracellular calcium concentrations in transfected HEK293 cells.


.0030 HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, 543-BP DEL, NT2682
  
RCV000008841

Lienhardt et al. (2000) reported a 3-generation family with autosomal dominant hypocalcemia (HYPOC1; 601198) caused by a large in-frame deletion of 181 amino acids in the C-terminal tail of CASR from ser895 to val1075. The affected grandfather was homozygous for the deletion but was not more severely affected than the heterozygous affected individuals. Functional properties of mutant and wildtype CASRs were studied in transiently transfected fura-2-loaded HEK293 cells. The mutant CASR exhibited a gain of function, but there was no difference between cells transfected with mutant cDNA alone or cotransfected with mutant and wildtype cDNAs, consistent with the similar phenotypes of heterozygous and homozygous family members. The authors concluded that this activating deletion may exert a dominant-positive effect on the wildtype CASR. The cell surface expression of the mutant CASR was greater than that of the wildtype CASR, potentially contributing to its gain of function.


.0031 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, PHE881LEU
  
RCV000008842...

In a large Swedish family in which 20 members had hypercalcemia, including 3 who were hypocalciuric and 7 who were hypercalciuric (HHC1; 145980), Carling et al. (2000) identified heterozygosity for a c.2641T-C transition in exon 7 of the CASR gene, resulting in a phe881-to-leu (F881L) substitution within the cytoplasmic tail of the calcium-sensing receptor. The mutation segregated fully with disease in the family. A construct of the mutant receptor expressed in HEK293 cells demonstrated a right-shifted dose-response relationship between the extracellular and intracellular calcium concentrations, consistent with an inactivating mutation.


.0032 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

HYPERPARATHYROIDISM, NEONATAL SEVERE, INCLUDED
CASR, ARG648TER
  
RCV000008843...

Jap et al. (2001) studied a 79-year-old male with hypocalciuric hypercalcemia (HHC1; 145980) without sibs or children. DNA sequence analysis of the CASR gene showed that the proband was heterozygous for a CGA-to-TGA transition in exon 7 of the CASR gene that encoded an arg648-to-ter (R648X) mutation. This mutation, located in the C terminus of the first intracellular loop of the calcium-sensing receptor, predicts a markedly truncated protein. The mutation was not found in a control group of 50 normal Chinese subjects in Taiwan.

Ward et al. (2004) found this mutation in compound heterozygosity with a G94X truncation of the receptor (601199.0042) in an Australian infant with neonatal severe hyperparathyroidism (NSHPT; 239200). Confocal microscopy demonstrated that the R648X receptor was present in the cytoplasm and also associated with the cell membrane. Functional assays in which R648X and wildtype receptor were cotransfected into HEK293 cells demonstrated a reduction in wildtype Ca(2+) responsiveness by the R648X receptor, even at physiologic Ca(2+) levels, thus simulating familial hypocalciuric hypercalcemia (145980) in relatives of the infant who were heterozygous for the R648X mutation. The R648X receptor alone was nonresponsive to Ca(2+).


.0033 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, IVS2AS, G-T, -1
  
RCV000008845...

In 2 affected individuals from a large kindred in which some members had familial hypocalciuric hypercalcemia (HHC1; 145980) and others had neonatal severe hyperparathyroidism (NSHPT; 239200), previously studied by Philips (1948), Hillman et al. (1964), and Marx et al. (1985), D'Souza-Li et al. (2001) identified heterozygosity for a G-to-T transversion in the last nucleotide of intron 2. Both affected individuals had HHC. Defects in mRNA splicing were studied by illegitimate transcription of the CASR gene in lymphoblastoid cells from an HHC1-affected individual. The mutation resulted predominantly in exon 3 skipping, causing a shift in the exon 4 reading frame and introducing a premature stop codon that led to a predicted truncated protein of 153 amino acids. D'Souza-Li et al. (2001) stated that this was the first description of a splice site mutation in the CASR gene. The 2 brothers with NSHPT in this branch of the family and their consanguineous parents with HCC were not studied, but D'Souza-Li et al. (2001) noted that previous reports had indicated that individuals who inherit 2 inactive copies of the CASR gene may have NSHPT.


.0034 HYPOCALCEMIA, AUTOSOMAL DOMINANT 1, WITH BARTTER SYNDROME

HYPOCALCEMIA, AUTOSOMAL DOMINANT 1, INCLUDED
CASR, ALA843GLU
  
RCV000008847...

Watanabe et al. (2002) reported the case of a 19-year-old man who showed tetany soon after birth and had striking autosomal dominant hypocalcemia, for which he was treated with vitamin D3. Because of nephrocalcinosis, his renal function gradually deteriorated. He also had clinical features of Bartter syndrome (see 601198): hypomagnesemia, hypokalemia with metabolic alkalosis, hyperreninemia, and hyperaldosteronemia. Direct sequencing of all coding exons of the CASR gene demonstrated a heterozygous substitution of adenine (GAA) for cytosine (GCA) at codon 843, resulting in an ala843-to-glu (A843E) substitution. Watanabe et al. (2002) noted that in rats it had been shown that activation of this calcium-sensing receptor by higher concentrations of extracellular calcium ions inhibits the activity of the renal outer-medullary potassium channel (KCNJ1; 600359) (see Brown and MacLeod, 2001); the KCNJ1 gene is mutated in type 2 Bartter syndrome.

Sato et al. (2002) found this mutation in a Japanese patient with hypercalciuric hypocalcemia (HYPOC1; 601198).


.0035 HYPOCALCEMIA, AUTOSOMAL DOMINANT 1, WITH BARTTER SYNDROME

CASR, CYS141TRP
  
RCV000008849

Watanabe et al. (2002) reported the case of a 26-year-old woman who showed tetany soon after birth and had autosomal dominant hypocalcemia, for which she was treated with vitamin D metabolites and calcium, as well as clinical features of Bartter syndrome (see 601198), including nephrocalcinosis, hypomagnesemia, hypokalemia with metabolic alkalosis, hyperreninemia, and hyperaldosteronemia. Direct sequencing of all coding exons of the CASR gene revealed that the patient had a heterozygous substitution of guanine (TGG) for cytosine (TGC) at codon 131, which resulted in a cys131-to-trp (C131W) substitution.


.0036 HYPERPARATHYROIDISM, NEONATAL SEVERE

CASR, ARG185TER
  
RCV000008850...

For discussion of the arg185-to-ter (R185X) mutation in the CASR gene that was found in compound heterozygous state in a child with severe neonatal hyperparathyroidism (NSHPT; 239200) by Kobayashi et al. (1997), see 601199.0020.


.0037 HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

HYPOCALCEMIA, AUTOSOMAL DOMINANT 1, WITH BARTTER SYNDROME, INCLUDED
CASR, LEU125PRO
  
RCV000008851...

In a Japanese patient with hypercalciuric hypocalcemia (HYPOC1; 601198), Sato et al. (2002) found a heterozygous leu125-to-pro (L125P) mutation in the N-terminal extracellular domain of the calcium-sensing receptor.

In a boy with hypocalcemia who also displayed features of Bartter syndrome (see 601198), with a decrease in the distal tubular fractional chloride reabsorption rate and negative NaCl balance, secondary hyperaldosteronism, and hypokalemia, Vargas-Poussou et al. (2002) identified heterozygosity for a de novo c.374T-C transition in exon 3 of the CASR gene, resulting in the L125P substitution at a highly conserved residue in the extracellular domain, in a region involved in maintaining the inactive conformation of the calcium-sensing receptor. The mutation was not present in his unaffected parents or sister or in 50 unrelated controls. Functional analysis in transfected HEK293 cells revealed that the L125P mutation was more potent than any previously reported gain-of-function mutation, with an EC50 value approximately one-third that of wildtype; Vargas-Poussou et al. (2002) proposed that mutant L125P CASR may reduce NaCl reabsorption in the cortical thick ascending limb sufficiently to result in renal loss of NaCl with secondary hyperaldosteronism and hypokalemia.


.0038 HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, SER820PHE
  
RCV000008852

Nagase et al. (2002) reported a novel activating mutation in the CASR gene in a Japanese family with autosomal dominant hypocalcemia (HYPOC1; 601198). The proband, a 15-year-old boy, and 5 other patients in 3 generations were asymptomatic, except for the proband's grandmother who had a history of seizures. Nucleotide sequencing revealed that the proband had a known polymorphism and a novel heterozygous mutation substituting phenylalanine for serine at codon 820 (S820F) in the sixth transmembrane helix of the CASR gene. In other family members, the S820F mutation cosegregated with hypocalcemia. The mutation was not detected in 50 control subjects. The known polymorphism was observed in 8 of 9 family members with or without hypocalcemia and in 36 of 50 controls.


.0039 HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, PHE788LEU
  
RCV000008853

In 2 sibs with hypocalcemia (HYPOC1; 601198), Hendy et al. (2003) found heterozygosity for a T-to-C transition in exon 7 of the CASR gene, resulting in a phe788-to-leu (F788L) substitution in the fifth transmembrane domain of the protein. Both parents and the third sib were clinically unaffected and were found to be genotypically normal by direct sequencing of their leukocyte exon 7 PCR amplicons. However, the mother was mosaic for the mutation, determined by sequence analysis of multiple subclones as well as by denaturing HPLC of the CASR exon 7 leukocyte PCR product. Transient transfection analyses of wildtype and mutant CASR proteins in HEK293 cells showed mutant CASR expressed at a similar level as the wildtype. The F788L mutant induced a significant shift to the left relative to the wildtype CASR protein in the MAPK (see 602448) response to increasing extracellular calcium concentrations. The authors stated that this was the first report of mosaicism for an activating CASR mutation and suggested that care should be exercised in counseling for risks of recurrence in a situation where a de novo mutation appears likely.


.0040 CASR POLYMORPHISM

CASR, ALA986SER
  
RCV000008854...

In female North American cohorts, Cole et al. (1999) and Cole et al. (2001) described an association between serum ionized calcium and a common polymorphism, ala986 to ser (A986S), in the cytoplasmic tail of the calcium-sensing receptor. Scillitani et al. (2004) confirmed the association in 377 healthy Italian Caucasian adults (184 men and 193 women). Their results also suggested that 2 neighboring exon 7 polymorphisms were predictive as well. Relative frequency for the minor 986S allele was 24%. Subjects with the AA genotype had significantly lower serum ionized calcium (P = 0.0001) than subjects with 1 or 2 S alleles.


.0041 HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, GLU604LYS
  
RCV000008855...

In a 3-generation family with autosomal dominant hypocalcemia (HYPOC1; 601198), Tan et al. (2003) reported a heterozygous single-base transition in the CASR gene, G2182A in exon 7, causing a novel activating mutation, glu604 to lys (E604K), in the calcium-sensing receptor. Whereas all affected individuals exhibited marked hypocalcemia, some cases with untreated hypocalcemia exhibited seizures in infancy, and others were largely asymptomatic from birth into adulthood. The missense mutation E604K, which affects an amino acid residue in the C terminus of the cysteine-rich domain of the extracellular head, cosegregated with hypocalcemia in all 7 individuals for whom DNA was available. The mutation was assessed in HEK293 cells transiently transfected with cDNA corresponding to either wildtype CASR or CASR carrying the E604K mutation derived by site-directed mutagenesis. There was a significant leftward shift in the concentration response curves for the effects of extracellular Ca(2+) on both intracellular Ca(2+) mobilization and MAPK (see 602448) activity. The C terminus of the cysteine-rich domain of the extracellular head may normally act to suppress receptor activity in the presence of low extracellular Ca(2+) concentrations.


.0042 HYPERPARATHYROIDISM, NEONATAL SEVERE

CASR, GLY94TER
  
RCV000008856

In a 5-month-old Australian infant with neonatal severe hyperparathyroidism (NSHPT; 239200) characterized by moderately severe hypercalcemia and very high PTH levels, coupled with evidence of hyperparathyroidism and effects on brain development not previously demonstrated, Ward et al. (2004) detected point mutations on separate alleles of the CASR, one a novel G-to-T transversion in exon 2 leading to a premature termination at gly94 (G94X), and the other an R648X mutation (601199.0032). The G94X mutation occurred early in the extracellular ligand-binding domain, and the mutated receptor was predicted to be unable to anchor to the membrane and to lack signaling capacity. Confocal microscopy demonstrated cytoplasmic localization of the G94X receptor. The G94X truncated receptor could not be detected by Western blot analysis. The authors stated that this infant represented the first report of complete functional deletion of the human calcium-sensing receptor.


.0043 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, ARG465GLN
  
RCV000008857...

In a 52-year-old woman with familial benign hypocalciuric hypercalcemia (HHC1; 145980), Leech et al. (2006) identified a heterozygous 1394G-A transition in exon 5 of the CASR gene, resulting in an arg465-to-gln (R465Q) substitution. They also identified heterozygosity for the A986S polymorphism (601199.0040). The proband's brother had the identical genotype. As the parents were not available for genetic analysis, it could not be determined if the mutation and polymorphism were on the same or different alleles. Receptors with either of these mutations localized to the plasma membrane of transfected HEK293 cells, and Western blot analysis showed that the quantity of the R465Q mutant receptor was higher than that of the wildtype receptor. Dose-response curves showed the R465Q mutation significantly reduced the sensitivity of the receptor to extracellular Ca(2+) concentrations. The A986S polymorphism seemed to mildly increase calcium sensitivity.


.0044 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, LEU13PRO
  
RCV000008858...

In a 9-year-old Brazilian girl with hypocalciuric hypercalcemia (HHC1; 145980), Miyashiro et al. (2004) detected homozygosity for a T-to-C transition at nucleotide 38 in exon 2 of the CASR gene, resulting in a leu13-to-pro (L13P) substitution. The patient was admitted with a 6-month history of headaches and emesis and was found to be severely hypercalcemic. Functional characterization of the mutant receptor showed a dose-response curve shifted to the right relative to that of wildtype. The proband's consanguineous parents, who had mild asymptomatic hypercalcemia, carried the same mutation in heterozygous state. Miyashiro et al. (2004) concluded that patients with homozygous inactivation of the CASR gene may present with severe hypercalcemia in late phases of life and, based on their report and those of others (Aida et al., 1995; Chikatsu et al., 1999), suggested that homozygous mutation found in the very beginning N-terminal portion of the CASR may be associated with this phenotype.

