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Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parathyroid carcinoma is one cause of primary hyperparathyroidism, a condition in which there is hypercalcemia and dysregulated hypersecretion of PTH. In normal, and in some neoplastic parathyroid cells, PTH secretion is mediated by the cell surface calcium-sensing receptor. We describe the first therapeutic use of a novel molecule, a calcimimetic, that has agonist action at the calcium-sensing receptor. A 78-yr-old man with parathyroid carcinoma was admitted with hypercalcemia, markedly elevated PTH, and a change in mental status. He was treated for 17 days with conventional therapy, which included saline hydration, furosemide, pamidronate, and calcitonin. This was ineffective, and on hospital day 18, calcimimetic at a dose of 50 mg, orally, every 6 h was added. On hospital day 25, the dose was increased to 100 mg, orally, every 6 h, and on hospital day 30, saline and furosemide were discontinued. He was discharged on hospital day 40. With several dose adjustments, he has been treated with monotherapy calcimimetic for over 600 days and has not required any other interventions for his parathyroid carcinoma. Mean daily precalcimimetic treatment values of serum ionized calcium and PTH were 1.83 mmol/L and 872 pg/mL, respectively. During hospitalization, at the lower dose of calcimimetic, calcium and PTH decreased to 1.67 mmol/L and 538 pg/mL; with the higher dose they further decreased to 1.51 mmol/L and 444 pg/mL. Since discharge, and despite increasing levels of PTH, serum calcium has remained high, but lower than the admission level and acutely responsive to changes in calcimimetic doses. This compound, a calcimimetic, the first of a new class of compounds with activity at the calcium-sensing receptor, has been used to treat a patient with parathyroid carcinoma. During 2 yr of treatment, no adverse clinical effects have been observed, and it appears to have been effective at controlling hypercalcemia.
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PMID:Treatment of hypercalcemia secondary to parathyroid carcinoma with a novel calcimimetic agent. 954 21

The calcium-sensing receptor (CaSR) regulates PTH secretion to control the extracellular calcium concentration in adults, but its role in fetal life is unknown. We used CaSR gene knockout mice to investigate the role of the CaSR in regulating fetal calcium metabolism. The normal calcium concentration in fetal blood is raised above the maternal level, an increase that depends upon PTH-related peptide (PTHrP). Heterozygous (+/-) and homozygous (-/-) disruption of the CaSR caused a further increase in the fetal calcium level. This increase was modestly blunted by concomitant disruption of the PTHrP gene and completely reversed by disruption of the PTH/ PTHrP receptor gene. Serum levels of PTH and 1, 25-dihydroxyvitamin D were substantially increased above the normal low fetal levels by disruption of the CaSR. The free deoxypyridinoline level was increased in the amniotic fluid (urine) of CaSR-/- fetuses; this result suggests that fetal bone resorption is increased. Placental calcium transfer was reduced, and renal calcium excretion was increased, by disruption of the CaSR. These studies indicate that the CaSR normally suppresses PTH secretion in the presence of the normal raised (and PTHrP-dependent) fetal calcium level. Disruption of the CaSR causes fetal hyperparathyroidism and hypercalcemia, with additional effects on placental calcium transfer.
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PMID:Regulation of murine fetal-placental calcium metabolism by the calcium-sensing receptor. 963 15

Hyperparathyroidism refers to a term representing a wide spectrum of parathyroid disorders that are characterized by the increased production of parathyroid hormone. Hyperparathyroidism was once thought to be rare but is now more commonly recognized, affecting 1 in 500 women over 40 years of age. Yet the interpretation of parathyroid pathology is still controversial and confusing. Over the past 10 years, genetic changes (ret and menin genes) involved in the pathogenesis of MEN 2 and MEN 1 have been discovered in succession. Different mutations of the calcium-sensing receptor gene have been identified in neonatal severe hyperparathyroidism and familial hypocalciuric hypercalcemia, respectively. The HRPT 2 gene responsible for the development of hereditary hyperparathyroidism and jaw tumors has been localized on the 1q21-31 locus. Several genetic alterations have also been characterized in primary and secondary hyperparathyroidism. Different genetic alterations appear to involve the development of different types of hyperparathyroidism. These novel advances give us new insights into the pathogenesis of hyperparathyroidism and allow better differentiation between the different types of parathyroid disorders.
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PMID:Genetic alterations in primary and secondary hyperparathyroidism. 973 2

