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)

Idiopathic low-molecular-weight (LMW) proteinuria is a newly described renal disease in Japan and Italy. We report on 7 patients who manifested bilateral or unilateral nephrocalcinosis, as demonstrated by abdominal computed tomography scans. Renal histology revealed calcinosis of renal tubules in 2 patients. Computed tomography is a reliable method for the detection of nephrocalcinosis in this disorder. Hypercalciuria was also seen in 6 patients. A calcium-loading test performed in 2 patients suggested that hypercalciuria was of renal origin. Although the true pathogenesis is still not known, hypercalciuria and nephrocalcinosis appear to be a common complication in patients with idiopathic LMW proteinuria. These complications and clinical features suggest that idiopathic LMW proteinuria in Japan is likely to be identical to Dent's disease in the United Kingdom.
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PMID:Hypercalciuria and nephrocalcinosis in patients with idiopathic low-molecular-weight proteinuria in Japan: is the disease identical to Dent's disease in United Kingdom? 775 56

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.
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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.
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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

Familial idiopathic low-molecular-weight proteinuria (FILMWP) is a renal proximal tubulopathy that occurs predominantly in males. FILMWP is characterized by mild proteinuria consisting of low-molecular-weight proteinuria, aminoaciduria and relatively conserved renal function, but without rickets. To determine whether FILMWP is related to the CLCN5 gene, which is responsible for Dent's disease and two related disorders, we analyzed the CLCN5 gene from four Japanese families with FILMWP. We identified two novel mutations: one was a single base insertion at codon 520 serine in exon 10 and the other was a single base deletion at codon 403 tyrosine in exon 8. These mutations caused a shift in the reading frame, resulting in synthesis of truncated CLC5 proteins that lacked 220 (29%) and 314 (42%) amino acids, respectively. These mutations were demonstrated to cosegregate with the disease in two families, respectively. We conclude that the CLCN5 gene is responsible for this proximal renal tubulopathy in some Japanese families and that FILMWP is possibly a variant of Dent's disease.
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PMID:Mutations in the CLCN5 gene in Japanese patients with familial idiopathic low-molecular-weight proteinuria. 932 27

Mutations in the CLCN5 gene have been demonstrated in three disorders of hypercalciuric nephrolithiasis, i.e., Dent's disease, X-linked recessive nephrolithiasis, and X-linked recessive hypophosphatemic rickets. Recently, a number of Japanese children with low molecular weight proteinuria (LMWP) showing symptoms similar to those shown by patients with Dent's disease in British families have also been reported to have mutations in the CLCN5 gene. The present study examines five unrelated Japanese families with LMWP, two of which lacked any signs other than LMWP, and three of which had several signs other than LMWP, i.e., hypercalciuria, aminoaciduria, hypophosphatemia, and rickets. One nonsense (E118X) and one missense (W22G) mutation were found in three patients in the two families having only LMWP. One genomic deletion including exons 5 to 8 in the CLCN5 gene was found in a patient with hypophosphatemic rickets, and a nonsense mutation (R347X) was found in one patient with LMWP and slight hypercalciuria. No mutations of the exons and exon-intron boundaries in the CLCN5 gene were found in one patient with LMWP, aminoaciduria, and hypokalemia. In addition to the predicted loss of chloride channel function in these nonsense and deletion mutations, the loss of function in the missense mutation W22G was confirmed in the Xenopus oocyte expression system. These results clarified four novel mutations in the CLCN5 genes, and additionally suggested that the loss-of-function mutation of the CLCN5 does not necessarily lead to hypercalciuria and nephrocalcinosis in the early stage of the disease, and that LMWP is an early and essential manifestation of disorders of the CLC-5 chloride channel.
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PMID:Mutations in CLCN5 chloride channel in Japanese patients with low molecular weight proteinuria. 959 78

