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 calcium-dependent secretion of parathyroid hormone (PTH) is mediated through an extracellular G protein-coupled calcium receptor (CaR). Inactivating point mutations of this receptor have been found in familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. These diseases feature a decreased calcium sensitivity of the parathyroid glands, resulting in a rightward shift of the Ca2(+)-PTH relationship. Severe non-suppressible renal hyperparathyroidism (rHPT) is often characterized by similar setpoint shifts to the right. Thus, point mutations of the CaR gene could contribute to non-suppressible rHPT. We examined genomic DNA of hyperplastic or mainly nodular tissues of 39 parathyroids from 25 rHPT-patients with resistance to calcitriol therapy. Amplification of the six exons of the CaR gene was followed by single-strand conformation polymorphism (SSCP) analysis. DNA sequencing was performed where band shifts were observed. No point mutations in the coding sequence of the CaR gene were detected using the PCR-SSCP strategy. Point mutations in the coding regions of the CaR gene probably play no role in the evolution of renal HPT and are not responsible for the calcitriol resistance of PTH secretion.
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PMID:Point mutations of the human parathyroid calcium receptor gene are not responsible for non-suppressible renal hyperparathyroidism. 950 99

The Ca(2+)-sensing receptor (CaR) is a member of the seven-transmembrane domain, G protein-coupled receptor super-family. In the parathyroid gland, it mediates the inhibitory effects of extracellular Ca2+ on the secretion of parathyroid hormone. In the kidney, activation of the CaR causes decreased reabsorption of Ca2+ from the tubular lumen. Mutations in the CaR gene produce abnormalities of Ca2+ homeostasis. Heterozygous loss-of-function mutations cause familial hypocalciuric hypercalcemia. Homozygous loss-of-function mutations cause neonatal severe hyperparathyroidism. In contrast, gain-of-function CaR mutations result in autosomal dominant and sporadic hypoparathyroidism. The resulting hypoparathyroidism and hypocalcemia can range from asymptomatic to life-threatening. Patients with hypocalcemia due to CaR mutations also show disproportionate hypercalciuria that may increase the risk of nephrocalcinosis, nephrolithiasis, and renal insufficiency.
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PMID:Molecular biology and clinical importance of the Ca(2+)-sensing receptor. 975 71

Primary hyperparathyroidism (PHPT), the most common cause of hypercalcemia due to excessive secretion of PTH, is usually associated with hypophosphatemia and elevated serum chloride. Although PHPT was often complicated by renal stone disease and osteitis fibrosa in the past, routine screening of serum calcium (Ca) and development of sophisticated assay of parathyroid hormone have contributed to earlier detection of asymptomatic PHPT (APHPT). The proportion of APHPT patients, who have a mild elevation of serum Ca levels, usually within 1.0 mg/dL above the upper limit of normal, rose from 10-20% to approximately 45% of all PHPT patients in 1990-1995 in our clinic. Although it has been reported that the prevalence of PHPT is about 0.1% of the American population, the prevalence of PHPT appears to be far less in the Japanese population. Determination of a strategy for the increasing number of APHPT patients, is a pressing need but has yet to be accomplished. Treatment with bone antiresorptive drugs has met with some success, although the long-term efficacy of this treatment is not clear. The therapeutic effects of Ca-sensing receptor agonists appear promising.
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PMID:Pathophysiology and diagnosis of primary hyperparathyroidism--strategy for asymptomatic primary hyperparathyroidism. 1091 83

Familial hypocalciuric hypocalcaemia (FHH) is a rare disorder, inherited in an autosomal dominant manner. It has earlier been believed that neonatal severe hyperparathyroidism (NSHPT) is the homozygous form of FHH, but in this case story we show that it is not always like that. We describe a girl who presents with a calcium metabolic disorder from birth. Genetic examination of the girl and her family shows a single abnormal allele in the calcium ion sensitive receptor. We discuss why some heterozygotic inactivating calcium receptor mutations cause NSHPT, while the majority of other mutations only cause mild, asymptomatic hypercalcaemia as in FHH.
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PMID:[Severe neonatal hyperparathyroidism in a family with familial hypocalciuric hypercalcemia]. 1096 66

