Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0033687 (proteinuria)
24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dent's disease is an X-linked renal tubular disorder characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and renal failure. The disease is caused by mutations in a renal chloride channel gene, CLCN5, which encodes a 746 amino acid protein (CLC-5), with 12 to 13 transmembrane domains. In this study, an additional six unrelated patients with Dent's disease were identified and investigated for CLCN5 mutations by DNA sequence analysis of the 11 coding exons of CLCN5. This revealed six mutations: four frameshift deletions involving codons 392, 394, 658, and 728, one nonsense mutation (Tyr617Stop), and an A to T transversion at codon 601 that would result in either a missense mutation (Asp601Val) or creation of a novel donor splice site. These mutations were confirmed by restriction endonuclease or sequence-specific oligonucleotide hybridization analysis and were not common polymorphisms. The frameshift deletions and nonsense mutation predict truncated and inactivated CLC-5. The effects of the putative missense Asp601Val mutant CLC-5 were assessed by heterologous expression in Xenopus oocytes, and this revealed a chloride conductance that was similar to that observed for wild-type CLC-5. However, an analysis of the mutant CLCN5 transcripts revealed utilization of the novel donor splice site, resulting in a truncated CLC-5. Thus, all of the six mutations are likely to result in truncated CLC-5 and a loss of function, and these findings expand the spectrum of CLCN5 mutations associated with Dent's disease.
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PMID:Characterization of renal chloride channel (CLCN5) mutations in Dent's disease. 1090 59

Two Japanese patients, belonging to unrelated families, with idiopathic low-molecular-weight proteinuria (LMWP; Japanese Dent's disease) showed novel mutations of the gene encoding renal-specific chloride channel 5 (CLC-5). Proteinuria was first noticed at the ages of 2 and 3 years in patients 1 and 2, respectively. During follow-up, marked increases in urinary ss(2)-microglobulin levels, hypercalciuria, and high levels of urinary excretion of growth hormone were observed in both patients. Nephrocalcinosis was detected in patient 2. Renal biopsy specimens from both patients showed minimal alterations in glomeruli and tubulointerstitium, except for mild mesangial proliferation in patient 2. DNA sequence analysis of the entire 2,238-bp coding region and exon-intron boundaries of the CLCN5 gene showed the presence of two novel mutations in exon 10, consisting of one missense mutation (I524K) in patient 1 and one nonsense mutation (R637X) in patient 2. DNA analysis and measurement of urinary ss(2)-microglobulin levels in family members indicated an X-linked mode of inheritance in patient 1 and sporadic occurrence in patient 2. These results have expanded our understanding of the association between idiopathic LMWP (Japanese Dent's disease) and mutations of the CLCN5 gene.
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PMID:Identification of two novel mutations in the CLCN5 gene in Japanese patients with familial idiopathic low molecular weight proteinuria (Japanese Dent's disease). 1113 79

The human CLC-5 chloride channel is expressed mainly in the kidney and its mutations cause Dent's disease (a familial renal tubular syndrome with hypercalciuria, tubular proteinuria, rickets, nephrocalcinosis, and eventual renal failure). To gain insight into the regulatory mechanism of CLC-5 expression, a genomic clone that contains the 5'-flanking region of the human CLC-5 gene was isolated and characterized. Two types of 5'-ends of cDNA were isolated by 5'-rapid amplification of cDNA ends, and one of them, approximately 2.1 kbp upstream of ATG-containing exon II, was first identified in human. The major promoter activity was detected in the 5'-flanking region of this newly identified exon Ia. The sequence of the proximal 5'-flanking region contained an activator protein (AP)-1-like site and cAMP-responsive element, but it lacked a TATA box, a GC-rich element, and an SP-1 site. Deletion analysis of the 5'-flanking region showed that the fragments containing the AP-1-like element (TGACTCC) positioned at -38 exhibited high promoter activities in CLC-5 expressing LLC-PK1 cells, but that further deletions not containing this AP-1-like element resulted in a great loss of luciferase activities. Gel-retardation analysis demonstrated the existence of a specific protein binding to this AP-1-like element in LLC-PK1 cells, which seemed to differ from an authentic AP-1. This study clarified the key element of the human CLCN5 promoter, and the mutation in this region could be the cause of Dent's disease.
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PMID:Isolation and characterization of the human CLC-5 chloride channel gene promoter. 1116 24

