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)

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

Dent's disease is an X-linked renal tubular disorder characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and eventual renal failure. Various types of mutations in the renal chloride channel gene, CLCN5, have been identified in patients with this disease. We studied a Spanish patient with Dent's disease and found, by polymerase chain reaction amplification of the CLCN5 exons, an abnormally large exon 11. Sequencing analysis revealed that this was attributable to the insertion in codon 650 of an Alu element of the "young" Ya5 subfamily. The Alu element was inserted with the same orientation as the CLCN5 gene and arose de novo on the maternal chromosome. Polymorphism analysis indicated that the insertion occurred in the germline of the maternal grandfather. The presence of a long poly(A) tract and evidence for a 16-bp target-site duplication implied that the Alu element was integrated by retrotransposition. This mutation predicts a truncated ClC-5 protein that lacks part of the carboxy-terminus and is likely to result in loss of function of the chloride channel. Insertions of Alu sequences, which are rarely found in coding regions, have occasionally been reported to cause other genetic diseases. However, this is the first report of a retrotransposon insertion in the CLCN5 gene associated with Dent's disease.
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PMID:De novo insertion of an Alu sequence in the coding region of the CLCN5 gene results in Dent's disease. 1456 59

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

Young adult heterozygous (carrier) female dogs with X-linked hereditary nephropathy (XLHN) have glomerular proteinuria but are otherwise healthy. Because data regarding dietary influences on the magnitude of proteinuria in dogs with spontaneous glomerular disease are not available, 12 such dogs were studied in a double crossover experiment intended to determine effects of altering dietary protein intake for up to 6 weeks. Dogs were blocked by urine protein : creatinine ratio (UPC) and randomly assigned to receive 2 diets: high protein (34.6% dry matter [DM], HP) or low protein (14.1% DM, LP) fed in HP-LP-HP or LP-HP-LP sequence. Food intake was measured daily, body weight (BW) was measured twice weekly, and UPC, plasma creatinine, blood urea nitrogen, phosphorus, albumin, and protein concentrations were measured at 2-week intervals. Nutrient digestibility was measured during the third treatment period. Diet had a significant effect (P < .0001) on all measured variables except plasma phosphorus (P > .5), but unintended differences in digestibility of protein and energy (P < or = .01) prevented assignment of the diet effect exclusively to protein. Proteinuria was greater (UPC 4.7 +/- 2.2 versus 1.8 +/- 1.1, P < .0001) when the HP diet was fed, but the LP diet did not maintain starting BW or plasma albumin concentration within the normal reference range. Diet greatly affects the magnitude of proteinuria in XLHN carrier females. Dietary protein restriction can reduce proteinuria in dogs with glomerular disease, but BW and blood protein concentrations may not be maintained if the restriction is too severe.
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PMID:Diet modulates proteinuria in heterozygous female dogs with X-linked hereditary nephropathy. 1505 67

X-linked Alport syndrome (XLAS) is a progressive disorder of basement membranes caused by mutations in the COL4A5 gene, encoding the alpha5 chain of type IV collagen. A mouse model of this disorder was generated by targeting a human nonsense mutation, G5X, to the mouse Col4a5 gene. As predicted for a nonsense mutation, hemizygous mutant male mice are null and heterozygous carrier female mice are mosaic for alpha5(IV) chain expression. Mutant male mice and carrier female mice are viable through reproductive age and fertile. Mutant male mice died spontaneously at 6 to 34 wk of age, and carrier female mice died at 8 to 45 wk of age, manifesting proteinuria, azotemia, and progressive and manifold histologic abnormalities of the kidney glomerulus and tubulointerstitium. Ultrastructural abnormalities of the glomerular basement membrane, including lamellation and splitting, were characteristic of human XLAS. The mouse model described here recapitulates essential clinical and pathologic findings of human XLAS. With alpha5(IV) expression reflecting X-inactivation patterns, it will be especially useful in studying determinants of disease variability in the carrier state.
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PMID:Mouse model of X-linked Alport syndrome. 1515 57

ClC-5 is a member of the ClC family of voltage-gated chloride channels. Loss-of-function mutations of its corresponding gene (CLCN5) cause Dent's disease, an X-linked kidney disorder, characterized by low-molecular weight proteinuria, hypercalciuria, nephrocalcinosis/nephrolithiasis, and progressive renal failure. Here, we examined the effect of different mutations on function and cellular trafficking of the recombinant protein. Mutant CLCN5 cDNAs were generated by site directed mutagenesis for two premature stop codon variants (R347X and M517IfsX528), and several missense mutations (C221R, L324R, G462 V, and R516 W). We also tested L521R (instead of L521RfsX526 observed) and mutants G506E and R648X (previously reported by others). After heterologous expression in Xenopus oocytes, ClC-5 channel activity and surface expression were determined by two-electrode voltage-clamp analysis and ClC-5 surface ELISA, respectively. Except for the R516 W and R648X variants, none of the mutated proteins induced functional chloride currents or reached the plasma membrane. This is readily understandable for the truncation mutations. Yet, the tested missense mutations are distributed over different transmembrane regions, implying that correct channel structure and orientation in the membrane is not only a prerequisite for proper ClC-5 function but also for Golgi exit. Interestingly, the R648X mutant although functionally compromised, displayed a significant increase in surface expression. This finding might be explained by the deletion of a ClC-5 carboxy-terminal PY-like internalization signal, which in turn impairs channel removal from the membrane. Our observations further imply that recruitment of ClC-5 to alternative routes (plasma membrane or early endosomes) in the trans-Golgi network is mediated via different signal sequences.
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PMID:Functional evaluation of Dent's disease-causing mutations: implications for ClC-5 channel trafficking and internalization. 1589 57