Pidasheva et al. (2005) showed that L11S and L13P mutants, which affect the N-terminal signal peptide, demonstrated reduced intracellular and plasma membrane expression and signaling to the MAPK pathway in response to extracellular calcium, relative to wildtype CASR. Both mutant CASR RNAs translated into protein normally. In cotranslational processing assays, wildtype CASR was targeted to microsomal vesicles, translocated into the vesicular lumen, and underwent core N-glycosylation. In contrast, the L11S and L13P mutants failed to be inserted in the microsomes and did not undergo proper glycosylation. Pidasheva et al. (2005) concluded that both L11S and L13P mutants are markedly impaired with respect to cotranslational processing, accounting for the observed parathyroid dysfunction.


.0045 HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, LEU727GLN
  
RCV000008859

In an infant presenting with hypocalcemia (HYPOC1; 601198) at 3 weeks of age, Mittelman et al. (2006) identified heterozygosity for a de novo leu727-to-gln (L727Q) mutation on the border between transmembrane helix-4 and the intracellular loop-2 of CASR. When transiently expressed in a human embryonic kidney 293 cell line, the mutant receptor demonstrated a significant leftward shift in the extracellular calcium/intracellular signaling dose-response curve versus that for the wildtype receptor. During treatment with PTH(1-34), the patient had no further serious hypocalcemic episodes, and his urinary calcium excretion declined remarkably.


.0046 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, PHE180CYS
  
RCV000008860

Zajickova et al. (2007) studied a kindred with familial hypocalciuric hypercalcemia (145980) in which the proband, a 34-year-old male, was initially diagnosed with primary hyperparathyroidism due to frankly elevated serum PTH levels. A heterozygous TTC-to-TGC transversion in exon 4 of the CASR gene, resulting in a phe180-to-cys (F180C) substitution 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 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 and the serum calcium level remained at a constant and moderately elevated level.


.0047 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, CYS582PHE
  
RCV000008861

In 6 patients from the same family with hypocalciuric hypercalcemia (145980), Nissen et al. (2007) identified a G-to-T transversion at nucleotide 1745 in exon 7 of the CASR gene that resulted in a substitution of phe for cys at codon 582 (C582F). Another mutation affecting this codon has been found (601199.0007). A similar biochemical phenotype was found for both mutations at cys582, with mild to moderate elevation of plasma PTH.


.0048 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, GLY553ARG
  
RCV000008862...

In 3 patients from 2 families with hypocalciuric hypercalcemia (145980), Nissen et al. (2007) identified a G-to-A transition at nucleotide 1657 in exon 6 of the CASR gene, resulting in a gly553-to-arg amino acid substitution (G553R). Mean plasma PTH was mild to moderately elevated in mutation carriers.


.0049 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, ARG227GLN
  
RCV000008833...

In 4 members of a Polish family with hypocalciuric hypercalcemia (145980), Wystrychowski et al. (2005) found a heterozygous G-to-A transition in exon 4 of the CASR gene that resulted in an arg227-to-gln amino acid substitution (R227Q). The proband presented in a typical fashion with slightly elevated serum calcium and magnesium and serum PTH values within the normal range, although inappropriately elevated given the prevailing serum calcium concentration. Parathyroidectomy failed to normalize the hypercalcemia. Noting that a de novo heterozygous R227L mutation had previously been identified in a case of neonatal hyperparathyroidism (601199.0006), Wystrychowski et al. (2005) performed a functional analysis by transiently transfecting wildtype and mutant (R227Q, R227L) CaSRs in HEK293 cells. Both mutant receptors were expressed at a similar level to that of the wildtype. Although both mutants were impaired in their MAPK responses to increasing extracellular calcium concentrations, this was more marked for R227L (EC50 = 9.7 mM) than R227Q (EC50 = 7.9 mM) relative to wildtype (EC50 = 3.7 mM). When cotransfected with wildtype CaSR to mimic the heterozygous state, the curves for both R227Q and R227L were right-shifted intermediate to the curves for wildtype and the respective mutant. Wystrychowski et al. (2005) concluded that this differential responsiveness may account, in part, for the markedly different clinical presentation of the R227Q mutation, familial benign hypercalcemia, versus the neonatal hyperparathyroidism of the R227L mutation.


.0050 EPILEPSY, IDIOPATHIC GENERALIZED, SUSCEPTIBILITY TO, 8 (1 family)

CASR, ARG898GLN
  
RCV000008864...

In affected members of a large 3-generation Indian family (family 1) with idiopathic generalized epilepsy (EIG8; 612899), Kapoor et al. (2008) identified a heterozygous c.2693G-A transition (c.2693G-A, NM_000388) in the CASR gene, resulting in an arg898-to-gln (R898Q) substitution at a highly conserved residue located close to 3 potential phosphorylation sites. The mutation segregated with the disorder in the family and was not detected in 504 control chromosomes. Seizure types in this family were variable, but included myoclonic seizures, absence seizures, febrile seizures, complex partial seizures, and generalized tonic-clonic seizures. None of the patients had electrolyte abnormalities. Four additional possibly pathogenic variants in the CASR gene were identified in 5 of 96 unrelated patients with juvenile myoclonic epilepsy from southern India.

Stepanchick et al. (2010) found that the R898Q mutation resulted in extracellular calcium-stimulated ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) phosphorylation levels equal to or greater than those of wildtype CASR, suggesting that this mutation induces a gain-of-function phenotype.


.0051 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, PRO221GLN
  
RCV000054482...

In a proband with hypocalciuric hypercalcemia (145980), Hannan et al. (2012) identified heterozygosity for a c.662C-A transversion in exon 4 of the CASR gene, resulting in a pro221-to-gln (P221Q) substitution in the VTFD portion of the extracellular domain. Homology modeling predicted that the side chain of the mutant glutamine residue would extend across the entrance of calcium binding site (CaBS)-1, impairing ligand entry and leading to a loss of CASR function. Functional analysis in transfected HEK293 cells confirmed that the P221Q mutant causes a loss of CASR function compared to wildtype.


.0052 HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, PRO221LEU
  
RCV000054481...

In a proband with hypocalcemia (HYPOC1; 601198), Hannan et al. (2012) identified heterozygosity for a c.662C-T transition in exon 4 of the CASR gene, resulting in a pro221-to-leu (P221L) substitution in the VTFD portion of the extracellular domain. Homology modeling predicted that the L221 mutant would enhance Ca(2+) entry into calcium binding site (CaBS)-1 due to the substitution of the rigid side chain of the wildtype proline residue at the entrance to the VFTD cleft with the more flexible leucine side chain. Functional analysis in transfected HEK293 cells confirmed that the P221L mutant causes a gain of CASR function compared to wildtype.


.0053 HYPOCALCEMIA, AUTOSOMAL DOMINANT 1, WITH BARTTER SYNDROME

CASR, LYS29GLU
  
RCV000054483

In monozygotic twin sisters of Italian origin who presented with severe hypocalcemia in the neonatal period (601198), Hu et al. (2004) identified heterozygosity for a de novo c.85A-G transition in exon 2 of the CASR gene, resulting in a lys29-to-glu (K29E) substitution in the extracellular VFT domain. The mutation was not present in their unaffected parents or older sister. In transfected HEK293 cells, the mutant K29E calcium-sensing receptor showed a marked increase in Ca(2+) sensitivity, including when it was cotransfected with wildtype CASR cDNA, consistent with a dominant effect. In a follow-up study, Vezzoli et al. (2006) reported that the twins developed Bartter syndrome (see 601198)-like features at age 22 years, with mild hypokalemia, mild hyperreninemia and hyperaldosteronism, but no alkalosis.


.0054 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, ARG886PRO
  
RCV000443461...

In a family (kindred 5780) with hypercalcemia, in which the proband and 1 affected son were hypercalciuric whereas a second affected son and 4 hypercalcemic grandchildren were hypocalciuric (HHC1; 145980), Simonds et al. (2002) identified heterozygosity for an arg866-to-pro (R866P) substitution in the CASR gene that was not found in 3 unaffected family members. The authors noted that findings typical of HHC in this family included hypercalcemia before 10 years of age, relative hypocalciuria, hypermagnesemia, and persistent postoperative hyperparathyroidism in the 2 patients who underwent subtotal parathyroidectomy. However, features atypical of HHC were also observed, including hypercalciuria in 2 affected family members as well as an intact PTH level of 179 pg/mL in the proband, more than 2 times above the value reported to discriminate between HHC and forms of hyperparathyroidism.


.0055 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, THR972MET
  
RCV000288087...

In a 68-year-old man with hypercalcemia, inappropriately normal PTH levels, hypercalciuria, and recurrent nephrolithiasis (HHC1; 145980), Mastromatteo et al. (2014) identified heterozygosity for a c.2915C-T transition in exon 7 of the CASR gene, resulting in a thr972-to-met (T972M) substitution in the cytoplasmic tail. Screening of the proband's 3 asymptomatic sons revealed 1 carrier, a 41-year-old man with an ionized calcium level at the upper limit of normal and normal PTH and urinary calcium levels. Functional evaluation demonstrated strong impairment of signaling activity of the mutant receptor compared to wildtype, even at higher Ca(2+) concentrations. The authors concluded that T972M represents an inactivating mutation of the CASR gene causing an atypical presentation of familial benign hypercalcemia with hypercalciuria. The variant was not present in the public CaSR or 1000 Genomes Project databases.


See Also:

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  56. Pearce, S. H. S., Williamson, C., Kifor, O., Bai, M., Coulthard, M. G., Davies, M., Lewis-Barned, N., McCredie, D., Powell, H., Kendall-Taylor, P., Brown, E. M., Thakker, R. V. A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor. New Eng. J. Med. 335: 1115-1122, 1996. [PubMed: 8813042, related citations] [Full Text]

  57. Philips, R. N. Primary diffuse parathyroid hyperplasia in an infant of four months. Pediatrics 2: 428-434, 1948. [PubMed: 18887540, related citations]

  58. Pidasheva, S., Canaff, L., Simonds, W. F., Marx, S. J., Hendy, G. N. Impaired cotranslational processing of the calcium-sensing receptor due to signal peptide missense mutations in familial hypocalciuric hypercalcemia. Hum. Molec. Genet. 14: 1679-1690, 2005. [PubMed: 15879434, related citations] [Full Text]

  59. Pidasheva, S., D'Souza-Li, L., Canaff, L., Cole, D. E. C., Hendy, G. N. CASRdb: calcium-sensing receptor locus-specific database for mutations causing familial (benign) hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. Hum. Mutat. 24: 107-111, 2004. [PubMed: 15241791, related citations] [Full Text]

  60. Pollak, M. R., Brown, E. M., Chou, Y.-H. W., Hebert, S. C., Marx, S. J., Steinmann, B., Levi, T., Seidman, C. E., Seidman, J. G. Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 75: 1297-1303, 1993. [PubMed: 7916660, related citations] [Full Text]

  61. Pollak, M. R., Brown, E. M., Estep, H. L., McLaine, P. N., Kifor, O., Park, J., Hebert, S. C., Seidman, C. E., Seidman, J. G. Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation. Nature Genet. 8: 303-307, 1994. [PubMed: 7874174, related citations] [Full Text]

  62. Pollak, M. R., Chou, Y.-H. W., Marx, S. J., Steinmann, B., Cole, D. E. C., Brandi, M. L., Papapoulos, S. E., Menko, F. H., Hendy, G. N., Brown, E. M., Seidman, C. E., Seidman, J. G. Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism: effects of mutant gene dosage on phenotype. J. Clin. Invest. 93: 1108-1112, 1994. [PubMed: 8132750, related citations] [Full Text]

  63. Pratt, E. L., Geren, B. B., Neuhauser, E. B. D. Hypercalcemia and idiopathic hyperplasia of the parathyroid glands in an infant. J. Pediat. 30: 388-399, 1947. [PubMed: 20290361, related citations] [Full Text]

  64. Purroy, J., Spurr, N. K. Molecular genetics of calcium sensing in bone cells. Hum. Molec. Genet. 11: 2377-2384, 2002. [PubMed: 12351573, related citations] [Full Text]

  65. Sato, K., Hasegawa, Y., Nakae, J., Nanao, K., Takahashi, I., Tajima, T., Shinohara, N., Fujieda, K. Hydrochlorothiazide effectively reduces urinary calcium excretion in two Japanese patients with gain-of-function mutations of the calcium-sensing receptor gene. J. Clin. Endocr. Metab. 87: 3068-3073, 2002. [PubMed: 12107202, related citations] [Full Text]

  66. Scillitani, A., Guarnieri, V., Battista, C., De Geronimo, S., Muscarella, L. A., Chiodini, I., Cignarelli, M., Minisola, S., Bertoldo, F., Francucci, C. M., Malavolta, N., Piovesan, A., Mascia, M. L., Muscarella, S., Hendy, G. N., D'Agruma, L., Cole, D. E. C. Primary hyperparathyroidism and the presence of kidney stones are associated with different haplotypes of the calcium-sensing receptor. J. Clin. Endocr. Metab. 92: 277-283, 2007. [PubMed: 17018660, related citations] [Full Text]

  67. Scillitani, A., Guarnieri, V., De Geronimo, S., Muscarella, L. A., Battista, C., D'Agruma, L., Bertoldo, F., Florio, C., Minisola, S., Hendy, G. N., Cole, D. E. C. Blood ionized calcium is associated with clustered polymorphisms in the carboxyl-terminal tail of the calcium-sensing receptor. J. Clin. Endocr. Metab. 89: 5634-5638, 2004. [PubMed: 15531522, related citations] [Full Text]

  68. Simonds, W. F., James-Newton, L. A., Agarwal, S. K., Yang, B., Skarulis, M. C., Hendy, G. N., Marx, S. J. Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds. Medicine 81: 1-26, 2002. [PubMed: 11807402, related citations] [Full Text]

  69. Steinmann, B., Gnehm, H. E., Rao, V. H., Kind, H. P., Prader, A. Neonatal severe primary hyperparathyroidism and alkaptonuria in a boy born to related parents with familial hypocalciuric hypercalcemia. Helv. Paediat. Acta 39: 171-186, 1984. [PubMed: 6543841, related citations]