Familial hypomagnesemia-hypercalciuria with nephrocalcinosis and renal insufficiency in childhood is a rarely described disease. Two siblings of consanguineous Tunesian parents (first cousins), a 2-year-old boy and a 4-year-old girl presented with renal insufficiency and severe bilateral nephrocalcinosis. Both were found to have decreased serum and intracellular magnesium concentrations, increased urinary excretion of magnesium and calcium, mild glomerular and severe tubular proteinuria and low citrate excretion in urine. Pathological biochemical findings and the severity of nephrocalcinosis of the boy compared to findings of the sister were strongly marked, Histology of the boy's kidney showed severe medullary nephrocalcinosis, tubular atrophy, focal lymphoplasmacellulary infiltration, focal cortical fibrosis, immature glomerula, segmental and global glomerulosclerosis. Subsequent mutation analysis revealed a homozygous frameshift mutation in the gene paracellin-1 in both affected individuals. Therapy consisted of sodium bicarbonate, cholecalciferol, calcitriol, hydrochlorothiazide, citrate salts and oral magnesium administration. Hypercalciuria decreased in both children by therapy with thiazide diuretics, but hypomagnesemia was unresponsive to magnesium administration. After a 32-month follow-up the boy commenced hemodialysis at the age of 5 years, whereas his sister showed no decline in renal function.
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PMID:Familial hypomagnesemia-hypercalciuria in 2 siblings. 1152 93

This report concerns 6 patients with renal involvement in sarcoidosis. Two of the patients had no clinical symptoms at all. In 3 patients, no extrarenal organ manifestation was found. All 6 patients had elevated levels of serum creatinine, 2 were hypercalcemic. Five patients manifested with mild proteinuria, but in none of the cases was a nephritic sediment with erythrocytes found. Kidney biopsies in 5 patients showed epitheloid cell granulomatous interstitial nephritis, and 1 patient presented with nephrocalcinosis. All patients were treated with corticosteroids. The serum creatinine levels decreased significantly in 4 patients (> 50% decrease), and slightly in 2 patients, elevated serum calcium levels were normalized. Thus, even in the absence of other organ manifestations, sarcoidosis can be the cause of renal insufficiency, and it responds well to corticosteroid treatment. These patients demonstrate the importance of kidney biopsy in the unexplained deterioration of renal function.
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PMID:Renal involvement in sarcoidosis--a report of 6 cases. 1186 25

Dent's disease, an X-linked tubulopathy secondary to defects in chloride channel CLC-5, is characterised by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, and renal stones. Mechanisms leading to nephrocalcinosis are unknown. Using a murine collecting duct cell line (mIMCD-3), we confirm endogenous expression of mCLC-5. During transfection of antisense CLC-5, we observe a reduction in CLC-5 protein expression that correlates with a reduction in the number of acidic endosomal compartments, as determined by quantitative analysis of confocal microscope images using LysoTracker Red. Using wheat germ agglutinin-lectin as an endocytic marker, an arrest of endocytosis is observed in antisense CLC-5 treated cells. Exposure of the cell surface to calcium oxalate crystals results in crystal agglomeration in a minority of sense CLC-5 transfectants (45%) and all antisense CLC-5 transfectants. We conclude that expression of CLC-5 in mIMCD-3 cells allows acidification of endosomes and endocytosis, and that disruption of CLC-5 expression causes abnormal crystal agglomeration.
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PMID:Disordered calcium crystal handling in antisense CLC-5-treated collecting duct cells. 1250 84

