Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The predominant variety of familial benign hypocalciuric hypercalcemia (FBHH) is FBHH(3q), which is associated with presumed inactivating mutations of the cell surface calcium receptor (CaR) gene on chromosome 3q13.3-q21. We sought mutations of the CaR gene in FBHH by direct sequencing of PCR-amplified genomic DNA from 14 affected families: 8 mapped to 3q13, 1 mapped to chromosome 19p, and 5 unmapped. We sequenced the entire coding region of the gene (exons 2-7) in one or two affected members of each family and found six point mutations that altered one amino acid, cosegregated with hypercalcemia, and were absent in more than 100 unaffected persons. Four mutations were unique (S53P, D215G, S657Y, and P748R), and two had been reported previously (P55L and R185Q). Of four mutant CaR proteins expressed in Xenopus oocytes, three were deficient in extracellular Ca2+-induced signaling. No CaR mutations were found in eight families, including the one mapped to chromosome 19p. Three benign polymorphisms occurred in the COOH-terminal region of the CaR protein in 10%, 15%, and 30% of more than 100 unaffected persons. Thus, FBHH-causing CaR mutations were clustered in the NH2-terminal extracellular and membrane-spanning regions of the receptor protein. We suggest that these are important functional domains, probably for calcium binding and signal transduction, respectively. Finally, mutations in regulatory or intronic regions of the CaR gene may also underlie many cases of FBHH.
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PMID:Clustered inactivating mutations and benign polymorphisms of the calcium receptor gene in familial benign hypocalciuric hypercalcemia suggest receptor functional domains. 863 22

The main factors which regulate parathyroid hormone (PTH) production are calcium, phosphate, vitamin D, and estrogens. Hypocalcemia leads to increased PTH secretion in seconds and minutes, gene expression in hours, and parathyroid (PT) cell number in weeks and months. Hypercalcemia leads to a decrease in PTH secretion by its action on the PT cell calcium receptor and no decrease in PTH mRNA levels. There is now convincing evidence that phosphate regulates the PT, independent of its effect on serum calcium and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. In vivo in rats hypophosphatemia markedly decreases PTH mRNA and serum intact PTH levels, independent of its effect on serum calcium and 1,25(OH)2D3. Clinical studies also indicate that phosphate regulates the PT independent of its effect on calcium and 1,25(OH)2D3; 1,25(OH)2D3 itself has a marked effect on the PT, where it decreases PTH gene transcription by a direct action on the PT. The application of basic science findings of how calcium, phosphate, and 1,25(OH)2D3 regulate the PT has led to an efficient and safe prescription for the management of the secondary hyperparathyroidism of chronic renal failure, which is the maintenance of a normal serum calcium and phosphate and the careful use of 1,25(OH)2D3.
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PMID:Calcium, phosphate, vitamin D, and the parathyroid. 879 7

The main factors which regulate parathyroid hormone (PTH) production are calcium, phosphate, vitamin D and the sex steroids, estrogens and progestagins. Hypocalcaemia leads to increased PTH secretion in seconds and minutes, gene expression in hours and parathyroid cell number in weeks and months. Hypercalcaemia leads to a decrease in PTH secretion by its action on the parathyroid cell calcium receptor and no decrease in PTH mRNA concentrations. There is now convincing evidence that phosphate regulates the parathyroids independent of its effect on serum calcium and 1,25-dihydroxyvitamin D3. (1,25(OH)2D3). In vivo in rats hypophosphataemia markedly decreases PTH mRNA and serum PTH independent of its effect on serum calcium and 1,25(OH)2D3. Clinical studies also indicate that phosphate regulates the parathyroids independent of its effect on serum calcium and 1,25(OH)2D3 1,25(OH)2D3 itself has a marked effect on the parathyroids where it decreases PTH gene transcription by a direct action. Parathyroid cell proliferation is regulated by dietary calcium and phosphate with hypocalcaemia markedly increasing and hypophosphataemia markedly decreasing the number of proliferating cells. The application of basic science findings of how calcium, phosphate and 1,25(OH)2D3 regulate the parathyroids has led to an efficient and safe prescription for the management of the secondary hyperparathyroidism of chronic renal failure which is the maintenance of a normal serum calcium and phosphate and the careful use of bolus doses of 1,25(OH)2D3.
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PMID:New insights into the regulation of parathyroid hormone synthesis and secretion in chronic renal failure. 884 Mar 3

