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Takashi Igarashi - One of the best experts on this subject based on the ideXlab platform.
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japanese dent disease has a wider clinical spectrum than dent disease in europe usa genetic and clinical studies of 86 unrelated patients with low molecular weight proteinuria
Nephrology Dialysis Transplantation, 2014Co-Authors: Fusako Komoda, Mitsunobu Shimadzu, Akira Ashida, Kenichiro Miura, Takeshi Matsuyama, Junko Takita, Takashi Sekine, Takashi IgarashiAbstract:Dent disease is an X-linked disorder characterized by low-molecular-weight (LMW) proteinuria, hypercalciuria, nephrocalcinosis, urolithiasis and renal dysfunction. Dent disease is caused by mutations in at least two genes, i.e. CLCN5 and OCRL1, and its genetic background and phenotypes are common among European countries and the USA. However, only few studies on Dent disease in Japan, which was originally called 'low-molecular-weight proteinuric disease', have been reported thus far. In this study, we analysed genetic background and clinical phenotype and laboratory data of 86 unrelated Japanese Dent disease patients. The results demonstrated that the genetic basis of Japanese Dent disease was nearly identical to those of Dent disease in other countries. Of 86 unrelated Japanese Dent patients, 61 possessed mutations in CLCN5 (Dent-1), of which 27 were novel mutations; 11 showed mutations in OCRL1 (Dent-2), six of which were novel, and the remaining 14 patients showed no mutations in CLCN5 or OCRL1 (Dent-NI). Despite the similarity in genetic background, hypercalciuria was detected in only 51%, rickets in 2% and nephrocalcinosis in 35%. Although the patients were relatively young, six patients (8%) showed apparent renal dysfunction. Japanese Dent disease has a wider clinical spectrum than Dent disease in Europe and the USA.
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Japanese Dent disease has a wider clinical spectrum than Dent disease in Europe/USA: genetic and clinical studies of 86 unrelated patients with low-molecular-weight proteinuria
Nephrology Dialysis Transplantation, 2013Co-Authors: Takashi Sekine, Fusako Komoda, Mitsunobu Shimadzu, Akira Ashida, Kenichiro Miura, Takeshi Matsuyama, Junko Takita, Takashi IgarashiAbstract:Dent disease is an X-linked disorder characterized by lowmolecular-weight (LMW) proteinuria, hypercalciuria, nephrocalcinosis, urolithiasis and renal dysfunction. Dent disease is caused by mutations in at least two genes, i.e. CLCN5 and OCRL1, and its genetic background and phenotypes are common among European countries and the USA. However, only few studies on Dent disease in Japan, which was originally called ‘low-molecular-weight proteinuric disease’, have been reported thus far. In this study, we analysed genetic background and clinical phenotype and laboratory data of 86 unrelated Japanese Dent disease patients. The results demonstrated that the genetic basis of Japanese Dent disease was nearly identical to those of Dent disease in other countries. Of 86 unrelated Japanese Dent patients, 61 possessed mutations in CLCN5 (Dent-1), of which 27 were novel mutations; 11 showed mutations in OCRL1 (Dent-2), six of which were novel, and the remaining 14 patients showed no mutations in CLCN5 or OCRL1 (Dent-NI). Despite the similarity in genetic background, hypercalciuria was detected in only 51%, rickets in 2% and nephrocalcinosis in 35%. Although the patients were relatively young, six patients (8%) showed apparent renal dysfunction. Japanese Dent disease has a wider clinical spectrum than Dent disease in Europe and the USA.
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renal fanconi syndrome dent s disease and bartter s syndrome
Devuyst Olivier; Igarashi Takashi (2012). Renal Fanconi syndrome dent's disease and bartter's syndrome. In: Thakker Rajesh V; Whyte Michael P; Eisman , 2013Co-Authors: Olivier Devuyst, Takashi IgarashiAbstract:Renal Fanconi syndrome is characterized by a generalized dysfunction of the proximal renal tubule (PT) and a metabolic bone disease (rickets or osteomalacia). Renal Fanconi syndrome is associated with various inborn errors of metabolism, immunological or hematological disorders, and through exposure to various toxic agents. Dent’s disease (X-linked recessive nephrolithiasis, or X-linked recessive hypercalciuric hypophosphatemic rickets) is a renal tubular disorder caused by mutations in either the CLCN5 or OCRL genes. CLCN5 encodes the electrogenic Cl − /H + exchanger ClC-5, which is primarily located in the endosomes of the PT cells. The pathophysiology of the disease is essentially due to defective receptor-mediated endocytosis causing a generalized dysfunction of PT cells. OCRL encodes a PIP 2 5-phosphatase and mutations are also associated with the oculo-cerebro-renal syndrome of Lowe, characterized by bilateral congenital cataract, severe mental retardation, and renal Fanconi syndrome. A few patients harboring CLCN5 mutations may present with a Bartter-like syndrome, and some forms of Bartter syndrome may be associated with hypercalciuria. The care of patients with Dent’s disease is supportive, focusing on the prevention of nephrolithiasis. The cautious use of thiazide diuretics has been suggested to treat the associated hypercalciuria.
