Disease relevance of CASR

• The inherited disorders, familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT), are caused by inactivating mutations in the CASR gene [1].
• In summary, the CASR gene has several functional kappaB elements that mediate its upregulation by proinflammatory cytokines and probably contribute to altered extracellular calcium homeostasis in the critically ill [2].
• Strong down-regulation of the CASR protein is seen in a proportion of parathyroid carcinomas with a high proliferation index [3].
• In contrast to the adenomas and hyperplasias, 31% of carcinomas demonstrated down-regulation of CASR [3].
• CONTEXT: Persistent hypercalciuria, with the attendant risk of nephrocalcinosis and eventual renal failure, is common in hypoparathyroid patients, especially those with activating mutations of the calcium-sensing receptor (CASR) gene, being treated with oral calcium and calcitriol [4].

Psychiatry related information on CASR

• A multiple regression analysis, including age, height, weight and physical activity, revealed that the CASR allelic variants were not independent predictors of BMD at any site measured (beta=-0.03-0.09; P>0.05) [5].
• This article reports a descriptive research study of the role identity and job satisfaction of 43 staff community health nurses practicing in home health care, generalized public health nursing, combined public health/home health care (PH/HHC), and specialized programmes [6].

High impact information on CASR

• In addition, the HIFalpha transcriptional activation function is modulated further by asparagine hydroxylation by FIH (factor-inhibiting HIF), which affects recruitment of the coactivators p300 and CBP [7].
• We demonstrate that mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT), two inherited conditions characterized by altered calcium homeostasis [8].
• In a few syndromes, tissue selectivity arises from mutation in the open reading frame of a regulatory gene (CASR, TSHR) with selective expression driven by its promoter [9].
• Missense mutations have been identified in the coding region of the extracellular calcium-sensing receptor (CASR) gene and cause human autosomal dominant hypo- and hypercalcemic disorders [10].
• In vitro transcription of exon 7 of the CASR containing the Alu sequence yielded the full-length mutant product and an additional shorter product that was truncated due to stalling of the polymerase at the poly(T) tract [10].

Chemical compound and disease context of CASR

• Extracellular Ca(2+) and 1,25(OH)(2)D(3) are potential candidates involved in regulating CaSR expression in the colon and the chemopreventive actions of Ca(2+) and 1,25(OH)(2)D(3) in colon cancer may be mediated, in part, through the CaSR [11].
• This article describes a patient with ADH due to a gain-of-function mutation in the CaSR, L125P, associated with a Bartter-like syndrome that is characterized by a decrease in distal tubular fractional chloride reabsorption rate and negative NaCl balance with secondary hyperaldosteronism and hypokalemia [12].
• Changes in calcium concentration were induced by an infusion of disodium-EDTA or calcium in 2 members of a family suffering from hypocalciuric hypercalcaemia ( FHH ) associated with interstitial lung disease [13].
• This study investigated involucrin staining patterns in fibrous inflammatory hyperplasia of oral mucous membrane (FIH) [14].

Biological context of CASR

• The CASR A986S polymorphism is a likely candidate locus for genetic predisposition to various bone and mineral disorders in which extracellular calcium concentrations have a prominent part [15].
• METHODS: We genotyped the CASR A986S variant (S allele frequency of 16.3%) in 163 healthy adult women and tested samples of their serum for total calcium, albumin, total protein, creatinine, phosphate, pH, and parathyroid hormone [15].
• The CASR, a cell surface glycoprotein expressed in parathyroid gland and kidney, is critical for maintaining extracellular calcium homeostasis [1].
• Mutagenesis of some, but not all, of the potential kappaB elements in the 5' part of the CASR gene led to loss of responsiveness to cytokine [2].
• Four haplotypes were defined on the basis of CASR gene SNP: haplotype 1 was characterized by the most frequent sequence; haplotypes 2, 3, or 4 by the presence of a single polymorphic variant at codon 986, 990, or 1011, respectively [16].

Anatomical context of CASR

• The CASR has an N-terminal, 19 amino acid signal peptide that is predicted to direct the nascent polypeptide chain, as it emerges from the ribosome, into the endoplasmic reticulum (ER) [1].
• Here, we show in vivo in the rat that parathyroid, thyroid, and kidney CASR mRNA and protein increased after injection of interleukin-1beta [2].
• The calcium-sensing receptor (CASR), expressed in parathyroid chief cells, thyroid C-cells, and cells of the kidney tubule, is essential for maintenance of calcium homeostasis [17].
• Roles of Ca2+ and the Ca2+-sensing receptor (CASR) in the expression of inducible NOS (nitric oxide synthase)-2 and its BH4 (tetrahydrobiopterin)-dependent activation in cytokine-stimulated adult human astrocytes [18].
• No germ-line mutation of the MEN1 gene was detected in three pedigrees of familial pituitary adenoma and three cases of FIHP [19].