  70. Stepanchick, A., McKenna, J., McGovern, O., Huang, Y., Breitwieser, G. E. Calcium sensing receptor mutations implicated in pancreatitis and idiopathic epilepsy syndrome disrupt an arginine-rich retention motif. Cell. Physiol. Biochem. 26: 363-374, 2010. [PubMed: 20798521, images, related citations] [Full Text]

  71. Stock, J. L., Brown, R. S., Baron, J., Coderre, J. A., Mancilla, E., De Luca, F., Ray, K., Mericq, M. V. Autosomal dominant hypoparathyroidism associated with short stature and premature osteoarthritis. J. Clin. Endocr. Metab. 84: 3036-3040, 1999. [PubMed: 10487661, related citations] [Full Text]

  72. Tan, Y. M., Cardinal, J., Franks, A. H., Mun, H.-C., Lewis, N., Harris, L. B., Prins, J. B., Conigrave, A. D. Autosomal dominant hypocalcemia: a novel activating mutation (E604K) in the cysteine-rich domain of the calcium-sensing receptor. J. Clin. Endocr. Metab. 88: 605-610, 2003. [PubMed: 12574188, related citations] [Full Text]

  73. Tu, Q., Pi, M., Karsenty, G., Simpson, L., Liu, S., Quarles, L. D. Rescue of the skeletal phenotype in CasR-deficient mice by transfer onto the Gcm2 null background. J. Clin. Invest. 111: 1029-1037, 2003. [PubMed: 12671052, images, related citations] [Full Text]

  74. Vargas-Poussou, R., Huang, C., Hulin, P., Houillier, P., Jeunemaitre, X., Paillard, M., Planelles, G., Dechaux, M., Miller, R. T., Antignac, C. Functional characterization of a calcium-sensing receptor mutation in severe autosomal dominant hypocalcemia with a Bartter-like syndrome. J. Am. Soc. Nephrol. 13: 2259-2266, 2002. [PubMed: 12191970, related citations] [Full Text]

  75. Vezzoli, G., Arcidiacono, T., Paloschi, V., Terranegra, A., Biasion, R., Weber, G., Mora, S., Syren, M. L., Coviello, D., Cusi, D., Bianchi, G., Soldati, L. Autosomal dominant hypocalcemia with mild type 5 Bartter syndrome. J. Nephrol. 19: 525-528, 2006. [PubMed: 17048213, related citations]

  76. Ward, B. K., Magno, A. L., Davis, E. A., Hanyaloglu, A. C., Stuckey, B. G. A., Burrows, M., Eidne, K. A., Charles, A. K., Ratajczak, T. Functional deletion of the calcium-sensing receptor in a case of neonatal severe hyperparathyroidism. J. Clin. Endocr. Metab. 89: 3721-3730, 2004. [PubMed: 15292296, related citations] [Full Text]

  77. 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 360: 692-694, 2002. [PubMed: 12241879, related citations] [Full Text]

  78. Watanabe, T., Bai, M., Lane, C. R., Matsumoto, S., Minamitani, K., Minagawa, M., Niimi, H., Brown, E. M., Yasuda, T. Familial hypoparathyroidism: identification of a novel gain of function mutation in transmembrane domain 5 of the calcium-sensing receptor. J. Clin. Endocr. Metab. 83: 2497-2502, 1998. [PubMed: 9661634, related citations] [Full Text]

  79. Woo, S. I., Song, H., Song, K. E., Kim, D. J., Lee, K. W., Kim, S. J., Chung, Y.-S. A case report of familial benign hypocalciuric hypercalcemia: a mutation in the calcium-sensing receptor gene. Yonsei Med. J. 47: 255-258, 2006. [PubMed: 16642557, images, related citations] [Full Text]

  80. Wystrychowski, A., Pidasheva, S., Canaff, L., Chudek, J., Kokot, F., Wiecek, A., Hendy, G. N. Functional characterization of calcium-sensing receptor codon 227 mutations presenting as either familial (benign) hypocalciuric hypercalcemia or neonatal hyperparathyroidism. J. Clin. Endocr. Metab. 90: 864-870, 2005. [PubMed: 15572418, related citations] [Full Text]

  81. Zajickova, K., Vrbikova, J., Canaff, L., Pawelek, P. D., Goltzman, D., Hendy, G. N. 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. J. Clin. Endocr. Metab. 92: 2616-2623, 2007. [PubMed: 17473068, related citations] [Full Text]


Marla J. F. O'Neill - updated : 07/25/2018
Patricia A. Hartz - updated : 7/6/2016
Marla J. F. O'Neill - updated : 8/12/2013
Ada Hamosh - updated : 1/7/2013
Cassandra L. Kniffin - updated : 7/8/2009
John A. Phillips, III - updated : 3/5/2009
John A. Phillips, III - updated : 6/24/2008
George E. Tiller - updated : 6/16/2008
John A. Phillips, III - updated : 3/20/2008
John A. Phillips, III - updated : 12/20/2007
John A. Phillips, III - updated : 12/19/2007
Ada Hamosh - updated : 12/6/2006
John A. Phillips, III - updated : 11/17/2006
Patricia A. Hartz - updated : 8/9/2006
John A. Phillips, III - updated : 7/22/2005
John A. Phillips, III - updated : 6/29/2005
John A. Phillips, III - updated : 4/12/2005
John A. Phillips, III - updated : 11/4/2004
Victor A. McKusick - updated : 10/21/2004
Victor A. McKusick - updated : 9/2/2004
Marla J. F. O'Neill - updated : 8/11/2004
George E. Tiller - updated : 12/2/2003
Patricia A. Hartz - updated : 11/17/2003
John A. Phillips, III - updated : 2/4/2003
John A. Phillips, III - updated : 1/6/2003
Victor A. McKusick - updated : 11/19/2002
John A. Phillips, III - updated : 7/1/2002
Victor A. McKusick - updated : 11/29/2001
John A. Phillips, III - updated : 7/3/2001
John A. Phillips, III - updated : 11/14/2000
John A. Phillips, III - updated : 9/29/2000
John A. Phillips, III - updated : 10/29/1999
Victor A. McKusick - updated : 9/8/1999
John A. Phillips, III - updated : 1/7/1999
John A. Phillips, III - updated : 10/31/1997
Michael J. Wright - updated : 9/25/1997
Beat Steinmann - updated : 3/13/1997
Moyra Smith - updated : 6/6/1996
Creation Date:
Victor A. McKusick : 4/11/1996
carol : 07/03/2023
carol : 09/24/2019
carol : 07/30/2018
carol : 07/25/2018
joanna : 02/21/2017
carol : 07/15/2016
carol : 7/14/2016
mgross : 7/6/2016
joanna : 6/23/2016
joanna : 6/23/2016
carol : 9/15/2015
mcolton : 8/17/2015
carol : 2/18/2015
carol : 8/13/2013
carol : 8/12/2013
carol : 8/12/2013
alopez : 1/7/2013
terry : 1/7/2013
alopez : 10/21/2009
wwang : 7/31/2009
ckniffin : 7/8/2009
alopez : 3/5/2009
wwang : 11/5/2008
alopez : 6/24/2008
wwang : 6/20/2008
terry : 6/16/2008
carol : 3/20/2008
carol : 12/21/2007
carol : 12/20/2007
carol : 12/20/2007
carol : 12/19/2007
carol : 2/28/2007
alopez : 12/15/2006
terry : 12/6/2006
alopez : 11/17/2006
carol : 9/27/2006
wwang : 8/24/2006
terry : 8/9/2006
wwang : 12/20/2005
alopez : 7/22/2005
alopez : 6/29/2005
alopez : 5/16/2005
wwang : 4/12/2005
terry : 4/5/2005
tkritzer : 2/4/2005
terry : 1/31/2005
carol : 11/11/2004
carol : 11/11/2004
alopez : 11/4/2004
tkritzer : 10/22/2004
terry : 10/21/2004
alopez : 9/5/2004
terry : 9/2/2004
carol : 8/11/2004
terry : 8/11/2004
alopez : 3/17/2004
mgross : 12/2/2003
mgross : 11/17/2003
mgross : 11/17/2003
tkritzer : 5/9/2003
tkritzer : 3/3/2003
cwells : 2/4/2003
alopez : 1/6/2003
alopez : 12/4/2002
tkritzer : 12/3/2002
tkritzer : 12/3/2002
tkritzer : 11/22/2002
terry : 11/19/2002
alopez : 7/1/2002
carol : 1/15/2002
mcapotos : 12/12/2001
terry : 11/29/2001
alopez : 7/3/2001
mgross : 12/1/2000
terry : 11/14/2000
terry : 10/23/2000
mgross : 10/3/2000
terry : 9/29/2000
carol : 3/8/2000
alopez : 10/29/1999
jlewis : 9/17/1999
terry : 9/8/1999
alopez : 1/7/1999
alopez : 1/7/1999
mark : 1/10/1998
alopez : 11/19/1997
alopez : 11/11/1997
alopez : 11/11/1997
alopez : 11/6/1997
dholmes : 10/31/1997
dholmes : 10/16/1997
mark : 6/16/1997
mark : 6/16/1997
mark : 6/16/1997
joanna : 3/13/1997
mark : 10/24/1996
mark : 10/23/1996
terry : 9/18/1996
marlene : 8/15/1996
mark : 6/19/1996
mark : 6/19/1996
carol : 6/9/1996
carol : 6/6/1996
mark : 4/18/1996
mark : 4/18/1996
mark : 4/15/1996
mark : 4/15/1996
mark : 4/15/1996
terry : 4/12/1996
mark : 4/11/1996

* 601199

CALCIUM-SENSING RECEPTOR; CASR


Alternative titles; symbols

PARATHYROID CA(2+)-SENSING RECEPTOR 1; PCAR1


HGNC Approved Gene Symbol: CASR

SNOMEDCT: 715218009;  


Cytogenetic location: 3q13.33-q21.1     Genomic coordinates (GRCh38): 3:122,183,668-122,291,629 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
3q13.33-q21.1 {?Epilepsy idiopathic generalized, susceptibility to, 8} 612899 Autosomal dominant 3
Hyperparathyroidism, neonatal 239200 Autosomal dominant; Autosomal recessive 3
Hypocalcemia, autosomal dominant 601198 Autosomal dominant 3
Hypocalcemia, autosomal dominant, with Bartter syndrome 601198 Autosomal dominant 3
Hypocalciuric hypercalcemia, type I 145980 Autosomal dominant 3

TEXT

Description

CASR is a plasma membrane G protein-coupled receptor that is expressed in the parathyroid hormone-producing chief cells of the parathyroid gland and the cells lining the kidney tubule. By virtue of its ability to sense small changes in circulating calcium concentration and to couple this information to intracellular signaling pathways that modify PTH secretion or renal cation handling, CASR plays an essential role in maintaining mineral ion homeostasis (Hendy et al., 2000).


Cloning and Expression

Parathyroid cells respond to decreases in extracellular calcium concentration by means of the calcium-sensing receptor, a cell surface receptor that alters phosphatidylinositol turnover and intracellular calcium, ultimately effecting an increase in parathyroid hormone (PTH; 168450) secretion. The 'set point' of parathyroid cells is defined as that calcium concentration at which PTH secretion is half-maximal. Parathyroid glands from familial hypocalciuric hypercalcemia (HHC1; 145980) patients have an increase in this set point, and in vitro studies of parathyroid tissue from neonatal severe hyperparathyroidism (NSHPT; 239200) patients show a still greater increase in this set point. Calcium handling by the kidney is also abnormal in individuals with HHC, who fail to show a hypercalciuric response to hypercalcemia. Brown et al. (1993) identified a putative bovine parathyroid cell Ca(2+)-sensing receptor cDNA by expression cloning in Xenopus laevis oocytes. The cDNA encoded a predicted 120-kD polypeptide containing a large extracellular domain and 7-membrane-spanning regions characteristic of G protein-coupled cell surface receptors. In addition to parathyroid tissue, the receptor was also expressed in regions of the kidney involved in Ca(2+)-regulated Ca(2+) and Mg(2+) reabsorption.

By screening a human adenoma cDNA library with bovine Casr, Garrett et al. (1995) cloned 2 CASR variants that differed at their 5-prime and 3-prime UTRs. The 1,078-amino acid protein has a large extracellular N-terminal domain, a central region of 7 transmembrane domains, and a long intracellular C-terminal domain. It contains 11 potential N-glycosylation sites in the extracellular domain, several sites for phosphorylation in the intracellular domain and the intracellular loop, and 20 conserved cysteines. Pidasheva et al. (2005) stated that the first 19 amino acids of CASR encode a signal peptide that is predicted to direct the nascent polypeptide chain into the endoplasmic reticulum (ER). Garrett et al. (1995) also identified a rare variant that encodes a protein with a 10-amino acid insertion in the extracellular domain close to the transmembrane region. Northern blot analysis of adenomatous parathyroid detected a major CASR transcript of about 5.4 kb and minor transcripts of about 10, 4.8, and 4.2 kb.


Gene Structure

The human calcium-sensing receptor is encoded by 6 exons that span more than 20 kb (Pollak et al., 1993). Chikatsu et al. (2000) identified alternatively spliced CASR exons 1a and 1b that are noncoding and provide alternative promoters. The upstream promoter has TATA and CAAT boxes, and the downstream promoter is GC-rich.


Gene Function

By expression in Xenopus oocytes, Garrett et al. (1995) demonstrated that CASR responded to extracellular application of physiologically relevant concentrations of Ca(2+) and other CASR agonists. The rank order of potency of CASR agonists displayed by the native receptor was maintained by the expressed receptor.

Using reporter gene constructs, Chikatsu et al. (2000) demonstrated that the CASR gene contains 2 functional promoters and that expression from only the upstream promoter was reduced in parathyroid adenomas compared with normal glands.

Canaff and Hendy (2002) demonstrated that Casr mRNA levels increased in rat parathyroid, thyroid, and kidney after intraperitoneal injection of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Cultured human thyroid C-cells and kidney proximal tubule cells also increased CASR mRNA in response to 1,25(OH)2D3. In kidney cells, transcriptional activity of the P1 promoter and P2 promoter were increased 11-fold and 33-fold by 1,25(OH)2D3, respectively. In both promoters, Canaff and Hendy (2002) identified vitamin D response elements (VDREs) in which 6-bp half-sites are separated by 3 nucleotides. These VDREs conferred 1,25(OH)2D3 responsiveness to a heterologous promoter, and responsiveness was lost when the VDREs were mutated.

