Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020438 (hypercalciuria)
 2,502 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dent's disease, an X-linked renal tubular disorder, is a form of Fanconi syndrome which is characterized by proteinuria, hypercalciuria, nephrocalcinosis, kidney stones and renal failure. Previous studies localised the gene responsible to Xp11.22, within a microdeletion involving the hypervariable locus DXS255. Further analysis using new probes which flank this locus indicate that the deletion is less than 515 kb. A 185 kb YAC containing DXS255 was used to screen a cDNA library from adult kidney in order to isolate coding sequences falling within the deleted region which may be implicated in the disease aetiology. We identified two clones which are evolutionarily conserved, and detect a 9.5 kb transcript which is expressed predominantly in the kidney. Sequence analysis of 780 bp of ORF from the clones suggests that the identified gene, termed hCIC-K2, encodes a new member of the CIC family of voltage-gated chloride channels. Genomic fragments detected by the cDNA clones are completely absent in patients who have an associated microdeletion. On the basis of the expression pattern, proposed function and deletion mapping, hCIC-K2 is a strong candidate for Dent's disease.
Hum Mol Genet 1994 Nov
PMID:Isolation and partial characterization of a chloride channel gene which is expressed in kidney and is a candidate for Dent's disease (an X-linked hereditary nephrolithiasis). 787 26

Dent's disease is a familial proximal renal tubular disorder which is associated with low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, kidney stones and renal failure. The mode of inheritance and the primary defect for this disorder are unknown. An analysis of 5 unrelated British families revealed a greater disease severity in males and an absence of male to male transmission. This suggested an X-linked inheritance and we investigated this further by linkage studies in 33 members (12 affected, 21 unaffected) from two 3-generation families. Twenty X-linked polymorphic markers were used and linkage was established with the Xp11 loci ARAFI, DXS426, DXS255 and DXS988 with peak LOD scores and recombination fractions (theta) of 5.42 (theta = 0.000), 3.61 (theta = 0.000), 5.48 (theta = 0.000) and 4.25 (theta = 0.045) respectively. In addition, DXS255 revealed a microdeletion in the affected members of one family, thereby further localising Dent's disease to Xp11.22. Combined multilocus linkage analysis and deletion mapping studies defined the locus order Xpter-MAOB-(ARAFI, DXS426)-SYP-TFE3-(DXS255, DENT'S)-DXS988-Xcen, thereby mapping the microdeletion associated with Dent's disease to a 4 centiMorgan interval flanked by TFE3 and DXS988. Thus, Dent's disease is an X-linked disorder which is associated with a microdeletion of Xp11.22, and a further characterisation of this gene will help to elucidate the factors controlling proximal renal tubular function and the development of kidney stones.
Hum Mol Genet 1993 Dec
PMID:Dent's disease, a renal Fanconi syndrome with nephrocalcinosis and kidney stones, is associated with a microdeletion involving DXS255 and maps to Xp11.22. 811 83

Vitamin D receptor (VDR) concentration was quantitated in human peripheral blood mononuclear cells (PBMC) from patients with absorptive hypercalciuria (AH) and patients with high 1,25(OH)2D3 due to acquired or transient disease states and the results compared to those in normal subjects. VDR concentration in resting cells was not different between the three groups and represented constitutive receptor expression of monocytes. Following activation with phytohemagglutinin, patients with hypercalcitriolemia demonstrated significantly greater VDR concentrations. Patients with AH demonstrated a normal value for the group, but 6 patients had significantly greater concentrations of VDR despite normal plasma 1,25(OH)2D3 in four of the patients. Proliferation, as assessed from [3H]thymidine incorporation was inversely correlated with serum 1,25(OH)2D3 and was significant (R = -0.299, p = 0.048). Taken together, the results suggest that PBMC provide a useful system for studying VDR status in transient or acquired states of hypercalcitriolemia. Furthermore, the studies in patients with absorptive hypercalciuria disclosed it to be a heterogeneous disorder, characterized by both vitamin D-dependent and D-independent forms of receptor up-regulation.
Mol Cell Endocrinol 1993 Oct
PMID:Vitamin D receptor quantitation in human blood mononuclear cells in health and disease. 827 25