Mutations in the gene CLCN5 encoding the vesicular chloride channel ClC-5 lead to Dent's disease, an X-linked renal disorder. Dent's disease is characterised by proteinuria, hyperphosphaturia and hypercalciuria, which eventually lead to kidney stones and nephrocalcinosis. As it was unclear how mutations in a chloride channel might cause these symptoms, we and others have generated genetic mouse models to elucidate the underlying pathophysiological mechanisms. We review results obtained from these three mouse models and present new data on endosomal acidification and vitamin D metabolism in ClC-5 knock-out (KO) mice. ClC-5 is expressed in apical endosomes of proximal tubular cells where it co-localizes with endocytosed proteins and the proton ATPase. ClC-5 may provide an electric shunt for the efficient operation of the electrogenic H(+)-ATPase. We confirmed this hypothesis by showing that endosomes from CLCN5 KO mice are acidified at a significantly lower rate than wild-type endosomes. This probably results in the drastic impairment of endocytosis observed in ClC-5 KO mice. Parathyroid hormone (PTH) is filtered into the lumen of the nephron, where it is endocytosed and degraded by proximal tubular cells. The defective endocytosis in ClC-5 KO mice entails an increased luminal concentration of PTH, subsequent stimulation of apical PTH receptors which causes an increased endocytosis of the phosphate transporter NaPi and phosphaturia. We now show that it also results in up-regulation of proximal tubular alpha-hydroxylase that generates the active form of vitamin D from its precursor. We discuss how the primary defect in endocytosis leads via secondary changes in calciotropic hormones to the tertiary symptoms hyperphosphaturia, hypercalciuria and kidney stones.
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PMID:The ClC-5 chloride channel knock-out mouse - an animal model for Dent's disease. 1254 89

A 5-year-old girl presented with short stature. She was found to have rickets due to renal phosphate wasting and nephrocalcinosis. Serum parathyroid hormone was suppressed, 25-OH vitamin D was within the normal range, and 1,25-(OH)(2 )vitamin D was elevated. In addition, she had hypercalciuria, proteinuria, which was partially tubular in origin, and a reduced glomerular filtration rate of 58 ml/min per 1.73 m(2). Treatment with phosphate supplements resulted in healing of the rickets and normalization of the serum 1,25-(OH)(2 )vitamin D level. This patient is an example of hypercalciuric rickets, most likely due to an inherited disorder of phosphate metabolism. Hypercalciuric rickets can be inherited as an autosomal recessive as well as autosomal dominant trait.
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PMID:A girl with rickets and nephrocalcinosis. 1464 29

The long-term outcome of 20 preterm infants with extremely low birth weight and acute renal failure in the neonatal period was studied retrospectively over an 18-year period. Those with progressive renal disease are compared with those with normal renal function. Current mean age is 7.5+/-4.6 years (range 3.2-18.5 years). Nine patients showed deterioration in renal function (low GFR group). Increasing proteinuria, as determined by random urine protein/creatinine ratio (Up/c), correlated with deterioration in renal function ( r=0.8, P<0.0001). Prominent risk factors for progression were Up/c >0.6 at 1 year of age [100% sensitivity, 75% positive predictive value (PPV), P<0.01], serum creatinine >0.6 mg/dl at 1 year of age (75% sensitivity, 80% PPV, P<0.01), and a tendency to obesity with body mass index >85th percentile (89% sensitivity, PPV 67%, P=0.03). Loss of renal mass and nephrocalcinosis were not prognostic indicators. This report begins to identify important clinical parameters that should lead to closer surveillance and potential treatment interventions for preservation of renal function in a growing population of surviving low birth weight individuals.
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PMID:Long-term follow-up of extremely low birth weight infants with neonatal renal failure. 1283 91

CLC-5 is a member of the CLC family of voltage-gated chloride channels. Mutations disrupting CLC-5 lead to Dent's disease, an X-linked renal tubular disorder, characterised by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, and renal stones. Sequence analysis of CLC-5 reveals a 746 amino acid protein with an intracellular amino-terminus, transmembrane spanning domains, and two CBS domains within its intracellular carboxy-terminus. CBS domains have been implicated in intracellular targetting and trafficking as well as protein-protein interactions. We investigate subcellular localisation of three naturally occurring CLC-5 mutants which all lead to a truncated protein, disrupting the second CBS domain. These mutants are unable to traffic normally to acidic endosomes but are retained in perinuclear compartments, colocalising with the Golgi complex. This is the first identification of the cellular pathogenesis of CBS domain mutations of CLC-5.
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PMID:A role for CBS domain 2 in trafficking of chloride channel CLC-5. 1452 53


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