Loss-of-function mutations of the ClC-5 chloride channel lead to Dent's disease, a syndrome characterized by low molecular weight proteinuria, hypercalciuria, and kidney stones. We show that ClC-5 is expressed in renal proximal tubule cells, which normally endocytose proteins passing the glomerular filter. Expression is highest below the brush border in a region densely packed with endocytotic vesicles, where ClC-5 colocalizes with the H+-ATPase and with internalized proteins early after uptake. In intercalated cells of the collecting duct it again localizes to apical intracellular vesicles and colocalizes with the proton pump in alpha-intercalated cells. In transfected cells, ClC-5 colocalizes with endocytosed alpha2-macroglobulin. Cotransfection with a GTPase-deficient rab5 mutant leads to enlarged early endosomes that stain for ClC-5. We suggest that ClC-5 may be essential for proximal tubular endocytosis by providing an electrical shunt necessary for the efficient acidification of vesicles in the endocytotic pathway, explaining the proteinuria observed in Dent's disease.
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PMID:ClC-5, the chloride channel mutated in Dent's disease, colocalizes with the proton pump in endocytotically active kidney cells. 965 42

Dent's disease is a rare type of proximal renal tubular defect characterized by hypercalciuria, low-molecular-weight (LMW) proteinuria, nephrocalcinosis and slowly progressive renal failure, short stature and osteopenia in children with clinical symptoms of rickets. This "hypercalciuric rickets" was originally described by Charles Dent and Max Friedman in 1964 [1]. The disease is probably linked to the X chromosome so that males are much more severely affected than females.
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PMID:Dent's disease--the hypercalciuric variant of Fanconi's syndrome. 974 95

Dent's disease, an inherited disorder characterized by hypercalciuria, nephrolithiasis, nephrocalcinosis, rickets, low-molecular-weight proteinuria, Fanconi's syndrome, and renal failure, is caused by mutations in the renal chloride channel, CLC5. The normal role of CLC5 is unknown. We have investigated the intrarenal and subcellular localization of CLC5 in rat kidney by in situ hybridization and immunohistochemistry. By in situ hybridization, CLC5 mRNA was detected predominantly in cortical medullary ray and outer medullary tubule epithelial cells. Polyclonal antiserum was generated against a CLC5 fusion protein, affinity purified, and immunoadsorbed against CLC3 and CLC4 to yield a CLC5 isoform-specific antiserum. By immunohistochemistry, CLC5 protein was localized to the intracellular domain of tubular epithelial cells in the S3 segment of the proximal tubule and the medullary thick ascending limb. By subcellular membrane fractionation and flow cytometry, CLC5 expression was found in outer medullary endosomes. These findings are consistent with a model in which CLC5 encodes an endosomal chloride channel that facilitates acidification and trafficking of renal epithelial endosomes.
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PMID:Intrarenal and subcellular localization of rat CLC5. 981 33

In Japanese patients idiopathic tubular proteinuria presents mainly as asymptomatic tubular low molecular weight proteinuria. This disease has recently been shown to resemble Dent's disease which is characterized by tubular proteinuria, hypercalciuria, rickets and eventual renal failure. We report on 4 children with idiopathic tubular proteinuria. Although they had normal renal function, as evidenced by serum creatinine or creatinine clearance, they had very poor renal accumulation of 99mTc-DMSA and the presence of large amounts of tracer in the bladder. Additionally, the patient with the largest amounts of tubular proteinuria had the poorest renal accumulation of the 4 patients. The renal accumulation of tracer decreased with time from a maximum at 10 min after injection. These findings demonstrate that the tracer, once taken to be confined to the proximal tubular cells, is immediately excreted to the tubular lumen. We suggest that poor renal accumulation of 99mTc-DMSA is very important in elucidating the mechanism of idiopathic tubular proteinuria, and that 99mTc-DMSA renoscintigraphy is useful in the evaluation of the patient's renal function over time.
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PMID:Poor renal accumulation of 99mTc-DMSA in idiopathic tubular proteinuria. 988 19

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.
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PMID:Intra-renal and subcellular distribution of the human chloride channel, CLC-5, reveals a pathophysiological basis for Dent's disease. 993 32


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