We recently cloned extracellular Ca(2+)-sensing receptors (CaRs) from bovine parathyroid and rat kidney that play key roles in Ca2+ homeostasis. Inactivating mutations of the CaR in the inherited human disorder, familial hypocalciuric hypercalcemia, cause reduced responsiveness of the parathyroid to extracellular Ca2+ (Cao2+), as well as abnormally avid renal tubular reabsorption of both Ca2+ and Mg2+ in the distal tubule, suggesting an important role for the CaR in regulating parathyroid hormone (PTH) secretion and renal handling of divalent cations. High Cao2+ also inhibits vasopressinstimulated adenosine 3',5'-cyclic monophosphate accumulation in the medullary thick ascending limb (MTAL) and water reabsorption in the collecting duct (CD) and modulates various other aspects of renal function. The relevance of the CaR to these processes, however, is uncertain. Reduced responsiveness of vasopressin-and PTH-mediated actions on the kidney have been described in the newborn that could potentially reflect effects of the CaR on these aspects of renal function. To define further the role of the CaR in regulating renal function, including the above-mentioned changes during the perinatal period, therefore, we have studied its ontogeny in rat kidney. Northern and Western blot analyses, as well as immunohistochemistry with CaR-specific probes, demonstrate that there is little prenatal expression of the extracellular Ca(2+)-sensing receptor, except in large tubules and branching ureteric buds of developing nephrons. Postnatally, CaR mRNA and protein increase markedly during the 1st wk, related principally to expression of the receptor in the developing TAL and, to a lesser extent, in the CD. The level of expression of the receptor remains nearly constant after postnatal day 14. These results demonstrate that the perinatal increases in expression of CaR mRNA and protein parallel its tissue-specific renal expression. Furthermore, it is possible that some of the previously described changes in renal handling of divalent cations and water in the perinatal and immediate postnatal period are related, in part, to the increasing levels of expression of the CaR and resultant inhibitory effects on the actions of PTH and antidiuretic hormone on the developing nephron.
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PMID:Ontogeny of the extracellular calcium-sensing receptor in rat kidney. 885 37

Using a strategy based on homology to the bovine parathyroid Ca(2+)-sensing receptor previously identified by us (5), we have recently isolated an extracellular, G protein-coupled Ca2+/ polyvalent cation-sensing receptor, RaKCaR (22), from rat kidney. The localization and physiological role(s) of this receptor in the kidney are not well understood. In the present study, we assessed the distribution of mRNAs for RaKCaR and the parathyroid hormone/parathyroid hormone-related protein (PTH/PTHrP) receptor along the rat nephron by in situ hybridization and reverse transcriptase-polymerase chain reaction of microdissected nephron segments. Our results show that transcripts for both receptors coexpress at glomeruli, proximal convoluted tubule, proximal straight tubule, cortical thick ascending limb, distal convoluted tubule, and cortical collecting duct. In addition, RaKCaR (but not PTH/PTHrP receptor) transcripts were found in the medullary thick ascending limb and outer medullary and inner medullary collecting ducts. These findings raise the possibility of roles for RaKCaR not only in the regulation of divalent mineral reabsorption but also in water reabsorption and urinary concentration. Taken together, our results provide new insights in understanding the effects of hypercalcemia on hormone-stimulated salt and water transport.
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PMID:Localization of the extracellular Ca(2+)-sensing receptor and PTH/PTHrP receptor in rat kidney. 889 27