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Renal Fanconi Syndrome, Dent’s Disease and Bartter’s Syndrome
Genetics of Bone Biology and Skeletal Disease, 2013Co-Authors: Olivier Devuyst, Takashi IgarashiAbstract:Renal Fanconi syndrome is characterized by a generalized dysfunction of the proximal renal tubule (PT) and a metabolic bone disease (rickets or osteomalacia). Renal Fanconi syndrome is associated with various inborn errors of metabolism, immunological or hematological disorders, and through exposure to various toxic agents. Dent’s disease (X-linked recessive nephrolithiasis, or X-linked recessive hypercalciuric hypophosphatemic rickets) is a renal tubular disorder caused by mutations in either the CLCN5 or OCRL genes. CLCN5 encodes the electrogenic Cl − /H + exchanger ClC-5, which is primarily located in the endosomes of the PT cells. The pathophysiology of the disease is essentially due to defective receptor-mediated endocytosis causing a generalized dysfunction of PT cells. OCRL encodes a PIP 2 5-phosphatase and mutations are also associated with the oculo-cerebro-renal syndrome of Lowe, characterized by bilateral congenital cataract, severe mental retardation, and renal Fanconi syndrome. A few patients harboring CLCN5 mutations may present with a Bartter-like syndrome, and some forms of Bartter syndrome may be associated with hypercalciuria. The care of patients with Dent’s disease is supportive, focusing on the prevention of nephrolithiasis. The cautious use of thiazide diuretics has been suggested to treat the associated hypercalciuria.
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ocrl1 mutations in dent 2 patients suggest a mechanism for phenotypic variability
Nephron Physiology, 2009Co-Authors: Anthony E Shrimpton, Richard R Hoopes, Stephen J Knohl, Paul Hueber, Paul T Christie, Colin White, Takashi Igarashi, Anna Lehman, Anita A C Reed, David V MilfordAbstract:Background/Aims: Dent disease is an X-linked renal proximal tubulopathy associated with mutations in CLCN5 (Dent 1) or OCRL1 (Dent 2).
Rajesh V Thakker - One of the best experts on this subject based on the ideXlab platform.
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REVIEW Dent’s disease
2013Co-Authors: Olivier Devuyst, Rajesh V ThakkerAbstract:Dent’s disease is a renal tubular disorder characterized by manifestations of proximal tubule dysfunction, including low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis, and progressive renal failure. These features are generally found in males only, and may be present in early childhood, whereas female carriers may show a milder phenotype. Prevalence is unknown; the disorder has been reported in around 250 families to date. Complications such as rickets or osteomalacia may occur. The disease is caused by mutations in either the CLCN5 (Dent disease 1) or OCRL1 (Dent disease 2) genes that are located on chromosome Xp11.22 and Xq25, respectively. CLCN5 encodes the electrogenic Cl- /H + exchanger ClC-5, which belongs to the CLC family of Cl- channels/transporters. OCRL1 encodes a phosphatidylinositol bisphosphate (PIP2) 5-phosphatase and mutations are also associated with Lowe Syndrome. The phenotype of Dent’s disease is explained by the predominant expression of ClC-5 in the proximal tubule segments of the kidney. No genotype-phenotype correlation has been described thus far, and there is considerable intra-familial variability in disease severity. A few patients with Dent’s disease do not harbour mutations in CLCN5 and OCRL1, pointing to the involvement of other genes. Diagnosis is based on the presence of all three of the following criteria: low-molecular-weight proteinuria, hypercalciuria and at least one of the following: nephrocalcinosis, kidney stones, hematuria, hypophosphatemia or renal insufficiency. Molecula
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Characterization of Dent's disease mutations of CLC-5 reveals a correlation between functional and cell biological consequences and protein structure.
American journal of physiology. Renal physiology, 2008Co-Authors: Andrew Smith, Anita A C Reed, Rajesh V Thakker, Nellie Y. Loh, Jonathan D. LippiatAbstract:Mutations of the human CLCN5 gene, which encodes the CLC-5 Cl−/H+ exchanger, lead to Dent's disease. Mutations result in functional defects that range from moderate reductions to complete loss of w...