Parathyroid hormone secretion is negatively regulated by a 7-transmembrane domain, G-protein coupled Ca(2+)-sensing receptor. We hypothesized that activating mutations in this receptor might cause autosomal dominant hypoparathyroidism (ADHP). Consistent with this hypothesis, we identified, in two families with ADHP, heterozygous missense mutations in the Ca(2+)-sensing receptor gene that cosegregated with the disorder. None of 50 normal controls had either mutation. We also identified a de novo, missense Ca(2+)-sensing receptor mutation in a child with severe sporadic hypoparathyroidism. The amino acid substitution in one ADHP family affected the N-terminal, extracellular domain of the receptor. The other mutations involved the transmembrane region. Unlike patients with acquired hypoparathyroidism, patients with these mutations had hypercalciuria even at low serum calcium concentrations. Their greater hypercalciuria presumably reflected activation of Ca(2+)-sensing receptors in kidney cells, where the receptor negatively regulates calcium reabsorption. This augmented hypercalciuria increases the risk of renal complications and thus has implications for the choice of therapy.
Hum Mol Genet 1996 May
PMID:Mutations in the Ca(2+)-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism. 873 26

The antenatal variant of Bartter's syndrome is an autosomal recessive kidney disease characterized by polyhydramnios, premature delivery, hypokalemic alkalosis and hypercalciuria. It is genetically heterogeneous, having been linked recently to mutations in an ATP-sensitive, renal outer medullary K+channel, ROMK, and earlier to mutations in the Na-K-2Cl co-transporter, NKCC2. We characterized four of the mutations reported in three heterozygous ROMK variants of antenatal Bartter's and found that each expressed a distinct phenotype in Sf9 cells. One mutation expressed normal function and appears to be an allelic polymorphism. The other three mutations produced channels with significantly reduced K+fluxes. However, the mechanisms in each case were different and reflected abnormalities in phosphorylation, proteolytic processing or protein trafficking. The different mechanisms may be important in the design of appropriate therapy for patients with this disease.
Hum Mol Genet 1998 Jun
PMID:Functional consequences of ROMK mutants linked to antenatal Bartter's syndrome and implications for treatment. 958 Jun 61

The Ca2+-sensing receptor (CaR) is a member of the seven-transmembrane domain, G-protein-coupled receptor superfamily. It is expressed in parathyroid, kidney, and other tissues. In parathyroid, activation of the CaR by extracellular Ca2+ negatively regulates the secretion of parathyroid hormone. In the the thick ascending limb of Henle's loop, receptor activation decreases renal reabsorption of Ca2+. Heterozygous inactivating mutations of the CaR cause familial benign hypocalciuric hypercalcemia while homozygous inactivating mutations cause neonatal severe hyperparathyroidism. Conversely, activating mutations of the CaR cause autosomal dominant and sporadic hypoparathyroidism. Affected individuals have hypocalcemia which ranges from mild and asymptomatic to life-threatening. They also show a greater tendency to hypercalciuria than do other patients with hypoparathyroidism. Most, but not all, of the reported activating mutations occur in the amino-terminal, extracellular domain of the receptor. When expressed in cultured cells, mutant receptors can show both increased receptor sensitivity to Ca2+ and increased maximal signal transduction capacity.
Mol Genet Metab 1998 Jul
PMID:Activating mutations of the Ca2+-sensing receptor. 971 29

The Milan hypertensive strain of rat (MHS) displays abnormalities in both renal function and adrenocortical activity. While the pressor role of the former has been studied in detail, the role of the latter has not yet been clearly evaluated. In the present study, glucocorticoid receptor (GR) binding characteristics in liver cytosol from adult MHS and Milan normotensive controls (MNS) have been investigated. Dexamethasone, aldosterone and corticosterone were bound with lower affinity to cytosol of MHS rats compared with that of MNS rats. This pattern of binding could explain the raised plasma corticosterone concentrations and adrenocortical hypertrophy previously noted in MHS. The coding sequence of MHS and MNS GR genes have been determined. The MHS gene differed in four respects from that of MNS: three silent point mutations and a polymorphic microsatellite region in exon 2. The latter polymorphism has been used in cosegregation studies of F2 hybrids of MHS x MNS. The MHS GR genotype was associated with hypercalciuria and lower blood pressure in female rats and lower body weight in male rats. Although the effect on blood pressure is small, it is consistent with the affinity data. MHS GR genotype cosegregated with lower blood pressure in F2 rats and displayed a lower affinity in binding studies. In conclusion, GR polymorphism may be responsible for differences of adrenocortical function between MHS and MNS. This may lead to a reduction in the blood pressure difference between the two strains.
J Mol Endocrinol 1998 Aug
PMID:Glucocorticoid receptor polymorphism in genetic hypertension. 972 62

