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 is an X-linked inherited disorder characterized by hypercalciuria, nephrocalcinosis, nephrolithiasis, low molecular weight proteinuria, Fanconi's syndrome, and renal failure. It is caused by inactivating mutations in CLC5, a member of the CLC voltage-gated chloride channel family. CLC5 is known to be expressed in the endosomal compartment of the renal proximal tubule, where it may be required for endosomal acidification and trafficking. Although the Fanconi's syndrome and low molecular weight proteinuria in Dent's disease can be explained by disruption of endosomal function in this nephron segment, the pathogenesis of the hypercalciuria in this disease is unknown. We have generated transgenic mice (RZ) with reduced CLC5 expression by introduction of an antisense ribozyme targeted against CLC5. RZ mice are markedly hypercalciuric compared with nontransgenic control mice, at a time when their serum electrolytes and renal function are otherwise normal. This suggests that hypercalciuria in Dent's disease is a direct consequence of CLC5 hypofunction and is not attributable to a gain of function by mutant CLC5, an effect of modifier genes, or a secondary result of nonspecific renal injury. Surprisingly, hypercalciuria in RZ mice is abolished by dietary calcium deprivation, suggesting that the hypercalciuria may be attributable to gastrointestinal hyperabsorption of calcium rather than a renal calcium leak.
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PMID:Diet-dependent hypercalciuria in transgenic mice with reduced CLC5 chloride channel expression. 1051 95

Recent studies of hereditary renal tubular disorders have facilitated the identification and roles of chloride channels and cotransporters in the regulation of the most abundant anion, Cl-, in the ECF. Thus, mutations that result in a loss of function of the voltage-gated chloride channel, CLC-5, are associated with Dent's disease, which is characterized by low-molecular weight proteinuria, hypercalciuria, nephrolithiasis, and renal failure. Mutations of another voltage-gated chloride channel, CLC-Kb, are associated with a form of Bartter's syndrome, whereas other forms of Bartter's syndrome are caused by mutations in the bumetanide-sensitive sodium-potassium-chloride cotransporter (NKCC2) and the potassium channel, ROMK. Finally, mutations of the thiazide-sensitive sodium-chloride cotransporter (NCCT) are associated with Gitelman's syndrome. These studies have helped to elucidate some of the renal tubular mechanisms regulating mineral homeostasis and the role of chloride channels.
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PMID:Chloride channels in renal disease. 1056 51

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.
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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

Dent's disease is a nephrolithiasis disorder associated with hypercalciuria and low molecular weight proteinuria that is caused by mutations in the voltage-gated chloride channel ClC-5. Because the exact cause of hypercalciuria in this disease is unknown and could come from a renal, intestinal, or bone origin, we have investigated overall calcium handling in the ClC-5 knockout mouse (ClC-5 KO). On a high calcium diet, ClC-5 KO mice had elevated serum 1alpha,25-dihydroxyvitamin D3 (1alpha,25D3), alkaline phosphatase (AP), osteocalcin (OC), and urinary deoxypyridinoline (DPD), but serum parathyroid hormone (PTH), calcium, and intestinal calcium uptake was similar to that of wild-type (WT) mice. A 30-fold decrease in dietary calcium intake caused elevation of serum PTH and urinary cyclic adenosine monophosphate in ClC-5 KO mice and decreased the renal calcium excretion, which still remained 2-fold above that of WT mice. On this low calcium diet, both groups of mice had the same serum 1alpha,25D3, with similar increments in intestinal calcium absorption, serum AP, OC, and urinary DPD. These data indicate that the hypercalciuria in the ClC-5 KO mice on low and high calcium diets is of bone and renal origin and is not caused by increased intestinal calcium absorption, despite an elevated serum 1alpha,25D3. These mice data suggest that young patients with this disease may have a propensity for altered bone homeostasis that should be monitored clinically.
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PMID:The ClC-5 knockout mouse model of Dent's disease has renal hypercalciuria and increased bone turnover. 1267 22

Dent's disease and familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) are inherited diseases in which hypercalciuria, nephrocalcinosis, and renal failure are prominent features. Dent's disease resembles a Fanconi syndrome, with impaired reabsorption in the proximal tubule; FHHNC, with urinary loss of magnesium and calcium, is associated with impaired cation transport in the thick ascending limb of Henle's loop. Gene mapping in families and positional cloning led in both cases to identification of the responsible gene. Dent's disease is associated with mutations that disrupt function of a voltage-gated chloride channel, CLC-5, expressed in subapical endosomes of the proximal tubule and in other nephron segments. Impaired function of this channel disturbs reabsorption of filtered proteins, as well as other transport functions of the proximal tubule, and leads, apparently indirectly, to hypercalciuria and renal failure. FHHNC results from mutations in paracellin-1, a tight-junction protein that appears to be important in conducting or regulating paracellular cation transport. Impaired function of paracellin-1 leads specifically to urinary losses of magnesium and calcium, but because transcellular transport is intact these patients do not have hypokalemia or salt wasting. Identification of both genes represent triumphs of a genetic approach to solving problems of pathophysiology.
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PMID:Inherited hypercalciuric syndromes: Dent's disease (CLC-5) and familial hypomagnesemia with hypercalciuria (paracellin-1). 1473 May 10