Kapoor et al. (2008) found CASR expression in the cerebral cortex, hypothalamus, hippocampus, whole adult brain, and fetal brain. Western blot analysis found an immunoreactive CASR protein in temporal, frontal, and parietal lobes, hippocampus, and cerebellum.

Stepanchick et al. (2010) stated that wildtype CASR assembles in the ER as a covalent disulfide-linked dimer. They identified an arginine-rich region in the proximal C terminus of human CASR (residues R890 to R898) that indirectly contributed to dimer formation by retaining nascent CASR in the ER, delaying its targeting to the plasma membrane. Patient mutations in this arginine-rich region enhanced targeting of CASR to the plasma membrane, and some mutations, including R898Q (601199.0050) enhanced calcium-stimulated ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) phosphorylation. Phosphorylation of S899, a protein kinase A (see 188830) site, negatively regulated CASR retention in the ER by facilitating transient interaction of 14-3-3 proteins (see 113508) with the arginine-rich motif.

Lee et al. (2012) showed that the murine CASR activates the NLRP3 (606416) inflammasome, mediated by increased intracellular calcium and decreased cellular cAMP. Calcium or other CASR agonists activate the NLRP3 inflammasome in the absence of exogenous ATP, whereas knockdown of CASR reduces inflammasome activation in response to known NLRP3 activators. CASR activates the NLRP3 inflammasome through phospholipase C (see 607120), which catalyzes inositol-1,4,5-trisphosphate production and thereby induces release of calcium from endoplasmic reticulum stores. The increased cytoplasmic ionized calcium promotes the assembly of inflammasome components, and intracellular calcium is required for spontaneous inflammasome activity in cells from patients with cryopyrin-associated periodic syndromes (CAPS). CASR stimulation also results in reduced intracellular cAMP, which independently activates the NLRP3 inflammasome. Cyclic AMP binds to NLRP3 directly to inhibit inflammasome assembly, and downregulation of cAMP relieves this inhibition. The binding affinity of cAMP for CAPS-associated mutant NLRP3 is substantially lower than for wildtype NLRP3, and the uncontrolled mature IL1-beta (147720) production from these patients' peripheral blood mononuclear cells is attenuated by increasing cAMP. Lee et al. (2012) concluded that, taken together, their findings indicated that ionized calcium and cAMP are 2 key molecular regulators of the NLRP3 inflammasome and have critical roles in the molecular pathogenesis of cryopyrin-associated periodic syndromes.


Mapping

By Southern analysis of hamster-human hybrid cell DNAs containing only human chromosome 3, Pollak et al. (1993) demonstrated that the human homolog of the bovine Casr gene is located on chromosome 3. Janicic et al. (1995) mapped the CASR gene to 3q13.3-q21 by fluorescence in situ hybridization. The localization to chromosome 3 was confirmed by somatic cell hybrid analysis. By interspecific backcross analysis, they found that the Casr gene segregated with D16Mit4 on mouse chromosome 16. The corresponding gene was found to be on rat chromosome 11.


Molecular Genetics

Hypocalciuric Hypercalcemia and Neonatal Severe Hyperparathyroidism

Pollak et al. (1993) demonstrated that mutations in the human Ca(2+)-sensing receptor gene cause both familial hypocalciuric hypercalcemia (HHC1; 145980) and neonatal severe hyperparathyroidism (NSHPT; 239200). They discovered 3 nonconservative missense mutations, 2 in the extracellular N-terminal domain of the receptor (601199.0002 and 601199.0003) and 1 in the final intracellular loop (601199.0001). The wildtype receptor expressed in Xenopus laevis oocytes elicited large inward currents in response to perfused polyvalent cations; in contrast, a markedly attenuated response was observed with the protein expressed by one of the mutations.

In affected members of a Japanese family with HHC, Aida et al. (1995) identified a mutation (601199.0021) in the CASR gene by PCR and SSCP. The proband was homozygous and the consanguineous parents were heterozygous for the mutation. The parents showed borderline elevations of serum calcium.

Chou et al. (1995) reported 5 novel mutations (601199.0022-601199.0025) in affected members of unrelated families with HHC or NSHPT. On the basis of their data and previous analyses, Chou et al. (1995) suggested that these disorders may be caused by a wide range of mutations.

Pearce et al. (1995) analyzed the CASR gene in 9 unrelated kindreds with a total of 39 affected members with familial benign hypercalcemia and in 3 unrelated children with sporadic NSHPT. In 6 of 9 HHC kindreds, heterozygosity for a novel mutation (1 missense and 5 missense) was found; in the 3 children with NSHPT, 2 de novo heterozygous missense mutations and 1 homozygous frameshift mutation were identified (see 601199.0006, 601199.0007, and 601199.0008). SSCP analysis was found by the authors to be a sensitive and specific mutational screening method that detected more than 85% of these CASR gene mutations. Pearce et al. (1995) noted that the identification of CASR mutations may help distinguish HHC from mild primary hyperparathyroidism, which otherwise can be clinically difficult. These results indicated that NSHPT is not exclusively the result of homozygosity for a mutation that causes familial benign hypercalcemia in the heterozygous state, but rather can be due to heterozygosity for mutations at the CASR locus. Indeed, the parents and sibs of the 3 children with NSHPT were normocalcemic. All 3 children with NSHPT presented with neonatal hypercalcemia that was associated with marked bony undermineralization. Parathyroidectomy and histologic examination revealed T-cell hyperplasia of all 4 parathyroid glands in the 3 NSHPT children, who all became hypocalcemic and required vitamin D replacement postoperatively. The clinical features of 2 of the cases had previously been reported by Dezateux et al. (1984) and Meeran et al. (1994).

Nissen et al. (2007) studied the mutation spectrum of the CASR gene in a Danish HHC population and investigated genotype-phenotype relationships regarding the different mutations. A total of 213 subjects clinically suspected to have HHC and 121 subjects enrolled as part of a family-screening program were studied. They identified 22 different mutations in 39 HHC families; 19 of these mutations were novel.

Hypocalcemia, Autosomal Dominant 1, with or without Bartter Syndrome

In addition to familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism, mutation in the CASR gene can cause an autosomal dominant form of hypocalcemia (HYPOC1; 601198). Pollak et al. (1994) hypothesized that, in contrast to familial hypocalciuric hypercalcemia in which mild hypercalcemia is caused by mutations that reduce the activity of the Ca(2+)-sensing receptor, mild hypocalcemia might be caused by a mutation that inappropriately activates the receptor at subnormal Ca(2+) levels. Such activating mutations have been described in other G protein-coupled receptors. In 1 of 2 probands with hypocalcemia, they indeed found a missense mutation (E128A; see 601199.0004) in the CASR gene, which they symbolized PCAR1. Pollak et al. (1994) discussed the effects of mutant gene dosage on the observed hypocalcemia phenotype.

Finegold et al. (1994) presented evidence for linkage of a form of autosomal dominant hypoparathyroidism to a region of 3q13 flanking marker D3S1303 and suggested that the disorder in this family may be caused by an activating mutation in the Ca(2+)-sensing receptor that suppresses PTH secretion and lowers the set point for serum calcium levels. Baron et al. (1996) identified 2 families with autosomal dominant hypoparathyroidism with heterozygous mutations in the CASR gene (601199.0009, 601199.0010). They also identified a de novo CASR missense mutation (601199.0011) in an infant with severe hypoparathyroidism. These mutations were not found in normal controls.

Lienhardt et al. (2001) identified activating CASR mutations in 8 (42%) of 19 unrelated probands with isolated hypoparathyroidism. The severity of hypocalcemic symptoms at diagnosis was independent of age, mutation type, or mode of inheritance but was related to the degree of hypocalcemia. Hypocalcemia segregated with the CASR mutation, but no phenotype-genotype relationships were identified. The authors concluded that mutational analysis of the CASR gene should be considered early in the work-up of isolated hypoparathyroidism and that the risk of nephrocalcinosis during treatment can be minimized by carefully monitoring urinary calcium excretion.

Bartter syndrome (see 241200) is a genetically heterogeneous disorder characterized by deficient renal reabsorption of sodium and chloride, and hypokalemic metabolic alkalosis with hyperreninemia and hyperaldosteronemia. Watanabe et al. (2002) described 2 hypocalcemic patients with deficient parathyroid hormone secretion, characteristics of Bartter syndrome, and activating mutations of the CASR gene (601199.0034 and 601199.0035). The authors noted that in rats it has been shown that activation of this calcium-sensing receptor by higher concentrations of extracellular calcium ions inhibits the activity of the renal outer-medullary potassium channel (KCNJ1; 600359) (see Brown and MacLeod, 2001); the KCNJ1 gene is mutated in type 2 Bartter syndrome.

In a boy with severe autosomal dominant hypocalcemia associated with Bartter syndrome-like features, who was negative for mutation in the CLCNKB gene (602023), Vargas-Poussou et al. (2002) identified a de novo missense mutation in the CASR gene (L125P; 601199.0037). Functional analysis in transfected HEK293 cells revealed that the L125P mutation was more potent than any previously reported gain-of-function mutation, with an EC50 value approximately one-third that of wildtype; Vargas-Poussou et al. (2002) proposed that mutant L125P CASR may reduce NaCl reabsorption in the cortical thick ascending limb of the loop of Henle sufficiently to result in renal loss of NaCl with secondary hyperaldosteronism and hypokalemia.

Hu et al. (2004) described monozygotic twin sisters of Italian origin with severe symptomatic hypocalcemia in whom they identified a heterozygous de novo gain-of-function missense mutation (K29E; 601199.0053). In a follow-up study, Vezzoli et al. (2006) reported that the twins developed Bartter syndrome-like features at 22 years of age, with mild hypokalemia, mild hyperreninemia and hyperaldosteronism, but no alkalosis; the authors designated the disorder 'type 5 Bartter syndrome.' Vezzoli et al. (2006) noted that all 4 CASR mutations causing hypocalcemia associated with Bartter syndrome-like features were highly activating, with EC50 values less than 1.5 mmol/L, whereas the EC50 values for other CASR mutations causing autosomal dominant hypocalcemia but not Bartter syndrome ranged between 1.5 and 3 mmol/L.

Serum Level of Calcium

Scillitani et al. (2004) evaluated the frequency of the ala986-to-ser (A986S; 601199.0040) and 2 neighboring CASR polymorphisms (R90G and Q1011E) and their association with ionized serum calcium in 377 unrelated healthy adults recruited from a blood donor clinic. Their study confirmed the association of increased serum ionized calcium with the 986S variant and also suggested that the 2 neighboring loci are also predictive.

Scillitani et al. (2007) examined the 3 SNPs in exon 7 of the CASR gene (A986S, R90G, and Q1011E) in 237 patients with sporadic primary hyperparathyroidism (see 145000) and 433 healthy controls and found significant association of the AGQ haplotype with kidney stones (p = 0.0007) within this patient population.

Idiopathic Generalized Epilepsy 8

By genomewide linkage analysis and candidate gene sequencing of a large Indian family with idiopathic generalized epilepsy (EIG8; 612899) mapping to chromosome 3q13.3-q21, Kapoor et al. (2008) identified a heterozygous mutation in the CASR gene (R898Q; 601199.0050) that segregated with the disorder in affected family members. The mutation occurred in a highly conserved residue and was not found in 504 control chromosomes. Four additional possibly pathogenic variants in the CASR gene were identified in 5 of 96 unrelated patients with juvenile myoclonic epilepsy from southern India. None of the patients had electrolyte abnormalities. Kapoor et al. (2008) postulated a role for calcium signaling abnormalities that may affect neuronal excitability in this form of epilepsy.

Reviews

Hendy et al. (2000) reviewed mutations in the CASR gene.

Purroy and Spurr (2002) reviewed the cell biology and molecular genetics of calcium sensing in bone cells.

Pidasheva et al. (2004) described a CASR mutation database. They stated that 112 naturally occurring mutations in the human CASR gene had been reported, of which 80 were unique and 32 recurrent.

Hannan and Thakker (2013) provided a review of CASR mutations and associated disorders.

Exclusion Studies

Using direct sequencing in a mutation screen of the CASR gene in 20 sporadic parathyroid adenomas, Cetani et al. (1999) found no mutations. A polymorphism that encoded a single amino acid change (ala826 to thr) was identified in 4 parathyroid adenomas and in 8 of 50 normal unrelated subjects. Loss of heterozygosity (LOH) studies performed on 3q, where the CASR gene is located, demonstrated no allelic loss.

Hannan et al. (2012) demonstrated that the CASR glu250-to lys (E250K) variant, previously believed to be a recurrent mutation found in patients with hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, or autosomal dominant hypocalcemia, is a functionally neutral polymorphism. They found that the variant was present in 0.3% of the approximately 5,400 samples in the NHLBI Exome Sequencing Project database.


Genotype/Phenotype Correlations

Pearce et al. (1996) demonstrated that 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. They studied 6 kindreds with a diagnosis of autosomal dominant hypoparathyroidism. Treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment. Mutations in the CASR gene were identified by restriction enzyme or DNA sequence analysis and were expressed in human embryonic kidney cells. Heterozygosity for 5 missense mutations was identified (see 601199.0013 through 601199.0017). All mutations were in the extracellular domain of the CASR gene and were shown to cosegregate with the disease. Analysis of the functional expression of 3 of the mutated receptors in embryonic kidney cells demonstrated negative shifts in the dose-response curves of the mutant receptor for extracellular calcium. Pearce et al. (1996) stated that this disorder is the mirror image of familial benign hypercalcemia (145980). The authors concluded that, depending on the site of the mutation in the CASR gene, it is possible to modify the response of the calcium-sensing receptor so that the serum calcium concentrations that inhibit the secretion of parathyroid hormone are either higher or lower than normal; the result, respectively, is hypercalcemia or hypocalcemia. Although the receptor is expressed in many tissues, the only obvious consequences of the abnormal receptor function in patients with these conditions have been changes in serum calcium, phosphate, and magnesium concentrations and in the renal handling of these ions.

In a large Swedish family in which 20 members had hypercalcemia, including 3 who were hypocalciuric and 7 who were hypercalciuric, Carling et al. (2000) identified heterozygosity for a missense mutation (F881L; 601199.0031) in the CASR gene, representing the first identified point mutation located within the cytoplasmic tail of the calcium-sensing receptor. The authors noted that some clinical characteristics displayed by affected individuals were atypical of familial benign hypocalciuric hypercalcemia (see 145980) and familial hyperparathyroidism (145000).