Calcium-sensing receptor (CASR) in parathyroid gland regulates calcium homeostasis by sensing decreases in extracellular calcium levels and effecting an increase in secretion of parathyroid hormone. A polymorphic dinucleotide (CA) sequence was isolated from a genomic clone containing the human CASR gene and was mapped to 3q13.3-q21. This polymorphism will be useful in the genetic study of disorders affecting calcium metabolism, such as hypercalcemia, hypocalcemia, osteoporosis, hyperparathyroidism, and hypoparathyroidism.
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PMID:Isolation and radiation hybrid mapping of a dinucleotide repeat polymorphism at the human calcium-sensing receptor (CASR) locus. 985 85

Calcium homeostasis by the kidneys and parathyroids is mediated by the calcium-sensing receptor (CaSR), which is located on 3q21-q24 and belongs to family C of the superfamily of G-protein coupled receptors that includes those for metabotropic glutamate, certain pheromones, and gamma-amino butyric acid (GABA-B). Inactivating CaSR mutations result in familial benign hypercalcemia (FBH), or familial hypocalciuric hypercalcemia (FHH), whereas activating mutations result in hypocalcemic hypercalciuria. However, not all FBH patients have CaSR mutations, which, together with the mapping of another FBH locus to 19p13.3, suggests that additional CaSRs or second messengers may be involved. These may be identified by positional cloning, and we therefore performed a genomewide search, using chromosome-specific sets of microsatellite polymorphisms, in an Oklahoma family with an FBH variant (FBHOk), for which linkage to 3q and 19p had been excluded. Linkage was established between FBHOk and eight chromosome 19q13 loci, with the highest LOD score, 6.67 (recombination fraction.00), obtained with D19S606. Recombinants further mapped FBHOk to a <12-cM interval flanked by D19S908 and D19S866. The calmodulin III gene is located within this interval, and DNA sequence analysis of the coding region, the 5' UTR, and part of the promoter region in an individual affected with FBHOk did not detect any abnormalities, thereby indicating that this gene is unlikely to be implicated in the etiology of FBHOk. This mapping of FBHOk to chromosome 19q13 will facilitate the identification of another CaSR or a mediator of calcium homeostasis.
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PMID:Localization of familial benign hypercalcemia, Oklahoma variant (FBHOk), to chromosome 19q13. 991 58

Autosomal dominant hypocalcemia (ADH), caused by activating mutations of the calcium-sensing receptor (CaSR), is characterized by hypocalcemia with an inappropriately low concentration of PTH. Among 11 missense mutations of CaSR reported to date in patients with ADH or sporadic hypocalcemia, functional properties of 8 mutant CaSRs were characterized. Here, we describe a novel mutation of CaSR and its functional property in a family with ADH. The 41-yr-old male proband had asymptomatic hypocalcemia with a history of recurrent nephrolithiasis. His father had asymptomatic hypocalcemia, but his mother was normocalcemic. 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. Using HEK293 cells transfected with wild-type or K47N CaSR complementary DNA, the intracellular Ca2+ concentration was assessed in response to changes in the extracellular Ca2+ concentration. The EC50 of the mutant CaSR for the extracellular Ca2+ concentration was 2.2 mmol/L and was significantly lower than that of wild-type (3.7 mmol/L). These results confirm that this mutation is responsible for ADH in this family. The fact that several inactivating mutations in familial hypocalciuric hypercalcemia occur in amino acid around K47 suggests the importance of the N-terminal portion of the receptor in extracellular Ca sensing.
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PMID:A novel activating mutation in calcium-sensing receptor gene associated with a family of autosomal dominant hypocalcemia. 992 Jan 8

The human calcium-sensing receptor (CaSR) is a 1078-amino-acid cell surface protein which is expressed in the parathyroids, thyroid cells and the kidney, and is a member of the family of G protein-coupled receptors. The CaSR allows regulation of parathyroid hormone (PTH) secretion and renal tubular calcium reabsorption in response to alterations in extracellular calcium concentrations. The human CaSR gene is located on chromosome 3q13.3-q21, and loss of function CaSR mutations have been reported in the hypercalcaemic disorders of familial benign (hypocalciuric) hypercalcaemia (FBH or FHH) and neonatal severe primary hyperparathyroidism (NSHPT). In addition, gain of function CaSR mutations have been observed in a novel familial syndrome of hypocalcaemia with hypercalciuria. The human CaSR gene on chromosome 3q13.3-q21 is likely to be one of several, as two other loci for FBH have been located on chromosome 19p and 19q13. Cloning and characterisation of these genes will help to further elucidate the mechanisms regulating extracellular calcium.
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PMID:Disorders of the calcium-sensing receptor. 992 Apr 7