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clinical and genetic studies of CLCN5 mutations in japanese families with dent s disease
Kidney International, 2000Co-Authors: Takashi Igarashi, Mitsunobu Shimadzu, Jun Inatomi, Toshio Ohara, Takashi Kuwahara, Rajesh V ThakkerAbstract:Clinical and genetic studies of CLCN5 mutations in Japanese families with Dent's disease. Background Dent's disease is an X-linked renal tubular disorder that is characterized by low molecular weight proteinuria, hypercalciuria, nephrolithiasis, and renal failure. The disease is caused by inactivation of a renal chloride channel gene, CLCN5 , that encodes a 746-amino acid protein with 12 to 13 transmembrane domains. The Japanese variant of Dent's disease has been observed to be less severe, and we have investigated two unrelated Japanese families for CLCN5 mutations. Methods Six patients from two unrelated families were studied. Leukocyte DNA from probands was used with CLCN5 -specific primers for polymerase chain reaction (PCR) amplification of the coding region and exon-intron boundaries, and the DNA sequences of the products were determined to identify abnormalities in the gene. RNA extracted from the kidney, leukocytes, or urine sediments was used to characterize further the effects of the identified mutations. Results β 2 -microglobulinuria was detected in five patients, hypercalciuria in two patients, nephrolithiasis in three patients (2 of whom were females), and one 51-year-old man had renal failure. Two novel CLCN5 mutations consisting of an a to g transition at the invariant ag acceptor splice site of intron 5 and an intragenic deletion that encompassed the region between intron 3 and intron 6 were identified. The acceptor splice site mutation led to the utilization of two alternative cryptic splice sites in exon 6 that resulted in a frameshift or skipping of the exon 6. The deletional mutation, which resulted in a loss of exons 4, 5, and 6, is predicted to lead to a loss of domains 1 through 4. Both mutations predict truncated chloride channels that are likely to result in a functional loss. Conclusions The observations of renal failure in one male and nephrolithiasis in two females represent important new findings in this Japanese variant of Dent's disease that is associated with CLCN5 mutations. In addition, our study is the first to demonstrate the use of urinary sediment cells and renal tissue for the detection of CLCN5 transcript abnormalities. These results help to expand the spectrum of CLCN5 mutations associated with Dent's disease.
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Clinical and genetic studies of CLCN5 mutations in Japanese families with Dent's disease
Kidney international, 2000Co-Authors: Takashi Igarashi, Mitsunobu Shimadzu, Jun Inatomi, Toshio Ohara, Takashi Kuwahara, Rajesh V ThakkerAbstract:Dent's disease is an X-linked renal tubular disorder that is characterized by low molecular weight proteinuria, hypercalciuria, nephrolithiasis, and renal failure. The disease is caused by inactivation of a renal chloride channel gene, CLCN5, that encodes a 746-amino acid protein with 12 to 13 transmembrane domains. The Japanese variant of Dent's disease has been observed to be less severe, and we have investigated two unrelated Japanese families for CLCN5 mutations. Six patients from two unrelated families were studied. Leukocyte DNA from probands was used with CLCN5-specific primers for polymerase chain reaction (PCR) amplification of the coding region and exon-intron boundaries, and the DNA sequences of the products were determined to identify abnormalities in the gene. RNA extracted from the kidney, leukocytes, or urine sediments was used to characterize further the effects of the identified mutations. beta2-microglobulinuria was detected in five patients, hypercalciuria in two patients, nephrolithiasis in three patients (2 of whom were females), and one 51-year-old man had renal failure. Two novel CLCN5 mutations consisting of an a to g transition at the invariant ag acceptor splice site of intron 5 and an intragenic deletion that encompassed the region between intron 3 and intron 6 were identified. The acceptor splice site mutation led to the utilization of two alternative cryptic splice sites in exon 6 that resulted in a frameshift or skipping of the exon 6. The deletional mutation, which resulted in a loss of exons 4, 5, and 6, is predicted to lead to a loss of domains 1 through 4. Both mutations predict truncated chloride channels that are likely to result in a functional loss. The observations of renal failure in one male and nephrolithiasis in two females represent important new findings in this Japanese variant of Dent's disease that is associated with CLCN5 mutations. In addition, our study is the first to demonstrate the use of urinary sediment cells and renal tissue for the detection of CLCN5 transcript abnormalities. These results help to expand the spectrum of CLCN5 mutations associated with Dent's disease.
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Pathogenesis of Dent's disease and related syndromes of X-linked nephrolithiasis.