Nagase et al. (2002) reported a novel activating mutation (601199.0038) in the CASR gene in a Japanese family with autosomal dominant hypocalcemia. The proband, a 15-year-old boy, and 5 other patients in 3 generations were asymptomatic, except for the proband's grandmother, who had a history of seizures. They showed mild hypocalcemia with normal urinary calcium excretion and low normal serum PTH levels. Their serum magnesium concentrations were below normal in 3 adults and within the normal range in 3 teenagers. There was a significant positive correlation between the serum calcium and magnesium concentrations of 6 affected members. The positive correlation between serum calcium and magnesium levels observed in this family may support the concept that renal CASR acts as a magnesium sensor as well as a calcium sensor.

In 66 HHC patients Nissen et al. (2007) evaluated data on circulating calcium and PTH for 11 different mutations, representing a spectrum of clinical phenotypes ranging from calcium concentrations moderately above the upper reference limit to calcium levels more than 20% above the upper reference limit. The mean plasma PTH concentration was within the normal range in 8 of 11 studied mutations, but mild to moderately elevated in families with the mutations C582Y (601199.0007), C582F (601199.0047), and G553R (601199.0048).

Hannan et al. (2012) analyzed the CASR gene in 294 unrelated probands, of whom 228 were hypercalcemic and 66 were hypocalcemic; 71 different CASR sequence abnormalities were detected in 86 (29%) of the patients, of which 59 variants were found in the 228 hypercalcemia patients (26% detection rate) and 27 in the 66 hypocalcemia patients (41% detection rate). The majority of these and previously reported CASR mutations associated with hyper- and hypocalcemic disorders were located in the extracellular domain. Mutations identified in patients with neonatal severe hyperparathyroidism, both in this report and in previous reports, were significantly more likely to be truncating than those found in patients with hypocalciuric hypercalcemia. Hannan et al. (2012) noted that the phenotypic features of familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia in patients with CASR mutations were similar to those patients without CASR mutations, indicating that phenotypic features alone are unlikely to be useful predictors for the presence or absence of a CASR mutation. In addition, different missense mutations at 2 so-called 'toggle' codons were found to be associated with either hyper- or hypocalcemia, respectively; e.g., at codon 221, P221Q (601199.0051) and P221L (601199.0052) were associated with familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia, respectively. Similarly, at codon 173 in CASR, an L173F mutation was identified in a patient with autosomal dominant hypocalcemia, whereas an L173P mutation had previously been reported by Felderbauer et al. (2003) in a patient with hypocalciuric hypercalcemia and chronic pancreatitis (167800), who also carried a mutation in the SPINK1 gene (167790). Functional characterization of these CASR variants confirmed that P221Q and L173P caused a loss of function, whereas P221L and L173F resulted in a gain of function.

In a 68-year-old man with hypercalcemia, hypercalciuria, and recurrent nephrolithiasis, Mastromatteo et al. (2014) identified heterozygosity for a missense mutation in the CASR gene (T972M; 601199.0055). Screening of his 3 asymptomatic sons revealed 1 carrier, a 41-year-old man with an ionized calcium level at the upper limit of normal and normal PTH and urinary calcium levels. Functional evaluation demonstrated strong impairment of signaling activity of the mutant receptor compared to wildtype. The authors concluded that T972M represents an inactivating mutation of the CASR gene causing an atypical presentation of FHH with hypercalciuria.


Animal Model

To examine the role of CASR in calcium homeostasis and elucidate the mechanism by which inherited human CASR gene defects cause disease, Ho et al. (1995) created mice in which the Casr gene was disrupted by standard methods of homologous recombination. They found that the phenotype of heterozygous mice mimicked familial hypocalciuric hypercalcemia and that homozygous deficient mice exhibited the phenotype of neonatal severe hyperparathyroidism. The authors suggested that human CASR mutations cause these disorders by reducing the number of functional receptor molecules on the cell surface.

Tu et al. (2003) observed that most homozygous Casr-deficient mice died by the end of the first week after birth, and none survived for more than 6 weeks. These mice showed hypocalciuric hyperparathyroidism and rickets/osteomalacia. In order to remove the confounding effects of elevated PTH and assess the independent function of Casr in bone and cartilage, Tu et al. (2003) generated double-homozygous Casr- and Gcm2 (603716)-deficient mice. Superimposed Gcm2 deficiency rescued the lethality of Casr deficiency, and correction of the severe hyperparathyroidism prevented the rickets and osteomalacia, but it did not rescue the hypocalciuria. Analysis of the skeletons of homozygous Casr- and Gcm2-deficient mice failed to identify any essential, nonredundant role for Casr in regulating growth-plate and bone mineralization. Tu et al. (2003) concluded that low urinary calcium is mediated by the absence of Casr in the kidney, but the defective mineralization of bone and cartilage is due to metabolic abnormalities associated with hyperparathyroidism rather than the absence of skeletal Casr.

Kos et al. (2003) generated Casr-null mice on a Pth-null background. Genetic ablation of Pth was sufficient to rescue the lethal Casr-null phenotype. Double-mutant mice survived to adulthood with no obvious difference in size and appearance relative to Pth-null littermates. Histologic examination of most organs revealed no abnormalities, but female double-mutant mice had elevated bone mineral density in the spine. Double-mutant mice exhibited a wider range of values for serum calcium and renal calcium excretion than was observed in control littermates, despite the absence of circulating Pth. Kos et al. (2003) concluded that CASR is necessary for the fine regulation of serum calcium levels and renal calcium excretion independent of its effect on PTH secretion.

Hough et al. (2004) described a mouse model for an activating mutation of the calcium-sensing receptor gene, named Nuf, originally identified by having opaque flecks in the nucleus of the lens in a screen for eye mutants. Nuf mice also displayed ectopic calcification, hypocalcemia, hyperphosphatemia, cataracts, and inappropriately reduced levels of plasma parathyroid hormone. These features are similar to those observed in patients with an autosomal dominant form of hypocalcemia (601198). Inheritance studies of Nuf mice revealed that the trait was transmitted in an autosomal dominant manner, and mapping studies located the locus to mouse chromosome 16, in the vicinity of the gene for the calcium-sensing receptor Gprc2a, which is the mouse ortholog of human CASR. DNA analysis identified a leu723-to-gln (L723Q) substitution in the Gprc2a gene. Transient expression of wildtype and mutant CASRs in human embryonic kidney (HEK293) cells demonstrated that the mutation resulted in a gain of function of the receptor, which had a significantly lower EC(50) value. Ectopic calcification and cataract formation tended to be milder in the heterozygous Nuf mice, indicating that an evaluation for such abnormalities in autosomal dominant hypocalcemia patients who have activating CASR mutations is required.

Adams et al. (2006) showed that through the calcium-sensing receptor, the simple ionic mineral content of the niche may dictate the preferential localization of adult mammalian hematopoiesis in bone. Antenatal mice deficient in calcium-sensing receptor had primitive hematopoietic cells in the circulation and spleen, whereas few were found in bone marrow. Calcium-sensing receptor-null hematopoietic stem cells from fetal liver were normal in number, in proliferative and differentiative function, and in migration and homing to the bone marrow. function, and in migration and homing to the bone marrow. Yet they were highly defective in localizing anatomically to the endosteal niche, behavior that correlated with defective adhesion to the extracellular matrix protein, collagen I (see 120150). Adams et al. (2006) concluded that calcium-sensing receptor has a function in retaining hematopoietic stem cells in close physical proximity to the endosteal surface and the regulatory niche components associated with it.


ALLELIC VARIANTS 55 Selected Examples):

.0001   HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, ARG796TRP
SNP: rs121909258, gnomAD: rs121909258, ClinVar: RCV000008810, RCV000517736, RCV000793559, RCV001199039

In a family (family J) with hypocalciuric hypercalcemia type I (HHC1; 145980) shown by Pollak et al. (1994) to map to 3q2, Pollak et al. (1993) found that one allele of the parathyroid Ca(2+)-sensing receptor gene had a change in codon 796 from CGG (arg) to TGG (trp). To detect the mutation, DNA derived from 2 affected members of the family were screened using RNase A protection assays.


.0002   HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

HYPERPARATHYROIDISM, NEONATAL SEVERE, INCLUDED
CASR, GLU297LYS
SNP: rs121909259, ClinVar: RCV000008811, RCV000008812, RCV002228021

Steinmann et al. (1984) described a boy who had both neonatal severe primary hyperparathyroidism (NSHPT; 239200) and alkaptonuria (203500). Both parents, who were related, had familial hypocalciuric hypercalcemia (HHC1; 145980). By the RNase A protection method, Pollak et al. (1993) detected an abnormality in exon 3 of the CASR gene, referred to as PCAR1 by them. In the male with both NSPH and alkaptonuria, Pollak et al. (1993) found that the wildtype GAG sequence of codon 298 was replaced by AAG in all clones, predicting that the normal glutamic acid residue would be replaced by a lysine residue (E298K) with concurrent loss of an MnII site. Thus, the boy was homozygous as predicted; both his parents, related as first cousins, were heterozygous.

In a 16-year-old boy of Turkish origin with familial hypocalciuric hypercalcemia and a parathyroid adenoma, Brachet et al. (2009) identified heterozygosity for a missense mutation in exon 4 of the CASR gene, which they stated was a glu297-to-lys (E297K) substitution. The proband's affected father and paternal grandmother were also heterozygous for the mutation, and the grandmother also had a parathyroid adenoma; the mutation status of the proband's affected brother and sister was not reported. The authors stated that this was the same mutation that had been identified in homozygosity in a patient with NSHPT and in heterozygosity in patients with HHC (Pollak et al., 1993; Woo et al., 2006).


.0003   HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

HYPERPARATHYROIDISM, NEONATAL SEVERE, INCLUDED
CASR, ARG185GLN
SNP: rs104893689, ClinVar: RCV000008813, RCV000008814, RCV000412784, RCV000627760, RCV001804716, RCV002496307, RCV003398473

In a large kindred (family N) with hypocalciuric hypercalcemia (HCC1; 145980) described previously by Marx et al. (1982) as family A, Pollak et al. (1993) found by RNase A protection assay that affected individuals were heterozygous for a mutation in exon 3 of the CASR gene: a G-to-A transition, predicting an arginine-to-glutamic acid change at amino acid residue 186 (ARG186GLU). Brown et al. (1995) pointed out in their legend to Figure 2 that Pollak et al. (1993) used the amino acid numbering based on the bovine receptor sequence and that the mutation was inadvertently reported as arg to glu instead of arg to gln; the correct designation of the mutation is therefore arg185 to gln or R185Q.

Bai et al. (1997) reported a de novo arg185-to-gln mutation in a female infant with neonatal hyperparathyroidism (NSHPT; 239200). The authors stated that the mutation may exert a strong dominant-negative effect on the function of the normal CASR, resulting in NHPT and unusually severe hypercalcemia. The severity of the initial clinical presentation was due to the secondary hyperparathyroidism brought on by gestation of a fetus with abnormal parathyroid set point for Ca(2+)-regulated PTH in a mother with normal calcium homeostasis.


.0004   HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, GLU128ALA
SNP: rs121909260, ClinVar: RCV000008815, RCV000489583, RCV001060775, RCV002482842

In a family in which at least 16 members of 4 generations had autosomal dominant hypocalcemia-1 (HYPOC1; 601198), Pollak et al. (1994) found a glu128-to-ala (E128A) mutation in the CASR gene. Xenopus oocytes expressing the mutant receptor exhibited a larger increase in inositol 1,4,5-triphosphate in response to Ca(2+) than did oocytes expressing the wildtype receptor. Parathyroid hormone levels were normal in affected individuals. Serum phosphate levels were normal or mildly elevated. Affected family members did not exhibit the usual signs and symptoms of hypocalcemia, with the exception of one who experienced intermittent overt tetany. Bone films of this patient were normal. Target organ responsiveness to PTH was also normal.


.0005   HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

HYPERPARATHYROIDISM, NEONATAL SEVERE, INCLUDED
CASR, ALU INS, CODON 877
ClinVar: RCV000008816, RCV000008817

Janicic et al. (1995) studied family members of a Nova Scotian deme in which both familial hypocalciuric hypercalcemia (HCC1; 145980) and neonatal severe hyperparathyroidism (NSHPT; 239200) were segregating and found, by PCR amplification of CASR exons, that HCC1 individuals were heterozygous and NSHPT individuals were homozygous for an abnormally long exon 7. This was due to an insertion at codon 877 of an Alu-repetitive element of the predicted-variant/human-specific-1 subfamily. The Alu insertion was in the opposite orientation to the PCAR1 gene and contained an exceptionally long poly(A) tract. Stop signals were found in all reading frames within the Alu sequence, leading to a predicted shortening of the Ca(2+)-sensing receptor protein. Janicic et al. (1995) observed that the loss of most of the C-terminal intracellular domain of the protein would dramatically impair its signal transduction capability. Identification of the specific mutation in this community will allow rapid testing of at-risk individuals. Clinical features of affected members of the kindred had previously been reported by Pratt et al. (1947), Goldbloom et al. (1972), and Cole et al. (1990). This was a common ancestry that dated back at least 11 generations to settlement of the area by New England fishing families in the mid-1700s.

Bai et al. (1997) demonstrated that insertion of the Alu-repetitive element documented by Janicic et al. (1995) resulted in the production of a nonfunctional protein 30 kD less than wildtype with decreased cell surface expression. They also showed that transcription of the Alu-containing CASR produced both a full-length product and a product that was truncated due to stalling at the poly(T) tract. Subsequent in vitro translation produced 3 truncated proteins due to termination in all reading frames as predicted.


.0006   HYPERPARATHYROIDISM, NEONATAL SEVERE

CASR, ARG227LEU
SNP: rs28936684, gnomAD: rs28936684, ClinVar: RCV000008818, RCV001384282, RCV003934811

In a sporadic case of neonatal hyperparathyroidism (NSHPT; 239200), Pearce et al. (1995) found a heterozygous CGA-to-CTA transversion in codon 227 of exon 4, resulting in an amino acid substitution of leucine for arginine (R227L).

Wystrychowski et al. (2005) performed a functional analysis comparing the R227L and R227Q mutations (see 601199.0049).