Dent's disease, a X-linked hypercalciuric nephrolithiasis, is caused by mutations of the CLCN5 gene. The disease is characterised by low molecular weight proteinuria with variable presence of hypercalciuria, hyperphosphaturia, nephrocalcinosis, and kidney stones. CLCN5 encodes a chloride channel belonging to the voltage-gated chloride channel family, which is predominantly expressed in the endosomes of proximal tubular cells. By shunting the current of electrogenic H+-ATPase, ClC-5 is crucial for efficient acidification of renal endosomes. As shown in knock-out mouse models, the ClC-5 loss of function causes severe impairment of receptor-mediated endocytosis, as well as the endocytotic retrieval of plasma membrane proteins including megalin. In a minority of patients with classical Dent's disease, the analysis of CLCN5 coding sequences failed to identify causative mutations. It is conceivable that mutations in the 5' upstream regulatory regions could impair the correct processing and translation of CLCN5. The complexity of its promoter region seems to support this hypothesis. Molecular diagnosis of Dent's disease is now available; since the risk of developing renal insufficiency in adult life is elevated for this type of nephrolithiasis, the correct diagnosis could potentially modify the natural history of the disease by preventing the evolution towards uraemia.
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PMID:[Dent's disease: hereditary nephrolithiasis related to defective tubular endocytosis processes]. 1473 9

Renal stone disease (nephrolithiasis) affects 5% of adults and is often associated with hypercalciuria. Hypercalciuric nephrolithiasis is a familial disorder in more than 35% of patients, and may occur as a monogenic disorder, or as a polygenic trait involving 3 to 5 susceptibility loci in man and rat, respectively. Studies of monogenic forms of hypercalciuric nephrolithiasis in man, for example, Bartter syndrome, Dent's disease, autosomal dominant hypocalcemic hypercalciuria (ADHH), hypercalciuric nephrolithiasis with hypophosphatemia, and familial hypomagnesemia with hypercalciuria have helped to identify a number of transporters, channels, and receptors that are involved in regulating the renal tubular reabsorption of calcium. Thus, Bartter syndrome, an autosomal recessive disease, is caused by mutations of the bumetanide-sensitive Na-K-Cl (NKCC2) cotransporter, the renal outer-medullary potassium channel (ROMK), the voltage-gated chloride channel, CLC-Kb, or in its beta subunit, Barttin. Dent's disease, an X-linked disorder characterized by low molecular weight proteinuria, hypercalciuria, and nephrolithiasis, is due to mutations of the chloride/proton antiporter, CLC-5; ADHH is associated with activating mutations of the calcium-sensing receptor, which is a G protein-coupled receptor; hypophosphatemic hypercalciuric nephrolithiasis associated with rickets is due to mutations in the type 2c sodium-phosphate cotransporter (NPT2c); and familial hypomagnesemia with hypercalciuria is due to mutations of paracellin-1, which is a member of the claudin family of membrane proteins that form the intercellular tight junction barrier in a variety of epithelia. These studies have provided valuable insights into the renal tubular pathways that regulate calcium reabsorption and predispose to kidney stones and bone disease.
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PMID:Genetics of hypercalciuric nephrolithiasis: renal stone disease. 1787 84

Renal stone disease (nephrolithiasis) affects 3-5% of the population and is often associated with hypercalciuria. Hypercalciuric nephrolithiasis is a familial disorder in over 35% of patients and may occur as a monogenic disorder that is more likely to manifest itself in childhood. Studies of these monogenic forms of hypercalciuric nephrolithiasis in humans, e.g. Bartter syndrome, Dent's disease, autosomal dominant hypocalcemic hypercalciuria (ADHH), hypercalciuric nephrolithiasis with hypophosphatemia, and familial hypomagnesemia with hypercalciuria have helped to identify a number of transporters, channels and receptors that are involved in regulating the renal tubular reabsorption of calcium. Thus, Bartter syndrome, an autosomal disease, is caused by mutations of the bumetanide-sensitive Na-K-Cl (NKCC2) co-transporter, the renal outer-medullary potassium (ROMK) channel, the voltage-gated chloride channel, CLC-Kb, the CLC-Kb beta subunit, barttin, or the calcium-sensing receptor (CaSR). Dent's disease, an X-linked disorder characterized by low molecular weight proteinuria, hypercalciuria and nephrolithiasis, is due to mutations of the chloride/proton antiporter 5, CLC-5; ADHH is associated with activating mutations of the CaSR, which is a G-protein-coupled receptor; hypophosphatemic hypercalciuric nephrolithiasis associated with rickets is due to mutations in the type 2c sodium-phosphate co-transporter (NPT2c); and familial hypomagnesemia with hypercalciuria is due to mutations of paracellin-1, which is a member of the claudin family of membrane proteins that form the intercellular tight junction barrier in a variety of epithelia. These studies have provided valuable insights into the renal tubular pathways that regulate calcium reabsorption and predispose to hypercalciuria and nephrolithiasis.
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PMID:Genetic causes of hypercalciuric nephrolithiasis. 1844 82