The cloning of a G protein-coupled, extracellular calcium-sensing receptor (CaSR) provided direct evidence that Ca(2+)-sensing can occur through receptor-mediated activation of G proteins and their associated downstream regulators of cellular function. CaSR transcripts and protein are present in various tissues that are involved in Ca2+ homeostasis and that do not have well-established roles in Ca balance as well. The physiological relevance of the CaSR has been established by identifying inherited hyper-and hypocalcemia disorders resulting from CaSR mutations: familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism result from inactivating CaSR mutations while autosomal dominant hypocalcemia is caused by activating mutations. CaSR may also play a role in water metabolism. Calcimimetics that activate CaSR are undergoing clinical trials and might prove effective in manipulation of serum calcium concentration and urinary calcium excretion through CaSR activities.
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PMID:[Calcium-sensing receptor and its related diseases]. 1019 62

Inactivating mutations in the calcium-sensing receptor (CaSR) cause familial hypocalciuric hypercalcaemia (FHH) and neonatal severe hyperparathyroidism (NSHPT). Earlier investigations showed patients with FHH are heterozygous, and NSHPT are homozygous for inactivating mutations. However, one adult patient with severe hypercalcaemia and hypocalciuria has been reported to have a homozygous inactivating mutation in CaSR (Pro39Ala). This suggested that mutant CaSR in this patient had some residual activity and hypercalcaemia was not so severe as to be fatal. However, the function of this mutant CaSR was not evaluated. In the present study, we describe a novel homozygous mutation in an adult patient with severe hypercalcaemia and hypocalciuria, and evaluate the function of the mutant CaSRs. The DNA sequence of CaSR gene was determined by direct sequencing of the polymerase chain reaction product. The function of mutant CaSR was analysed by creating mutant cDNAs by in vitro mutagenesis, transfection of mutant cDNAs into HEK293 cells and measuring intracellular ionized Ca in response to changes in extracellular Ca. A 26-year-old Japanese woman showed marked hypercalcaemia with an elevated parathyroid hormone (PTH) level. Her consanguineous parents had asymptomatic hypercalcaemia with relative hypocalciuria. The proband had a homozygous mutation at codon 27 of CaSR gene (CAA-->CGA, Gln27Arg). Her parents were heterozygous for this mutation. EC50 for Ca of this mutant CaSR (GIn27Arg) was 4.9 mM. EC50 of another mutant CaSR (Pro39Ala) whose homozygous mutation was discovered in an adult patient was 4.4 mM. These EC50s were significantly higher than that of wild-type CaSR (3.7} 0.1 mM), but were the lowest among the reported EC50s for inactivating mutations of CaSR. These results indicate that serum Ca and PTH levels are determined by residual function of mutant CaSR in patients with homozygous mutation in CaSR, and that patients having homozygous mutant CaSRs with mild dysfunction do not suffer from fatal hypercalcaemia in infancy and can survive into adulthood.
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PMID:An adult patient with severe hypercalcaemia and hypocalciuria due to a novel homozygous inactivating mutation of calcium-sensing receptor. 1046 15

The calcium-sensing receptor gene was recently shown to be expressed in rat pancreatic islets and purified islet B-cells. In this study, we investigated the possible role of this receptor in the regulation of insulin release from isolated rat pancreatic islets. Poly-L-arginine (0.2-0.3 microM) and poly-L-lysine (0.03-0.1 microM) increased insulin output evoked by D-glucose (8.3 mM). This positive effect faded out at higher concentrations of the basic peptides. Likewise, the release of insulin evoked by 8.3 mM D-glucose was significantly lower at high (1.0 mM) than low (0.05-0.1 mM) concentrations of neomycin. The insulinotropic action of Ba2+ in Ca2+-deprived islets was potentiated in rats pretreated with pertussis toxin. However, Gd3+ inhibited insulin release evoked by D-glucose in islets prepared from normal rats or animals pretreated with pertussis toxin and incubated in the absence or presence of either theophylline or forskolin. Gd3+ (0.3 mM) failed to affect effluent radioactivity from islets prelabeled with myo-[2-3H]inositol and cyclic AMP net production in islets incubated in the absence or presence of forskolin. Gd3+ decreased, however, 45Ca efflux from prelabeled islets perifused in the absence or presence of extracellular Ca2+. It is speculated that a negative insulinotropic action mediated by the calcium-sensing receptor, and possibly attributable to a fall in cytosolic Ca2+ concentration, may prevent excessive insulin secretion in pathological situations of hypercalcemia.
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PMID:Possible participation of an islet B-cell calcium-sensing receptor in insulin release. 1078 26


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