The uremic milieu generates chronic stimulatory input to the parathyroid glands, which is mediated principally by low calcium, high phosphate and low calcitriol, and results in increased parathyroid hormone (PTH) synthesis and release and an increase in parathyroid mitotic activity with the development of monoclonal areas of nodular hyperplasia. Such glands do not fully express the machinery required to mediate the suppressive inputs to the parathyroids; the extracellular calcium receptor (CaR) and the vitamin D receptor (VDR) are both downregulated. In most of these patients ablation, by parathyroidectomy or ethanol injection, provides the only means of correcting the hyperparathyroidism; apoptosis in parathyroid cells is negligible and clinically irrelevant. In practice, surgery is often delayed by a doomed and ultimately futile attempt to effect control by medical means. Better predictors of the likely success or failure of optimal non surgical management are needed. Gland size exceeding 1 cm3 and elevated PTH despite hypercalcemia (implying loss of suppressibility by calcium), in the presence of good phosphate control and adequate calcitriol provision point strongly to eventual failure of medical treatment and the need for parathyroid ablation. Parathyroidectomy, usually subtotal, remains the standard management, with ultrasound guided injection of ethanol or calcitriol showing promise in some centers. The above scenario is unlikely to be changed greatly by the new emerging vitamin D metabolites, but calcimimetic agents may well increase the scope of non surgical management.
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PMID:Are parathyroidectomies still appropriate in chronic dialysis patients? 1101 87

The extracellular Ca(2+)-sensing receptor (CaR) responds to polycations, including Ca(2+) and neomycin. This receptor is a physiological regulator of systemic Ca(2+) metabolism and may also mediate the toxic effects of hypercalcemia. A number of divalent cations, including Pb(2+), Co(2+), Cd(2+), and Fe(2+), are toxic to the kidney, brain, and other tissues where the CaR is expressed. To determine which divalent cations can activate the CaR, we expressed the human CaR in HEK-293 cells and measured activation of phospholipase A(2) (PLA(2)) and the mitogen-activated protein kinase p42ERK in response to potential agonists for the receptor. HEK-293 cells expressing the nonfunctional mutant CaR R796W served as controls. Extracellular Ca(2+), Ba(2+), Cd(2+), Co(2+), Fe(2+), Gd(3+), Ni(2+), Pb(2+), and neomycin activated the CaR, but Hg(2+) and Fe(3+) did not. We analyzed the kinetics of activation of p42ERK and PLA(2) by the CaR in response to Ca(2+), Co(2+), and Pb(2+). The EC(50) values ranged from approximately 0.1 mM for Pb(2+) to approximately 4.0 mM for Ca(2+). The Hill coefficients were >3, indicating multiple cooperative ligand binding sites or subunits. Submaximal concentrations of Ca(2+) and Pb(2+) were additive for activation of the CaR. The EC(50) for Ca(2+) or Pb(2+) was reduced four- to fivefold by the presence of the other ion. These divalent cations also activated PLA(2) via the CaR in Madin-Darby canine kidney cells that stably express the CaR. We conclude that many divalent cations activate the CaR and that their effects are additive. The facts that the CaR is a promiscuous polycation sensor and that the effects of these ions are additive to activate it suggest that the CaR may contribute to the toxicity of some heavy metals such as Pb(2+), Cd(2+), Co(2+), and Fe(2+) for the kidney and other tissues where it is expressed.
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PMID:Extracellular Ca(2+)-sensing receptor is a promiscuous divalent cation sensor that responds to lead. 1109 27

Parathyroidectomy provides effective treatment for primary and secondary hyperparathyroidism with a predictable response of symptoms related to hypercalcemia and elevated parathyroid hormone. Calcium and vitamin D supplementation has reduced the need for parathyroidectomy in dialysis patients with secondary hyperparathyroidism. However, surgery continues to be the only effective treatment of primary hyperparathyroidism. Potential nonoperative treatments for hyperparathyroidism have included the use of estrogen replacement, bisphosphonates, and a new class of drugs known as calcimimetics. Hormone replacement therapy with estrogen has been reported to improve cortical bone density in postmenopausal women with asymptomatic or mildly symptomatic primary hyperparathyroidism. Calcimimetic agents are a new class of drugs that increase the sensitivity of the calcium receptor to ionized calcium. Initial studies have shown that calcimimetics can acutely lower parathyroid hormone levels in patients with primary and secondary hyperparathyroidism. These drugs are currently being evaluated in phase II clinical trials. Ultimately, these medical modalities will need to be compared to parathyroidectomy in randomized controlled clinical trials.
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PMID:Nonoperative management of hyperparathyroidism: present and future. 1114 83