.0007   HYPERPARATHYROIDISM, NEONATAL SEVERE

CASR, CYS582TYR
SNP: rs104893690, ClinVar: RCV000008819, RCV000477640

In a sporadic case of neonatal hyperparathyroidism (NSHPT; 239200), Pearce et al. (1995) described a heterozygous TGT-to-TAT transition in codon 582 of exon 7, resulting in a cys-to-tyr amino acid change (C582Y).


.0008   HYPERPARATHYROIDISM, NEONATAL SEVERE

CASR, 2-BP DEL/1-BP INS, CCC747TC
SNP: rs869320729, ClinVar: RCV000008820

In a sporadic case of neonatal hyperparathyroidism (NSHPT; 239200), Pearce et al. (1995) detected a change in codon 747 in exon 7 from CCC to TC. The mutation resulted in a frameshift with a 28-amino acid stretch of missense peptide in which a stop signal (TGA) occurred at codon 776. The mutation was associated with the loss of an HhaI site, which was used to confirm that the proband was homozygous for the mutation and that the normocalcemic parents were heterozygous. Although the parents denied consanguinity, it is likely that they share a common ancestor.


.0009   HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, GLU681HIS
SNP: rs121909261, ClinVar: RCV000008821

In 5 affected members of a 3-generation family (family N) with autosomal dominant hypocalcemia (HYPOC1; 601198), Baron et al. (1996) identified a heterozygous 2043G-T transversion in the CASR gene that resulted in a glu681-to-his (Q681H) substitution. Affected members of family N had low serum calcium concentrations, elevated serum phosphate concentrations, and low serum levels of parathyroid hormone; most presented in childhood with seizures or tetany.


.0010   HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, ALA116THR
SNP: rs104893691, ClinVar: RCV000008822, RCV001818146

In affected members of a family with autosomal dominant hypocalcemia-1 (HYPOC1; 601198), Baron et al. (1996) identified 2 mutations in the CASR gene: a T-to-A transversion at position 2550 that resulted in a substitution of serine for cysteine at residue 851 (C851S), and a G-to-A transition at position 346 that resulted in a substitution of threonine for alanine at residue 116 (A116T). Since the former mutation was also present in unaffected members of this family, Baron et al. (1996) suggested that the C851S mutation was a rare polymorphism.


.0011   HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, PHE806SER
SNP: rs104893693, ClinVar: RCV000008823, RCV002512921

In an infant with severe hypocalcemia (HYPOC1; 601198), Baron et al. (1996) identified a T-to-C transition at position 2415 that resulted in a substitution of serine for phenylalanine at residue 806 (F806S). No other affected members of the family were known; hence, Baron et al. (1996) referred to the disorder as sporadic severe hypoparathyroidism.


.0012   HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, THR151MET
SNP: rs104893694, ClinVar: RCV000008824, RCV001818147, RCV001851746

In affected members of a large Norwegian family with isolated autosomal dominant hypocalcemia (HYPOC1; 601198), Lovlie et al. (1996) identified a C-to-T transition in exon 2 (cDNA position 452) of the CASR gene, predicting a thr151-to-met (T151M) substitution. A StyI restriction site created by the nucleotide substitution was used to confirm the mutation in all affected individuals, as well as to exclude it in 100 normal alleles from blood donors. The T151M mutation is located in the extracellular N-terminal domain of CASR, which belongs to the superfamily of G protein-coupled receptors. Lovlie et al. (1996) suggested that this is a gain-of-function mutation that increases the sensitivity of the receptor to calcium ion, thereby decreasing the calcium set point.

In a family with hypercalciuric hypocalcemia, Pearce et al. (1996) identified heterozygosity for the T151M mutation in the CASR gene.


.0013   HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, ASN118LYS
SNP: rs104893695, ClinVar: RCV000008825

Pearce et al. (1996) identified heterozygosity for an asn118-to-lys (N118K) mutation of the CASR gene in a family with hypercalciuric hypocalcemia (HYPOC1; 601198).

De Luca et al. (1997) described a patient with sporadic hypoparathyroidism who was severely symptomatic from infancy and was heterozygous for the N118K mutation affecting the N-terminal, extracellular domain of CASR. The proband's parents did not carry the mutation, indicating that the mutation, although potentially familial, arose de novo.


.0014   HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, PHE128LEU
SNP: rs104893696, ClinVar: RCV000008827

In a family with hypercalciuric hypocalcemia (HYPOC1; 601198), Pearce et al. (1996) identified heterozygosity for a phe128-to-leu (F128L) mutation of the CASR gene.


.0015   REMOVED FROM DATABASE


.0016   HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, GLU191LYS
SNP: rs104893697, ClinVar: RCV000008828

In a family with hypercalciuric hypocalcemia (HYPOC1; 601198), Pearce et al. (1996) identified heterozygosity for a glu191-to-lys mutation (E191K) of the CASR gene.


.0017   HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, PHE612SER
SNP: rs104893698, ClinVar: RCV000008829

In a family with hypercalciuric hypocalcemia (HYPOC1; 601198), Pearce et al. (1996) identified heterozygosity for a phe612-to-ser mutation (F612S) of the CASR gene.


.0018   MOVED TO 601199.0036


.0019   HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, LEU773ARG
SNP: rs104893699, ClinVar: RCV000008830

De Luca et al. (1997) described a patient with sporadic hypoparathyroidism (HYPOC1; 601198), who presented with mild symptoms at age 18 years. The patient was heterozygous for a leu773-to-arg (L773R) mutation in the CASR gene that involved the fifth transmembrane domain. The proband's parents lacked the corresponding mutation, indicating that the mutation arose de novo.


.0020   HYPERPARATHYROIDISM, NEONATAL SEVERE

CASR, GLY670GLU
SNP: rs104893700, ClinVar: RCV000008831

Kobayashi et al. (1997) reported a Japanese child with severe neonatal hyperparathyroidism (NSHPT; 239200). The child was a genetic compound for codon 185 (CGA to TGA/R185X; 601199.0036) and codon 670 (GGG-to-GAG/G670E) mutations located in exons 4 and 7, respectively. The R185X mutation was also present in samples from the proband's unaffected father and paternal grandmother. The G670E mutation was also found in the sample from the proband's unaffected mother of Philippine origin.


.0021   HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, PRO39ALA
SNP: rs121909262, ClinVar: RCV000008832

In a Japanese family with hypocalciuric hypercalcemia (HHC1; 145980), Aida et al. (1995) identified a mutation in the CASR gene by PCR and SSCP. Nucleotide sequencing showed a G-to-C transversion at nucleotide 118 that resulted in a pro40-to-ala (P40A) amino acid substitution. The proband was homozygous and the consanguineous parents were heterozygous for the mutation. The parents showed borderline elevations of serum calcium. Aida et al. (1995) stated that they designated this mutation 'P40A' based on numbering according to bovine cDNA.


.0022   HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, ARG228GLN
SNP: rs28936684, gnomAD: rs28936684, ClinVar: RCV000008833, RCV000516668, RCV000524505, RCV002265551, RCV002496308, RCV003407305

In studies of DNA from 22 unrelated families or individuals with definite or possible familial hypocalciuric hypercalcemia (HHC1; 145980) or neonatal severe hyperparathyroidism (NSHPT; 239200), Chou et al. (1995) found 5 novel mutations in the CASR gene, including an arg228-to-gln (R228Q) substitution. All 5 mutations resulted in a nonconservative amino acid alteration and all were predicted to be in the large extracellular domain of the Ca(2+)-sensing receptor. In the case of the probands from 3 other families with HHC linked to 3q, no mutations were identified in CASR.


.0023   HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, THR139MET
SNP: rs121909263, ClinVar: RCV000008834, RCV002228022, RCV002476947, RCV003390662, RCV003480025

In studies of DNA from 22 unrelated families or individuals with definite or possible familial hypocalciuric hypercalcemia (HHC1; 145980) or neonatal severe hyperparathyroidism (NSHPT; 239200), Chou et al. (1995) found 5 novel mutations in the CASR gene, including a thr139-to-met (T139M) substitution. All 5 mutations resulted in a nonconservative amino acid alteration and all were predicted to be in the large extracellular domain of the Ca(2+)-sensing receptor.


.0024   HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, GLY144GLU
SNP: rs121909264, ClinVar: RCV000008835, RCV000498830, RCV000549803, RCV002271366

In studies of DNA from 22 unrelated families or individuals with definite or possible familial hypocalciuric hypercalcemia (HHC1; 145980) or neonatal severe hyperparathyroidism (NSHPT; 239200), Chou et al. (1995) found 5 novel mutations in the CASR gene, including a gly144-to-glu (G144E) substitution. All 5 mutations resulted in a nonconservative amino acid alteration and all were predicted to be in the large extracellular domain of the Ca(2+)-sensing receptor.


.0025   HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, ARG63MET
SNP: rs121909265, ClinVar: RCV000008836

In studies of DNA from 22 unrelated families or individuals with definite or possible familial hypocalciuric hypercalcemia (HHC1; 145980) or neonatal severe hyperparathyroidism (NSHPT; 239200), Chou et al. (1995) found 5 novel mutations in the CASR gene, including an arg63-to-met (R63M) substitution. All 5 mutations resulted in a nonconservative amino acid alteration and all were predicted to be in the large extracellular domain of the Ca(2+)-sensing receptor.


.0026   HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, ARG67CYS
SNP: rs121909266, ClinVar: RCV000008837, RCV000498645, RCV001851747, RCV003398474

For discussion of the arg67-to-cys (R67C) mutation in the CASR gene that was found in compound heterozygous state in studies of DNA from 22 unrelated families or individuals with definite or possible familial hypocalciuric hypercalcemia (HHC1; 145980) by Chou et al. (1995), see 601199.0022.


.0027   HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, PHE788CYS
SNP: rs104893701, ClinVar: RCV000008838, RCV001851748

In a Japanese family with severe familial hypocalcemia (HYPOC1; 601198), Watanabe et al. (1998) reported a heterozygous missense mutation encoding a phe788-to-cys (F788C) substitution in the fifth transmembrane domain of the CASR gene product. The mutation was absent in DNA from 50 control subjects. The proband presented with a seizure at 6 days of age. Her older brother and mother, who had also experienced seizures and tetany, respectively, likewise had hypoparathyroidism. Some patients in the family did not experience seizures despite their severe hypocalcemia. The authors concluded that the gain-of-function F788C mutation causes severe hypoparathyroidism by rendering the receptor more sensitive than normal to activation by cytosolic calcium.


.0028   HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, LYS47ASN
SNP: rs104893702, ClinVar: RCV000008839

Okazaki et al. (1999) reported a 41-year-old male who had asymptomatic hypocalcemia (HYPOC1; 601198) with a history of recurrent nephrolithiasis. His father had asymptomatic hypocalcemia, but his mother was normocalcemic. PCR-SSCP and DNA sequencing revealed that both the proband and his father were heterozygous for a CASR mutation that was predicted to encode a lysine-to-asparagine substitution at codon 47 (K47N), which is in the CASR extracellular domain. The authors concluded that the N-terminal portion of CASR is important in extracellular calcium sensing.


.0029   HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, LEU616VAL
SNP: rs104893703, ClinVar: RCV000008840

Stock et al. (1999) evaluated a 3-generation family segregating autosomal dominant hypocalcemia (HYPOC1; 601198), short stature, and premature osteoarthritis. A 74-year-old female (generation I) presented with hypoparathyroidism, a movement disorder secondary to ectopic calcification of the cerebellum and basal ganglia, and a history of knee and hip replacements for osteoarthritis. Two members of generation II and 1 member of generation III were also documented with hypoparathyroidism, short stature, and premature osteoarthritis evident as early as 11 years of age. Sequencing of PCR-amplified genomic DNA revealed a C-to-G transversion at nucleotide 1846 of the CASR gene, resulting in a leu616-to-val (L616V) substitution in the first transmembrane domain. The mutation cosegregated with the disorder; however, this amino acid sequence change did not affect the total accumulation of inositol phosphates as a function of extracellular calcium concentrations in transfected HEK293 cells.


.0030   HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, 543-BP DEL, NT2682
SNP: rs1553769169, ClinVar: RCV000008841

Lienhardt et al. (2000) reported a 3-generation family with autosomal dominant hypocalcemia (HYPOC1; 601198) caused by a large in-frame deletion of 181 amino acids in the C-terminal tail of CASR from ser895 to val1075. The affected grandfather was homozygous for the deletion but was not more severely affected than the heterozygous affected individuals. Functional properties of mutant and wildtype CASRs were studied in transiently transfected fura-2-loaded HEK293 cells. The mutant CASR exhibited a gain of function, but there was no difference between cells transfected with mutant cDNA alone or cotransfected with mutant and wildtype cDNAs, consistent with the similar phenotypes of heterozygous and homozygous family members. The authors concluded that this activating deletion may exert a dominant-positive effect on the wildtype CASR. The cell surface expression of the mutant CASR was greater than that of the wildtype CASR, potentially contributing to its gain of function.


.0031   HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, PHE881LEU
SNP: rs104893704, ClinVar: RCV000008842, RCV000549191

In a large Swedish family in which 20 members had hypercalcemia, including 3 who were hypocalciuric and 7 who were hypercalciuric (HHC1; 145980), Carling et al. (2000) identified heterozygosity for a c.2641T-C transition in exon 7 of the CASR gene, resulting in a phe881-to-leu (F881L) substitution within the cytoplasmic tail of the calcium-sensing receptor. The mutation segregated fully with disease in the family. A construct of the mutant receptor expressed in HEK293 cells demonstrated a right-shifted dose-response relationship between the extracellular and intracellular calcium concentrations, consistent with an inactivating mutation.


.0032   HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

HYPERPARATHYROIDISM, NEONATAL SEVERE, INCLUDED
CASR, ARG648TER
SNP: rs104893705, gnomAD: rs104893705, ClinVar: RCV000008843, RCV000054484, RCV002318944, RCV003764537

Jap et al. (2001) studied a 79-year-old male with hypocalciuric hypercalcemia (HHC1; 145980) without sibs or children. DNA sequence analysis of the CASR gene showed that the proband was heterozygous for a CGA-to-TGA transition in exon 7 of the CASR gene that encoded an arg648-to-ter (R648X) mutation. This mutation, located in the C terminus of the first intracellular loop of the calcium-sensing receptor, predicts a markedly truncated protein. The mutation was not found in a control group of 50 normal Chinese subjects in Taiwan.