Associations of CASR with chemical compounds

• Sequence analysis demonstrated, in addition to the already described A986S polymorphism, a novel heterozygous G--> A substitution in CASR exon 5 that causes an arginine to glutamine substitution at codon 465 (R465Q) [20].
• Treatment of these same cells with a calcimimetic, NPS-R-568, augments the CaSR response to Ca(2+), increasing phosphatidylinositol turnover and ERK1/2 phosphorylation, and overcoming the autoantibody effects [21].
• These results suggest that extracellular Ca(2+) and the CaSR may function to regulate the differentiation of colonic epithelial cells and that disruption of this ligand receptor system may contribute to abnormal differentiation and malignant progression [22].
• The Ca(2+)-sensing receptor (CaSR) belongs to the class III G-protein-coupled receptors (GPCRs), which include receptors for pheromones, amino acids, sweeteners, and the neurotransmitters glutamate and gamma-aminobutyric acid (GABA) [23].
• PCR-single strand conformation polymorphism and sequencing revealed that both the proband and the father had a novel heterozygous mutation in CaSR gene that causes lysine to asparagine substitution at codon 47 (K47N), which is in the extracellular domain of CaSR, like 6 of 11 known activating mutations [24].

Physical interactions of CASR

• Our CaSR model should facilitate the development of novel drugs of this important therapeutic target and the identification of the molecular determinants involved in the binding of allosteric modulators of class 3 G-protein-coupled receptors [25].
• However, the magnesium binding site responsible for inhibition of PTH secretion is not identical with the extracellular ion binding site of the CaSR, because the magnesium deficiency-dependent signal enhancement was not altered on CaSR receptor mutants with increased or decreased affinity for calcium and magnesium [26].

Regulatory relationships of CASR

• Our findings also suggest that CaSR signaling may act via both Gq and Gi to inhibit PTH secretion [21].
• Also, osteocalcin, a calcium-binding protein highly expressed in bone, dose-dependently stimulated GPRC6A activity in the presence of calcium but inhibited the calcium-dependent activation of CASR [27].
• Neonatal severe hyperparathyroidism results from homozygosity for inactivating mutations in the CASR gene [28].
• Direct sequencing of the polymerase chain reaction product showed that the first patient was heterozygous for an already reported inactivating mutation of CaSR (P55L) [29].

Other interactions of CASR

• We investigated 32 families with FIHP to determine the frequency of occult mutation in HRPT2, the gene causing HPT-JT [30].
• The CaSR allows regulation of parathyroid hormone (PTH) secretion and renal tubular calcium reabsorption in response to alterations in extracellular calcium concentrations [31].
• BACKGROUND: The regulation of extracellular calcium concentration by parathyroid hormone is mediated by a calcium-sensing, G-protein-coupled cell-surface receptor (CASR) [15].
• A significant correlation was found between CASR expression and the Ki-67 proliferation index [3].
• Activating mutations in the CASR gene have been described in autosomal dominant hypoparathyroidism and familial hypocalcemia [32].

Analytical, diagnostic and therapeutic context of CASR

• Here we show parathyroid, thyroid, and kidney CASR mRNA levels increased 2-fold at 15 h after intraperitoneal injection of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in rats [17].
• CASR exon 7 single nucleotide polymorphisms (SNP), G/T at codon 986, G/A at codon 990, and C/G at codon 1011, were evaluated by PCR amplification and direct sequencing in 97 normocalciuric stone formers, 134 hypercalciuric stone formers, and 101 normocalciuric healthy controls [16].
• Direct sequence analysis of exon 4 of her CASR gene identified a heterozygous R227Q mutation in the extracellular domain of the receptor [33].
• Parathyroid surgery in familial HPT syndromes in the setting of underlying mutations in the calcium receptor (CASR) gene involves radical subtotal parathyroidectomy [34].
• The human CASR gene was mapped to Chromosome (Chr) 3q13.3-21 by fluorescence in situ hybridization (FISH) [32].

References