1. The aim of this study was to investigate some of the cellular mechanisms involved in the effects caused by changes in extracellular Ca2+ concentration ([Ca2+](o)). 2. Current- and voltage-clamp experiments were carried out on acutely isolated thalamic neurons of rats. 3. Increasing [Ca2+](o) alone induced a transition of the discharge from single spike to burst mode in isolated current-clamped neurons. 4. Increasing [Ca(2+)](o) caused the voltage-dependent characteristics of the low voltage-activated (LVA) transient Ca2+ currents to shift towards positive values on the voltage axis. Changing [Ca2+](o) from 0.5 to 5 mM caused the inactivation curve to shift by 21 mV. 5. Extracellular Ca2+ blocked a steady cationic current. This current reversed at -35 mV, was scarcely affected by Mg2+ and was completely blocked by the non-selective cation channel inhibitor gadolinium (10 microM). The effect of [Ca2+](o) was mimicked by 500 microM spermine, a polyamine which acts as an agonist for the Ca(2+)-sensing receptor, and was modulated by intracellular GTP-gamma-S. 6. At the resting potential, both the voltage shift and the block of the inward current removed the inactivation of LVA calcium channels and, together with the increase in the Ca2+ driving force, favoured a rise in the low threshold Ca2+ spikes, causing the thalamic firing to change to the oscillatory mode. 7. Our data indicate that [Ca2+](o) is involved in multiple mechanisms of control of the thalamic relay and pacemaker activity. These findings shed light on the correlation between hypercalcaemia, low frequency EEG activity and symptoms such as sleepiness and lethargy described in many clinical papers.
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PMID:Changes in extracellular Ca2+ can affect the pattern of discharge in rat thalamic neurons. 1150 56

Development of sporadic parathyroid tumors is accompanied by loss of heterozygosity (LOH) on several chromosomes like 1p, 1q, 6q, 11q, and 15q. Here, we investigate a unique variant of familial hypercalcemia, unrelated to multiple endocrine neoplasia and hyperparathyroidism-jaw tumor syndromes, with hypercalcemia due to a point mutation in the intracellular part of the calcium receptor (CaR) gene. The hypercalcemia and hypercalciuria of the family is accompanied by age-related growth of the parathyroid glands and transition from diffuse to nodular parathyroid hyperplasia. Genome-wide screening for allelic loss was performed on nine enlarged parathyroid glands (weighing 40-680 mg) from eight parathyroidectomized members of the family (aged 22-66 yr). Using 139 fluorescent- or (32)P-labeled microsatellite markers, informative results were obtained on all examined chromosome arms and 1p, 1q, 6q, 11q, and 15q were investigated more closely. All parathyroid glands displayed allelic loss on at least one chromosomal arm (range 1-7). Most of the common loci for allelic loss corresponded to findings in sporadic parathyroid tumors, but the unique variant of familial hypercalcemia also exhibited frequent LOH on 12q (67%) and 7q (44%). LOH could not be detected at 3q, where the CaR gene is located, and additional somatic mutations in exons 2-7 of the CaR gene was not found by sequencing. The point mutation resulting in alteration of the intracellular portion of CaR seems to cause sensitivity to secondary genetic hits, with increased frequency of allelic loss (P < 0.01, r(2) = 0.66) and weight of parathyroid tumors with age in this family.
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PMID:Loss of heterozygosity in parathyroid glands of familial hypercalcemia with hypercalciuria and point mutation in calcium receptor. 1216 40

The parathyroid glands play a key role in maintaining near constancy of the extracellular calcium concentration ( Ca(o)2+) through their capacity to sense even minute changes in the level of blood calcium from its normal level. The G protein-coupled, Ca(o)(2+)-sensing receptor (CaSR) is the mechanism through which the parathyroid chief cells senses changes in Ca(o)2+. In primary hyperparathyroidism (PHPT), Ca(o)2+ is reset upward from its normal level. This defect likely arises from increases in both the mass of pathological parathyroid tissue as well as the set point for Ca(o)(2+)-regulated parathyroid hormone (PTH) release. The former likely arises from somatic mutations that enhance parathyroid cellular proliferation, although our understanding of the mechanism(s) underlying the latter is incomplete. However, substantial insights have been achieved through the study of inherited disorders caused by mutations in CaSR gene. In familial hypocalciuric hypercalcemia (FHH), heterozygous inactivating mutations in the CaSR gene produce mild, generally asymptomatic hypercalcemia, whereas in neonatal severe hyperparathyroidism (NSHPT), homozygous inactivating mutations cause severe hypercalcemia and hyperparathyroidism. Thus, the body's "calciostat" is reset upward in FHH and NSHPT because of resistance of CaSR-expressing cells, including the parathyroid cells, to Ca(o)2+. In FHH, there is a reduced complement of normal CaSRs (e.g., haploinsufficiency) that likely provides an explanation for the Ca(o)(2+)-resistance in this condition, whereas in NSHPT, there are no normally functioning CaSRs, thereby engendering more severe Ca(o)2+ resistance. Although somatic mutations in the CaSR gene could provide an explanation for the Ca(o)(2+)-resistance in PHPT, no such mutations have been found. Instead, in PHPT, the resistance of pathological parathyroid glands to Ca(o)2+ results, at least in part, from a reduced expression of otherwise apparently structurally normal CaSRs. Thus, PTH-dependent hypercalcemia can occur in the setting of either inherited, generalized resistance to Ca(o)2+ (i.e., FHH and NSHPT) or acquired tissue selective resistance of pathological parathyroid glands to Ca(o)2+ (e.g., PHPT).
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PMID:The pathophysiology of primary hyperparathyroidism. 1241 74


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