Ward et al. (2004) found this mutation in compound heterozygosity with a G94X truncation of the receptor (601199.0042) in an Australian infant with neonatal severe hyperparathyroidism (NSHPT; 239200). Confocal microscopy demonstrated that the R648X receptor was present in the cytoplasm and also associated with the cell membrane. Functional assays in which R648X and wildtype receptor were cotransfected into HEK293 cells demonstrated a reduction in wildtype Ca(2+) responsiveness by the R648X receptor, even at physiologic Ca(2+) levels, thus simulating familial hypocalciuric hypercalcemia (145980) in relatives of the infant who were heterozygous for the R648X mutation. The R648X receptor alone was nonresponsive to Ca(2+).


.0033   HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, IVS2AS, G-T, -1
SNP: rs797044441, ClinVar: RCV000008845, RCV001390066, RCV002318945

In 2 affected individuals from a large kindred in which some members had familial hypocalciuric hypercalcemia (HHC1; 145980) and others had neonatal severe hyperparathyroidism (NSHPT; 239200), previously studied by Philips (1948), Hillman et al. (1964), and Marx et al. (1985), D'Souza-Li et al. (2001) identified heterozygosity for a G-to-T transversion in the last nucleotide of intron 2. Both affected individuals had HHC. Defects in mRNA splicing were studied by illegitimate transcription of the CASR gene in lymphoblastoid cells from an HHC1-affected individual. The mutation resulted predominantly in exon 3 skipping, causing a shift in the exon 4 reading frame and introducing a premature stop codon that led to a predicted truncated protein of 153 amino acids. D'Souza-Li et al. (2001) stated that this was the first description of a splice site mutation in the CASR gene. The 2 brothers with NSHPT in this branch of the family and their consanguineous parents with HCC were not studied, but D'Souza-Li et al. (2001) noted that previous reports had indicated that individuals who inherit 2 inactive copies of the CASR gene may have NSHPT.


.0034   HYPOCALCEMIA, AUTOSOMAL DOMINANT 1, WITH BARTTER SYNDROME

HYPOCALCEMIA, AUTOSOMAL DOMINANT 1, INCLUDED
CASR, ALA843GLU
SNP: rs104893706, ClinVar: RCV000008847, RCV000054480

Watanabe et al. (2002) reported the case of a 19-year-old man who showed tetany soon after birth and had striking autosomal dominant hypocalcemia, for which he was treated with vitamin D3. Because of nephrocalcinosis, his renal function gradually deteriorated. He also had clinical features of Bartter syndrome (see 601198): hypomagnesemia, hypokalemia with metabolic alkalosis, hyperreninemia, and hyperaldosteronemia. Direct sequencing of all coding exons of the CASR gene demonstrated a heterozygous substitution of adenine (GAA) for cytosine (GCA) at codon 843, resulting in an ala843-to-glu (A843E) substitution. Watanabe et al. (2002) noted that in rats it had been shown that activation of this calcium-sensing receptor by higher concentrations of extracellular calcium ions inhibits the activity of the renal outer-medullary potassium channel (KCNJ1; 600359) (see Brown and MacLeod, 2001); the KCNJ1 gene is mutated in type 2 Bartter syndrome.

Sato et al. (2002) found this mutation in a Japanese patient with hypercalciuric hypocalcemia (HYPOC1; 601198).


.0035   HYPOCALCEMIA, AUTOSOMAL DOMINANT 1, WITH BARTTER SYNDROME

CASR, CYS141TRP
SNP: rs121909267, ClinVar: RCV000008849

Watanabe et al. (2002) reported the case of a 26-year-old woman who showed tetany soon after birth and had autosomal dominant hypocalcemia, for which she was treated with vitamin D metabolites and calcium, as well as clinical features of Bartter syndrome (see 601198), including nephrocalcinosis, hypomagnesemia, hypokalemia with metabolic alkalosis, hyperreninemia, and hyperaldosteronemia. Direct sequencing of all coding exons of the CASR gene revealed that the patient had a heterozygous substitution of guanine (TGG) for cytosine (TGC) at codon 131, which resulted in a cys131-to-trp (C131W) substitution.


.0036   HYPERPARATHYROIDISM, NEONATAL SEVERE

CASR, ARG185TER
SNP: rs104893707, gnomAD: rs104893707, ClinVar: RCV000008850, RCV001040159

For discussion of the arg185-to-ter (R185X) mutation in the CASR gene that was found in compound heterozygous state in a child with severe neonatal hyperparathyroidism (NSHPT; 239200) by Kobayashi et al. (1997), see 601199.0020.


.0037   HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

HYPOCALCEMIA, AUTOSOMAL DOMINANT 1, WITH BARTTER SYNDROME, INCLUDED
CASR, LEU125PRO
SNP: rs104893708, ClinVar: RCV000008851, RCV000190877, RCV001781207, RCV002482843, RCV003764538

In a Japanese patient with hypercalciuric hypocalcemia (HYPOC1; 601198), Sato et al. (2002) found a heterozygous leu125-to-pro (L125P) mutation in the N-terminal extracellular domain of the calcium-sensing receptor.

In a boy with hypocalcemia who also displayed features of Bartter syndrome (see 601198), with a decrease in the distal tubular fractional chloride reabsorption rate and negative NaCl balance, secondary hyperaldosteronism, and hypokalemia, Vargas-Poussou et al. (2002) identified heterozygosity for a de novo c.374T-C transition in exon 3 of the CASR gene, resulting in the L125P substitution at a highly conserved residue in the extracellular domain, in a region involved in maintaining the inactive conformation of the calcium-sensing receptor. The mutation was not present in his unaffected parents or sister or in 50 unrelated controls. Functional analysis in transfected HEK293 cells revealed that the L125P mutation was more potent than any previously reported gain-of-function mutation, with an EC50 value approximately one-third that of wildtype; Vargas-Poussou et al. (2002) proposed that mutant L125P CASR may reduce NaCl reabsorption in the cortical thick ascending limb sufficiently to result in renal loss of NaCl with secondary hyperaldosteronism and hypokalemia.


.0038   HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, SER820PHE
SNP: rs104893710, ClinVar: RCV000008852

Nagase et al. (2002) reported a novel activating mutation in the CASR gene in a Japanese family with autosomal dominant hypocalcemia (HYPOC1; 601198). The proband, a 15-year-old boy, and 5 other patients in 3 generations were asymptomatic, except for the proband's grandmother who had a history of seizures. Nucleotide sequencing revealed that the proband had a known polymorphism and a novel heterozygous mutation substituting phenylalanine for serine at codon 820 (S820F) in the sixth transmembrane helix of the CASR gene. In other family members, the S820F mutation cosegregated with hypocalcemia. The mutation was not detected in 50 control subjects. The known polymorphism was observed in 8 of 9 family members with or without hypocalcemia and in 36 of 50 controls.


.0039   HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, PHE788LEU
SNP: rs104893711, ClinVar: RCV000008853

In 2 sibs with hypocalcemia (HYPOC1; 601198), Hendy et al. (2003) found heterozygosity for a T-to-C transition in exon 7 of the CASR gene, resulting in a phe788-to-leu (F788L) substitution in the fifth transmembrane domain of the protein. Both parents and the third sib were clinically unaffected and were found to be genotypically normal by direct sequencing of their leukocyte exon 7 PCR amplicons. However, the mother was mosaic for the mutation, determined by sequence analysis of multiple subclones as well as by denaturing HPLC of the CASR exon 7 leukocyte PCR product. Transient transfection analyses of wildtype and mutant CASR proteins in HEK293 cells showed mutant CASR expressed at a similar level as the wildtype. The F788L mutant induced a significant shift to the left relative to the wildtype CASR protein in the MAPK (see 602448) response to increasing extracellular calcium concentrations. The authors stated that this was the first report of mosaicism for an activating CASR mutation and suggested that care should be exercised in counseling for risks of recurrence in a situation where a de novo mutation appears likely.


.0040   CASR POLYMORPHISM

CASR, ALA986SER
SNP: rs1801725, gnomAD: rs1801725, ClinVar: RCV000008854, RCV000152933, RCV000299158, RCV000343555, RCV000356249, RCV000405678, RCV001269361, RCV001510800, RCV002336079

In female North American cohorts, Cole et al. (1999) and Cole et al. (2001) described an association between serum ionized calcium and a common polymorphism, ala986 to ser (A986S), in the cytoplasmic tail of the calcium-sensing receptor. Scillitani et al. (2004) confirmed the association in 377 healthy Italian Caucasian adults (184 men and 193 women). Their results also suggested that 2 neighboring exon 7 polymorphisms were predictive as well. Relative frequency for the minor 986S allele was 24%. Subjects with the AA genotype had significantly lower serum ionized calcium (P = 0.0001) than subjects with 1 or 2 S alleles.


.0041   HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, GLU604LYS
SNP: rs104893712, ClinVar: RCV000008855, RCV000414467, RCV001804717, RCV001851749, RCV003343599, RCV003390663

In a 3-generation family with autosomal dominant hypocalcemia (HYPOC1; 601198), Tan et al. (2003) reported a heterozygous single-base transition in the CASR gene, G2182A in exon 7, causing a novel activating mutation, glu604 to lys (E604K), in the calcium-sensing receptor. Whereas all affected individuals exhibited marked hypocalcemia, some cases with untreated hypocalcemia exhibited seizures in infancy, and others were largely asymptomatic from birth into adulthood. The missense mutation E604K, which affects an amino acid residue in the C terminus of the cysteine-rich domain of the extracellular head, cosegregated with hypocalcemia in all 7 individuals for whom DNA was available. The mutation was assessed in HEK293 cells transiently transfected with cDNA corresponding to either wildtype CASR or CASR carrying the E604K mutation derived by site-directed mutagenesis. There was a significant leftward shift in the concentration response curves for the effects of extracellular Ca(2+) on both intracellular Ca(2+) mobilization and MAPK (see 602448) activity. The C terminus of the cysteine-rich domain of the extracellular head may normally act to suppress receptor activity in the presence of low extracellular Ca(2+) concentrations.


.0042   HYPERPARATHYROIDISM, NEONATAL SEVERE

CASR, GLY94TER
SNP: rs104893709, ClinVar: RCV000008856

In a 5-month-old Australian infant with neonatal severe hyperparathyroidism (NSHPT; 239200) characterized by moderately severe hypercalcemia and very high PTH levels, coupled with evidence of hyperparathyroidism and effects on brain development not previously demonstrated, Ward et al. (2004) detected point mutations on separate alleles of the CASR, one a novel G-to-T transversion in exon 2 leading to a premature termination at gly94 (G94X), and the other an R648X mutation (601199.0032). The G94X mutation occurred early in the extracellular ligand-binding domain, and the mutated receptor was predicted to be unable to anchor to the membrane and to lack signaling capacity. Confocal microscopy demonstrated cytoplasmic localization of the G94X receptor. The G94X truncated receptor could not be detected by Western blot analysis. The authors stated that this infant represented the first report of complete functional deletion of the human calcium-sensing receptor.


.0043   HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, ARG465GLN
SNP: rs104893716, ClinVar: RCV000008857, RCV000459271, RCV002390100, RCV003482226

In a 52-year-old woman with familial benign hypocalciuric hypercalcemia (HHC1; 145980), Leech et al. (2006) identified a heterozygous 1394G-A transition in exon 5 of the CASR gene, resulting in an arg465-to-gln (R465Q) substitution. They also identified heterozygosity for the A986S polymorphism (601199.0040). The proband's brother had the identical genotype. As the parents were not available for genetic analysis, it could not be determined if the mutation and polymorphism were on the same or different alleles. Receptors with either of these mutations localized to the plasma membrane of transfected HEK293 cells, and Western blot analysis showed that the quantity of the R465Q mutant receptor was higher than that of the wildtype receptor. Dose-response curves showed the R465Q mutation significantly reduced the sensitivity of the receptor to extracellular Ca(2+) concentrations. The A986S polymorphism seemed to mildly increase calcium sensitivity.


.0044   HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, LEU13PRO
SNP: rs104893717, ClinVar: RCV000008858, RCV002362572

In a 9-year-old Brazilian girl with hypocalciuric hypercalcemia (HHC1; 145980), Miyashiro et al. (2004) detected homozygosity for a T-to-C transition at nucleotide 38 in exon 2 of the CASR gene, resulting in a leu13-to-pro (L13P) substitution. The patient was admitted with a 6-month history of headaches and emesis and was found to be severely hypercalcemic. Functional characterization of the mutant receptor showed a dose-response curve shifted to the right relative to that of wildtype. The proband's consanguineous parents, who had mild asymptomatic hypercalcemia, carried the same mutation in heterozygous state. Miyashiro et al. (2004) concluded that patients with homozygous inactivation of the CASR gene may present with severe hypercalcemia in late phases of life and, based on their report and those of others (Aida et al., 1995; Chikatsu et al., 1999), suggested that homozygous mutation found in the very beginning N-terminal portion of the CASR may be associated with this phenotype.

Pidasheva et al. (2005) showed that L11S and L13P mutants, which affect the N-terminal signal peptide, demonstrated reduced intracellular and plasma membrane expression and signaling to the MAPK pathway in response to extracellular calcium, relative to wildtype CASR. Both mutant CASR RNAs translated into protein normally. In cotranslational processing assays, wildtype CASR was targeted to microsomal vesicles, translocated into the vesicular lumen, and underwent core N-glycosylation. In contrast, the L11S and L13P mutants failed to be inserted in the microsomes and did not undergo proper glycosylation. Pidasheva et al. (2005) concluded that both L11S and L13P mutants are markedly impaired with respect to cotranslational processing, accounting for the observed parathyroid dysfunction.


.0045   HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, LEU727GLN
SNP: rs104893718, ClinVar: RCV000008859

In an infant presenting with hypocalcemia (HYPOC1; 601198) at 3 weeks of age, Mittelman et al. (2006) identified heterozygosity for a de novo leu727-to-gln (L727Q) mutation on the border between transmembrane helix-4 and the intracellular loop-2 of CASR. When transiently expressed in a human embryonic kidney 293 cell line, the mutant receptor demonstrated a significant leftward shift in the extracellular calcium/intracellular signaling dose-response curve versus that for the wildtype receptor. During treatment with PTH(1-34), the patient had no further serious hypocalcemic episodes, and his urinary calcium excretion declined remarkably.