A missense mutation in the Ca(2+)-sensing receptor (CaSR) gene was previously identified in a Japanese family with familial hypocalciuric hypercalcemia. Five members of this family with the mutation in the CaSR gene also showed abnormal glucose tolerance, whereas family members homozygous for the wildtype CaSR gene were normal in this respect. The potential relation between mutations in the CaSR gene and the incidence of diabetes mellitus was therefore investigated in 27 non-insulin dependent diabetic and 40 normal Japanese subjects. Each exon of the CaSR gene was amplified by the polymerase chain reaction and subjected to single-strand conformation polymorphism (SSCP) analysis. The region of the gene containing the sixth exon showed three distinct patterns on SSCP analysis in both diabetic patients and normal subjects. Direct sequencing of DNA revealed a T/C polymorphism in the fifth intron. The TT genotype was apparent in 59.3% of diabetic patients and in 45.0% of normal subjects. The CC genotype was present in 25.9% of diabetics and in 22.5% of normal subjects. The diabetic patients were divided into three groups on the basis of genotype for the polymorphism (TT, TC, or CC). However, there was no significant difference among the three groups with regard to the method of therapy, the incidence or severity of diabetic complications, duration or family history of disease, HbA1c level, or laboratory data. The polymorphism in the fifth intron of the CaSR gene does not therefore appear to be associated with non-insulin dependent diabetes mellitus.
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PMID:Polymorphism of the human Ca(2+)-sensing receptor gene in Japanese individuals: no relation to non-insulin dependent diabetes mellitus. 893 12

The relationship between PTH and calcium is best represented as a sigmoidal curve. In the normal animal and human, basal PTH is positioned at approximately 25% of maximal PTH and responds rapidly to small changes in calcium in either direction. Since PTH secretion is designed to respond to either hypo- or hypercalcemia, the study was performed to evaluate whether the parathyroid gland would respond differently to hypocalcemia when the reduction in serum calcium was initiated from sustained hypercalcemia with maximal PTH suppression. Nine dogs were studied and the experimental protocol consisted of two separate parts in which the same dogs were used and the order of study was randomly assigned. For the hypercalcemic part, calcium chloride was infused intravenously to increase serum calcium to between 1.60 and 1.70 mM at 30 minutes and then continued for another 90 minutes to clamp the serum calcium at this level. Sodium EDTA was then infused to lower the serum calcium at a constant rate to less than 0.85 mM. For the normocalcemic part, 5% dextrose in water was infused for two hours to control for fluid volume and time, and then EDTA was infused to lower the serum calcium at a constant rate to less than 0.85 mM. The results show that for the same serum calcium concentration at every 0.05 mM decrement in serum calcium below normal, PTH was less in the hypercalcemic than the normocalcemic dogs (P < 0.02). During the induction of hypocalcemia in the normocalcemic dogs, a characteristic sigmoidal curve was observed in which a small decrease in the serum calcium induced a brisk increase in PTH and a maximal PTH level was rapidly attained; however, during the induction of hypocalcemia in the hypercalcemic dogs, the increase in PTH was progressive, but linear and it was not certain that a maximal PTH level was attained. In conclusion, a sustained period of hypercalcemia resulted in a decreased PTH response to hypocalcemia and reduced the efficiency of the sigmoidal PTH-calcium relationship. Whether the mechanism for this difference in PTH secretion is due to secretory products, modification of the calcium receptor, or changes in intercellular communication among parathyroid cells deserves further study.
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PMID:A reduced PTH response to hypocalcemia after a short period of hypercalcemia: a study in dogs. 894 17

In vivo dynamic tests of parathyroid gland function have provided useful information about the secretory behavior of parathyroids in various clinical disorders, but the limitations of this approach must be recognized when applied to studies of parathyroid gland physiology. Set point abnormalities have been documented in vivo both in primary hyperparathyroidism and in familial hypocalciuric hypercalcemia. Such findings are consistent with in vitro results obtained in studies of dispersed parathyroid cells from patients with primary hyperparathyroidism and with recently described alteration in calcium receptor expression in patients with FHH. The assessment of parathyroid gland function in patients with end-stage renal disease presents distinct methodological problems, however, because of marked variation in the degree of parathyroid gland enlargement. Neither the four parameter model originally used to describe set point abnormalities both in vitro and in vivo or alternative approaches to the assessment of PTH secretion in vivo adequately address this important issue. Results from recent in vivo studies of patients with chronic renal failure do not support the view that the set point for calcium-regulated PTH release is abnormal in secondary hyperparathyroidism or that treatment with calcitriol lowers the set point for calcium-regulated PTH release in patients with uremic secondary hyperparathyroidism. The concept of set point disturbances has strongly influenced discussions about the pathogenesis of secondary hyperparathyroidism, and it has served as a focal point for examining the therapeutic response to calcitriol in patients with this disorder. This matter requires careful reconsideration, however, in light of recent clinical findings and the development of techniques to directly assess the molecular mechanisms responsible for regulating calcium-mediated PTH release in renal failure and other disorders of mineral metabolism. Although knowledge in this area remains limited, the extent of parathyroid hyperplasia and the role of factors that influence the development of parathyroid gland enlargement may ultimately prove to be particularly important modifiers of parathyroid gland function in chronic renal failure.
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PMID:In vivo assessments of calcium-regulated parathyroid hormone release in secondary hyperparathyroidism. 894 64