Anderson-Fabry disease (AFD) is a rare X-linked lipid storage disorder due to a deficient lysosomal a-galactosidase A (a-Gal) activity. In males with the classic form of the disease the enzymatic defect leads to progressive accumulation of glycosphingolipids (GL) in different organs, mainly in the kidney, heart, and brain, causing severe multisystem failure. AFD is usually mild in heterozygous females, but severe cerebrovascular, renal, and cardiac manifestations have been rarely described. The aim of this study is to describe renal involvement of mild symptomatic female carriers by ultrastructural analysis focusing to microvascular lesions, considered to be one of the major causes of systemic disease in AFD. Resin-embedded renal biopsies from 2 sisters with isolated mild proteinuria and belonging to a family group with AFD were observed by light and electron microscopy. In spite of the mild clinical symptoms, diffuse GL storages were demonstrated in all types of glomerular cells and in interstitial endothelial cells. Moreover, platelets were frequently observed in glomerular vassels, a feature coherent with a possible role of prothrombotic state, and platelet activation, in early glomerular lesions.
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PMID:Ultrastructural study of renal involvement in two females with Anderson-Fabry disease. 1603 75

Alu sequences are short, interspersed elements that have generated more than one million copies in the human genome. They propagate by transcription followed by reverse transcription and integration, causing mutations, recombination, and changes in pre-mRNA splicing. We have recently identified a 345-bp long Alu Ya5 element inserted in codon 650 within exon 11 of the chloride channel ClC-5 gene (CLCN5) of a patient with Dent's disease. A microsatellite pedigree analysis indicated that the insertion occurred in the germline of the maternal grandfather. Dent's disease is an X-linked renal tubular disorder characterized by low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, and nephrocalcinosis. Here, we found, by RT-PCR amplification of RNA extracted from the patient's blood and subsequent DNA sequencing, that the Alu insertion led to an aberrant splicing of the CLCN5 pre-mRNA that skipped exon 11. Using the ESE finder and RESCUE-ESE Web interfaces, we identified two high-score exonic splicing enhancer (ESE) sequences in the site of insertion. The functional significance of these ESE motifs is suggested by our observation that these sequences are highly conserved among mammal CLCN5 genes. Therefore, we suggest that the Alu insertion causes exon skipping by interfering with splicing regulatory elements. The altered splicing would predict a truncated ClC-5 protein that lacks critical domains for sorting and chloride channel function.
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PMID:The Alu insertion in the CLCN5 gene of a patient with Dent's disease leads to exon 11 skipping. 1604 95

Fabry disease is a rare X-linked lysosomal storage disorder caused by deficient activity of alpha-galactosidase A (alpha-Gal A) resulting in the storage of glycosphingolipids, especially globotriaosylceramide (Gb3), in cells throughout the body, causing life-threatening renal, cardiac, and cerebrovascular complications in hemizygous males and some heterozygous females. Disease manifestations in heterozygotes are being recognized increasingly, but quantitative prospective data on their extent and severity are limited. Prospective clinical and laboratory assessments were performed in a 7-day study of 61 women with signs and symptoms of Fabry disease. Analyses included medical history and physical, neurologic, cardiac, and ophthalmologic assessments; laboratory assessments; renal function tests; magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) of the head; and Fabry-related blood and urine tests, including Gb3 levels in blood and urine, skin biopsies, and DNA genotype analysis of the alpha-Gal A gene to identify causative mutations. Quality of life, pain and concomitant medication were documented using validated questionnaires and diaries. All patients had normal Gb3 levels in plasma; only 1 patient had visible storage material in the superficial dermal vascular endothelial cells. Cardiac, renal, or cerebrovascular abnormalities were documented in 52 of the 57 patients (91%) with confirmed Fabry genotypes. These included electrocardiographic abnormalities in 38 of 52 patients (73%), echocardiographic abnormalities in 8 of 57 (14%), proteinuria (>150 g protein/24-h urine) in 23 of 38 (61%), low estimated glomerular filtration rate (<90 mL/min per 1.73 m) in 24 of 57 (42%), abnormal MRI in 4 of 54 (7%), and abnormal MRA in 10 of 50 patients (20%). Angiokeratomas and corneal epitheliopathy were documented in 63% and 82% of the 57 patients, respectively. Despite the virtual absence of storage material in plasma and skin vascular endothelial cells, this population of women with Fabry disease exhibited a wide spectrum of clinical abnormalities. Useful outcome measures for assessment of specific therapies need to be developed. Studies limited to homogeneously affected subjects may be possible.
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PMID:The relationship of vascular glycolipid storage to clinical manifestations of Fabry disease: a cross-sectional study of a large cohort of clinically affected heterozygous women. 1614 26

The rare Dent's disease manifests with medullary nephrocalcinosis, nephrolithiasis, hypercalciuria, low molecular weight proteinuria and other tubular dysfunctions, rickets or osteomalacia, and renal failure, in various combinations. It is a recessive X-linked condition. Clinicians consider family history a fundamental pointer to its diagnosis, but this is not invariably the case as clearly pointed out by the two reported cases.
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PMID:Family history may be misleading in the diagnosis of Dent's disease. 1641 11


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