.0046   HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, PHE180CYS
SNP: rs121909268, ClinVar: RCV000008860

Zajickova et al. (2007) studied a kindred with familial hypocalciuric hypercalcemia (145980) in which the proband, a 34-year-old male, was initially diagnosed with primary hyperparathyroidism due to frankly elevated serum PTH levels. A heterozygous TTC-to-TGC transversion in exon 4 of the CASR gene, resulting in a phe180-to-cys (F180C) substitution 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 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 and the serum calcium level remained at a constant and moderately elevated level.


.0047   HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, CYS582PHE
SNP: rs104893690, ClinVar: RCV000008861

In 6 patients from the same family with hypocalciuric hypercalcemia (145980), Nissen et al. (2007) identified a G-to-T transversion at nucleotide 1745 in exon 7 of the CASR gene that resulted in a substitution of phe for cys at codon 582 (C582F). Another mutation affecting this codon has been found (601199.0007). A similar biochemical phenotype was found for both mutations at cys582, with mild to moderate elevation of plasma PTH.


.0048   HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, GLY553ARG
SNP: rs104893719, ClinVar: RCV000008862, RCV003320545

In 3 patients from 2 families with hypocalciuric hypercalcemia (145980), Nissen et al. (2007) identified a G-to-A transition at nucleotide 1657 in exon 6 of the CASR gene, resulting in a gly553-to-arg amino acid substitution (G553R). Mean plasma PTH was mild to moderately elevated in mutation carriers.


.0049   HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, ARG227GLN
SNP: rs28936684, gnomAD: rs28936684, ClinVar: RCV000008833, RCV000516668, RCV000524505, RCV002265551, RCV002496308, RCV003407305

In 4 members of a Polish family with hypocalciuric hypercalcemia (145980), Wystrychowski et al. (2005) found a heterozygous G-to-A transition in exon 4 of the CASR gene that resulted in an arg227-to-gln amino acid substitution (R227Q). The proband presented in a typical fashion with slightly elevated serum calcium and magnesium and serum PTH values within the normal range, although inappropriately elevated given the prevailing serum calcium concentration. Parathyroidectomy failed to normalize the hypercalcemia. Noting that a de novo heterozygous R227L mutation had previously been identified in a case of neonatal hyperparathyroidism (601199.0006), Wystrychowski et al. (2005) performed a functional analysis by transiently transfecting wildtype and mutant (R227Q, R227L) CaSRs in HEK293 cells. Both mutant receptors were expressed at a similar level to that of the wildtype. Although both mutants were impaired in their MAPK responses to increasing extracellular calcium concentrations, this was more marked for R227L (EC50 = 9.7 mM) than R227Q (EC50 = 7.9 mM) relative to wildtype (EC50 = 3.7 mM). When cotransfected with wildtype CaSR to mimic the heterozygous state, the curves for both R227Q and R227L were right-shifted intermediate to the curves for wildtype and the respective mutant. Wystrychowski et al. (2005) concluded that this differential responsiveness may account, in part, for the markedly different clinical presentation of the R227Q mutation, familial benign hypercalcemia, versus the neonatal hyperparathyroidism of the R227L mutation.


.0050   EPILEPSY, IDIOPATHIC GENERALIZED, SUSCEPTIBILITY TO, 8 (1 family)

CASR, ARG898GLN
SNP: rs121909269, gnomAD: rs121909269, ClinVar: RCV000008864, RCV000687562, RCV002433450, RCV002476948

In affected members of a large 3-generation Indian family (family 1) with idiopathic generalized epilepsy (EIG8; 612899), Kapoor et al. (2008) identified a heterozygous c.2693G-A transition (c.2693G-A, NM_000388) in the CASR gene, resulting in an arg898-to-gln (R898Q) substitution at a highly conserved residue located close to 3 potential phosphorylation sites. The mutation segregated with the disorder in the family and was not detected in 504 control chromosomes. Seizure types in this family were variable, but included myoclonic seizures, absence seizures, febrile seizures, complex partial seizures, and generalized tonic-clonic seizures. None of the patients had electrolyte abnormalities. Four additional possibly pathogenic variants in the CASR gene were identified in 5 of 96 unrelated patients with juvenile myoclonic epilepsy from southern India.

Stepanchick et al. (2010) found that the R898Q mutation resulted in extracellular calcium-stimulated ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) phosphorylation levels equal to or greater than those of wildtype CASR, suggesting that this mutation induces a gain-of-function phenotype.


.0051   HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, PRO221GLN
SNP: rs397514728, ClinVar: RCV000054482, RCV002515738

In a proband with hypocalciuric hypercalcemia (145980), Hannan et al. (2012) identified heterozygosity for a c.662C-A transversion in exon 4 of the CASR gene, resulting in a pro221-to-gln (P221Q) substitution in the VTFD portion of the extracellular domain. Homology modeling predicted that the side chain of the mutant glutamine residue would extend across the entrance of calcium binding site (CaBS)-1, impairing ligand entry and leading to a loss of CASR function. Functional analysis in transfected HEK293 cells confirmed that the P221Q mutant causes a loss of CASR function compared to wildtype.


.0052   HYPOCALCEMIA, AUTOSOMAL DOMINANT 1

CASR, PRO221LEU
SNP: rs397514728, ClinVar: RCV000054481, RCV000518374, RCV001384281, RCV001797617, RCV002490628, RCV003343624, RCV003934995

In a proband with hypocalcemia (HYPOC1; 601198), Hannan et al. (2012) identified heterozygosity for a c.662C-T transition in exon 4 of the CASR gene, resulting in a pro221-to-leu (P221L) substitution in the VTFD portion of the extracellular domain. Homology modeling predicted that the L221 mutant would enhance Ca(2+) entry into calcium binding site (CaBS)-1 due to the substitution of the rigid side chain of the wildtype proline residue at the entrance to the VFTD cleft with the more flexible leucine side chain. Functional analysis in transfected HEK293 cells confirmed that the P221L mutant causes a gain of CASR function compared to wildtype.


.0053   HYPOCALCEMIA, AUTOSOMAL DOMINANT 1, WITH BARTTER SYNDROME

CASR, LYS29GLU
SNP: rs397514729, ClinVar: RCV000054483

In monozygotic twin sisters of Italian origin who presented with severe hypocalcemia in the neonatal period (601198), Hu et al. (2004) identified heterozygosity for a de novo c.85A-G transition in exon 2 of the CASR gene, resulting in a lys29-to-glu (K29E) substitution in the extracellular VFT domain. The mutation was not present in their unaffected parents or older sister. In transfected HEK293 cells, the mutant K29E calcium-sensing receptor showed a marked increase in Ca(2+) sensitivity, including when it was cotransfected with wildtype CASR cDNA, consistent with a dominant effect. In a follow-up study, Vezzoli et al. (2006) reported that the twins developed Bartter syndrome (see 601198)-like features at age 22 years, with mild hypokalemia, mild hyperreninemia and hyperaldosteronism, but no alkalosis.


.0054   HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, ARG886PRO
SNP: rs1057520791, ClinVar: RCV000443461, RCV000664400, RCV000694836

In a family (kindred 5780) with hypercalcemia, in which the proband and 1 affected son were hypercalciuric whereas a second affected son and 4 hypercalcemic grandchildren were hypocalciuric (HHC1; 145980), Simonds et al. (2002) identified heterozygosity for an arg866-to-pro (R866P) substitution in the CASR gene that was not found in 3 unaffected family members. The authors noted that findings typical of HHC in this family included hypercalcemia before 10 years of age, relative hypocalciuria, hypermagnesemia, and persistent postoperative hyperparathyroidism in the 2 patients who underwent subtotal parathyroidectomy. However, features atypical of HHC were also observed, including hypercalciuria in 2 affected family members as well as an intact PTH level of 179 pg/mL in the proband, more than 2 times above the value reported to discriminate between HHC and forms of hyperparathyroidism.


.0055   HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I

CASR, THR972MET
SNP: rs200620134, gnomAD: rs200620134, ClinVar: RCV000288087, RCV000345436, RCV000383567, RCV000525899, RCV000664401, RCV000711038, RCV002319481

In a 68-year-old man with hypercalcemia, inappropriately normal PTH levels, hypercalciuria, and recurrent nephrolithiasis (HHC1; 145980), Mastromatteo et al. (2014) identified heterozygosity for a c.2915C-T transition in exon 7 of the CASR gene, resulting in a thr972-to-met (T972M) substitution in the cytoplasmic tail. Screening of the proband's 3 asymptomatic sons revealed 1 carrier, a 41-year-old man with an ionized calcium level at the upper limit of normal and normal PTH and urinary calcium levels. Functional evaluation demonstrated strong impairment of signaling activity of the mutant receptor compared to wildtype, even at higher Ca(2+) concentrations. The authors concluded that T972M represents an inactivating mutation of the CASR gene causing an atypical presentation of familial benign hypercalcemia with hypercalciuria. The variant was not present in the public CaSR or 1000 Genomes Project databases.


See Also:

Lyons et al. (1990)

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Contributors:
Marla J. F. O'Neill - updated : 07/25/2018
Patricia A. Hartz - updated : 7/6/2016
Marla J. F. O'Neill - updated : 8/12/2013
Ada Hamosh - updated : 1/7/2013
Cassandra L. Kniffin - updated : 7/8/2009
John A. Phillips, III - updated : 3/5/2009
John A. Phillips, III - updated : 6/24/2008
George E. Tiller - updated : 6/16/2008
John A. Phillips, III - updated : 3/20/2008
John A. Phillips, III - updated : 12/20/2007
John A. Phillips, III - updated : 12/19/2007
Ada Hamosh - updated : 12/6/2006
John A. Phillips, III - updated : 11/17/2006
Patricia A. Hartz - updated : 8/9/2006
John A. Phillips, III - updated : 7/22/2005
John A. Phillips, III - updated : 6/29/2005
John A. Phillips, III - updated : 4/12/2005
John A. Phillips, III - updated : 11/4/2004
Victor A. McKusick - updated : 10/21/2004
Victor A. McKusick - updated : 9/2/2004
Marla J. F. O'Neill - updated : 8/11/2004
George E. Tiller - updated : 12/2/2003
Patricia A. Hartz - updated : 11/17/2003
John A. Phillips, III - updated : 2/4/2003
John A. Phillips, III - updated : 1/6/2003
Victor A. McKusick - updated : 11/19/2002
John A. Phillips, III - updated : 7/1/2002
Victor A. McKusick - updated : 11/29/2001
John A. Phillips, III - updated : 7/3/2001
John A. Phillips, III - updated : 11/14/2000
John A. Phillips, III - updated : 9/29/2000
John A. Phillips, III - updated : 10/29/1999
Victor A. McKusick - updated : 9/8/1999
John A. Phillips, III - updated : 1/7/1999
John A. Phillips, III - updated : 10/31/1997
Michael J. Wright - updated : 9/25/1997
Beat Steinmann - updated : 3/13/1997
Moyra Smith - updated : 6/6/1996

Creation Date:
Victor A. McKusick : 4/11/1996

Edit History:
carol : 07/03/2023
carol : 09/24/2019
carol : 07/30/2018
carol : 07/25/2018
joanna : 02/21/2017
carol : 07/15/2016
carol : 7/14/2016
mgross : 7/6/2016
joanna : 6/23/2016
joanna : 6/23/2016
carol : 9/15/2015
mcolton : 8/17/2015
carol : 2/18/2015
carol : 8/13/2013
carol : 8/12/2013
carol : 8/12/2013
alopez : 1/7/2013
terry : 1/7/2013
alopez : 10/21/2009
wwang : 7/31/2009
ckniffin : 7/8/2009
alopez : 3/5/2009
wwang : 11/5/2008
alopez : 6/24/2008
wwang : 6/20/2008
terry : 6/16/2008
carol : 3/20/2008
carol : 12/21/2007
carol : 12/20/2007
carol : 12/20/2007
carol : 12/19/2007
carol : 2/28/2007
alopez : 12/15/2006
terry : 12/6/2006
alopez : 11/17/2006
carol : 9/27/2006
wwang : 8/24/2006
terry : 8/9/2006
wwang : 12/20/2005
alopez : 7/22/2005
alopez : 6/29/2005
alopez : 5/16/2005
wwang : 4/12/2005
terry : 4/5/2005
tkritzer : 2/4/2005
terry : 1/31/2005
carol : 11/11/2004
carol : 11/11/2004
alopez : 11/4/2004
tkritzer : 10/22/2004
terry : 10/21/2004
alopez : 9/5/2004
terry : 9/2/2004
carol : 8/11/2004
terry : 8/11/2004
alopez : 3/17/2004
mgross : 12/2/2003
mgross : 11/17/2003
mgross : 11/17/2003
tkritzer : 5/9/2003
tkritzer : 3/3/2003
cwells : 2/4/2003
alopez : 1/6/2003
alopez : 12/4/2002
tkritzer : 12/3/2002
tkritzer : 12/3/2002
tkritzer : 11/22/2002
terry : 11/19/2002
alopez : 7/1/2002
carol : 1/15/2002
mcapotos : 12/12/2001
terry : 11/29/2001
alopez : 7/3/2001
mgross : 12/1/2000
terry : 11/14/2000
terry : 10/23/2000
mgross : 10/3/2000
terry : 9/29/2000
carol : 3/8/2000
alopez : 10/29/1999
jlewis : 9/17/1999
terry : 9/8/1999
alopez : 1/7/1999
alopez : 1/7/1999
mark : 1/10/1998
alopez : 11/19/1997
alopez : 11/11/1997
alopez : 11/11/1997
alopez : 11/6/1997
dholmes : 10/31/1997
dholmes : 10/16/1997
mark : 6/16/1997
mark : 6/16/1997
mark : 6/16/1997
joanna : 3/13/1997
mark : 10/24/1996
mark : 10/23/1996
terry : 9/18/1996
marlene : 8/15/1996
mark : 6/19/1996
mark : 6/19/1996
carol : 6/9/1996
carol : 6/6/1996
mark : 4/18/1996
mark : 4/18/1996
mark : 4/15/1996
mark : 4/15/1996
mark : 4/15/1996
terry : 4/12/1996
mark : 4/11/1996