Dent's disease, which is a renal tubular disorder characterized by low molecular weight proteinuria, hypercalciuria and nephrolithiasis, is associated with inactivating mutations of the X-linked chloride channel, CLC-5. However, the manner in which a functional loss of CLC-5 leads to such diverse renal abnormalities remains to be defined. In order to elucidate this, we performed studies to determine the segmental expression of CLC-5 in the human kidney and to define its intracellular distribution. We raised and characterized antisera against human CLC-5, and identified by immunoblotting an 83 kDa band corresponding to CLC-5 in human kidney cortex and medulla. Immunohistochemistry revealed CLC-5 expression in the epithelial cells lining the proximal tubules and the thick ascending limbs of Henle's loop, and in intercalated cells of the collecting ducts. Studies of subcellular human kidney fractions established that CLC-5 distribution was associated best with that of Rab4, which is a marker of recycling early endosomes. In addition, confocal microscopy studies using the proximal tubular cell model of opossum kidney cells, which endogenously expressed CLC-5, revealed that CLC-5 co-localized with the albumin-containing endocytic vesicles that form part of the receptor-mediated endocytic pathway. Thus, CLC-5 is expressed at multiple sites in the human nephron and is likely to have a role in the receptor-mediated endocytic pathway. Furthermore, the functional loss of CLC-5 in the proximal tubules and the thick ascending limbs provides an explanation for the occurrences of low molecular weight proteinuria and hypercalciuria, respectively. These results help to elucidate further the patho-physiological basis of the renal tubular defects of Dent's disease.
Hum Mol Genet 1999 Feb
PMID:Intra-renal and subcellular distribution of the human chloride channel, CLC-5, reveals a pathophysiological basis for Dent's disease. 993 32

Nephrolithiasis (kidney stones) affects 5-10% of adults and is most commonly associated with hypercalciuria, which may be due to monogenic renal tubular disorders. One such hypercalciuric disorder is Dent's disease, which is characterized by renal proximal tubular defects that include low molecular weight proteinuria, aminoaciduria and glycosuria, together with rickets in some patients. Dent's disease is due to inactivating mutations of the renal-specific voltage-gated chloride channel, CLC-5, which is expressed in the proximal tubule, thick ascending limb and collecting duct. The subcellular localization of CLC-5 to the proximal tubular endosomes has suggested a role in endocytosis, and to facilitate in vivo investigations of CLC-5 in Dent's disease we generated mice lacking CLC-5 by targeted gene disruption. CLC-5-deficient mice developed renal tubular defects which included low molecular weight (<70 kDa) proteinuria, generalized aminoaciduria that was more pronounced for neutral and polar amino acids, and glycosuria. They also developed hypercalciuria and renal calcium deposits and some had deformities of the spine. Furthermore, endocytosis as assessed by horseradish peroxidase uptake in the proximal tubule was severely impaired in CLC-5-deficient mice, thereby demonstrating a role for CLC-5 in endosomal uptake of low molecular weight proteins. Thus, CLC-5-deficient mice provide a model for Dent's disease and this will help in elucidating the function of this chloride channel in endocytosis and renal calcium homeostasis.
Hum Mol Genet 2000 Dec 12
PMID:Mice lacking renal chloride channel, CLC-5, are a model for Dent's disease, a nephrolithiasis disorder associated with defective receptor-mediated endocytosis. 1111 37

Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disease characterized by mild hypercalcemia, an inappropriately high parathyroid hormone level, and absence of hypercalciuria. Heterozygous inactivating mutations of calcium-sensing receptor (CaSR) are found in about two thirds of patients with FHH. Histologic examination of parathyroid glands in FHH is reported to show normal histology or chief cell hyperplasia. Thus, histologic features of the parathyroid glands in FHH vary, and there is no clear histologic criterion that indicates FHH. The authors have encountered three hypercalcemic patients with characteristic histologic features of enlarged parathyroid glands. Clusters of parenchymal cells were mixed with fat cells, and the area of fat cells was 33% to 49% of the total area. These features are similar to those described as parathyroid lipohyperplasia. Postoperative evaluation showed that fractional excretion of calcium was low in these patients. Direct sequencing of the polymerase chain reaction product showed that the first patient was heterozygous for an already reported inactivating mutation of CaSR (P55L). The second patient was also heterozygous for a novel inactivating mutation (R220W). The third was homozygous for an inactivating mutation (Q27R). These results indicate that histologic features of parathyroid lipohyperplasia suggest the presence of inactivating mutations of CaSR.
Diagn Mol Pathol 2001 Dec
PMID:Inactivating mutations of calcium-sensing receptor results in parathyroid lipohyperplasia. 1176 15


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