The divalent mineral cations Ca2+ and Mg2+ play many and diverse roles both in the function of cells and in extracellular processes. The metabolism of these cations is a complex process involving the coordinated function of several organ systems and endocrine glands. A recently cloned G-protein-coupled receptor responds to extracellular calcium concentration (Ca2+0-sensing receptor, CaSR) and mediates several of the known effects of Ca2+0 on parathyroid and renal function. The CaSR, which is also expressed in a number of other tissues including thyroidal C-cells, brain and gastrointestinal tract, may function as a Ca2+0 sensor in these tissues as well. Thus, Ca2+0 is a first messenger (or hormone) which, via CaSR-mediated activation of second messenger systems (e.g. phospholipases C and A2, cyclic AMP) leads to altered function of these cells. Several mutations in the human CaSR gene have been identified and shown to cause three inherited diseases of calcium homeostasis, clearly implicating the CaSR as an important component of the homeostatic mechanism for divalent mineral ions. Ca2+ and Mg2+ losses from the body are regulated by altering the urinary excretion of these divalent cations. The localization of the CaSR transcripts and protein in the kidney not only provides a basis for a direct Ca2+0 (or Mg2+0)-mediated regulation of Ca2+ (and Mg2+) excretion but also suggests a functional link between divalent mineral and water metabolism. In the kidney, the thick ascending limb of Henle (TAL) plays crucial roles in regulating both divalent mineral reabsorption and urine concentration. Recent studies have suggested models whereby extracellular Ca2+, via the CaSR expressed in the TAL as well as in the collecting duct system, modulates both Ca2+ 0 and Mg2+ 0 as well as water reabsorbtion. When taken together, these studies suggest that the CaSR not only provides the primary mechanism for Ca2+ 0-mediated regulation of parathyroid hormone secretion from parathyroid glands but also for direct modulation of renal divalent mineral excretion and urinary concentrating ability. These latter functions may furnish a mechanism for integrating and balancing water and divalent cation losses that minimizes the risk of urinary tract stone formation. This mechanism can explain hypercalcemia-mediated polyuria (diabetes insipidus).
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PMID:Role of the Ca(2+)-sensing receptor in divalent mineral ion homeostasis. 905 Feb 37

In a brief review of advances in endocrinology in the last two years the author discusses above all the vain expectations of a drug against obesity-the adipose tissue hormone leptin. Its elevated blood level in human obesity indicates that its secretion depends on the mass of adipose tissue and it is not certain whether leptin reduces the food intake in humans. Perhaps resistance to leptin is involved. New receptor diseases were revealed: mutation of LH receptors leads in both sexes to hypogonadism. Mutation of the calcium receptor in parathyroid cells leads to familial hypocalciuric hypercalcaemia or autosomal dominant hypocalcaemia. The complex regulation of the tonus of the vascular wall by endothelins is still the object of interest. Aquaporin is a renal protein which mediates the action of vasopressin. In the sphere of stress evidence is emerging on the participation of CRH in brain activity and the possibility to influence autoimmune inflammations and perhaps even AIDS by interference with the CRH-proopiomelanocortin-ACTH-cortisol system.
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PMID:[Endocrinology 1995-1996]. 926 67


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