Kidney international, 2000Co-Authors: Rajesh V ThakkerAbstract:Renal stone disease, which affects 12% of males and 5% of females by the seventh decade, occurs as an inherited disorder in 45% of patients and is most commonly associated with hypercalciuria. The biochemical basis for hereditary nephrolithiasis and hypercalciuria is unknown, and this has therefore been investigated by a "positional cloning" approach. As a first step in this approach, the chromosomal locations of two disorders referred to as Dent's disease and X-linked recessive nephrolithiasis (XRN) were determined. These two disorders, which represent unusual forms of the renal Fanconi syndrome, are characterized by a low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis and renal failure. An X-linked inheritance for XRN was established by studies of a North American kindred, and a similar inheritance for Dent's disease was indicated by the observation of a greater disease severity in males and an absence of male-to-male transmission in five British families. X-linked polymorphic genetic markers were used in linkage studies of these families, and the genes causing Dent's disease and XRN were mapped to Xp11. In addition, in one family with Dent's disease, a microdeletion involving the DNA probe M27 beta was identified. This microdeletion was further characterized by using yeast artificial chromosomes (YACs) and its size was estimated to be 515 Kb. A search for renal-expressed genes from this region identified a novel gene encoding a chloride channel (CLCN5) with similarities to a family of voltage-gated chloride channels. Molecular genetic studies of CLCN5 demonstrated that mutations, which resulted in a functional loss, were associated with Dent's disease and XRN. In addition, such CLCN5 mutations that would result in a functional loss have also been demonstrated in Japanese children with idiopathic low molecular weight proteinuria, hypercalciuria and nephrocalcinosis, and an Italian kindred with X-linked recessive hypophosphatemic rickets (XLRH) and hypercalciuria. Thus, four hereditary disorders of nephrolithiasis are due to mutations of the novel chloride channel, CLCN5.
Takashi Sekine - One of the best experts on this subject based on the ideXlab platform.
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japanese dent disease has a wider clinical spectrum than dent disease in europe usa genetic and clinical studies of 86 unrelated patients with low molecular weight proteinuria
Nephrology Dialysis Transplantation, 2014Co-Authors: Fusako Komoda, Mitsunobu Shimadzu, Akira Ashida, Kenichiro Miura, Takeshi Matsuyama, Junko Takita, Takashi Sekine, Takashi IgarashiAbstract:Dent disease is an X-linked disorder characterized by low-molecular-weight (LMW) proteinuria, hypercalciuria, nephrocalcinosis, urolithiasis and renal dysfunction. Dent disease is caused by mutations in at least two genes, i.e. CLCN5 and OCRL1, and its genetic background and phenotypes are common among European countries and the USA. However, only few studies on Dent disease in Japan, which was originally called 'low-molecular-weight proteinuric disease', have been reported thus far. In this study, we analysed genetic background and clinical phenotype and laboratory data of 86 unrelated Japanese Dent disease patients. The results demonstrated that the genetic basis of Japanese Dent disease was nearly identical to those of Dent disease in other countries. Of 86 unrelated Japanese Dent patients, 61 possessed mutations in CLCN5 (Dent-1), of which 27 were novel mutations; 11 showed mutations in OCRL1 (Dent-2), six of which were novel, and the remaining 14 patients showed no mutations in CLCN5 or OCRL1 (Dent-NI). Despite the similarity in genetic background, hypercalciuria was detected in only 51%, rickets in 2% and nephrocalcinosis in 35%. Although the patients were relatively young, six patients (8%) showed apparent renal dysfunction. Japanese Dent disease has a wider clinical spectrum than Dent disease in Europe and the USA.
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Japanese Dent disease has a wider clinical spectrum than Dent disease in Europe/USA: genetic and clinical studies of 86 unrelated patients with low-molecular-weight proteinuria
Nephrology Dialysis Transplantation, 2013Co-Authors: Takashi Sekine, Fusako Komoda, Mitsunobu Shimadzu, Akira Ashida, Kenichiro Miura, Takeshi Matsuyama, Junko Takita, Takashi IgarashiAbstract:Dent disease is an X-linked disorder characterized by lowmolecular-weight (LMW) proteinuria, hypercalciuria, nephrocalcinosis, urolithiasis and renal dysfunction. Dent disease is caused by mutations in at least two genes, i.e. CLCN5 and OCRL1, and its genetic background and phenotypes are common among European countries and the USA. However, only few studies on Dent disease in Japan, which was originally called ‘low-molecular-weight proteinuric disease’, have been reported thus far. In this study, we analysed genetic background and clinical phenotype and laboratory data of 86 unrelated Japanese Dent disease patients. The results demonstrated that the genetic basis of Japanese Dent disease was nearly identical to those of Dent disease in other countries. Of 86 unrelated Japanese Dent patients, 61 possessed mutations in CLCN5 (Dent-1), of which 27 were novel mutations; 11 showed mutations in OCRL1 (Dent-2), six of which were novel, and the remaining 14 patients showed no mutations in CLCN5 or OCRL1 (Dent-NI). Despite the similarity in genetic background, hypercalciuria was detected in only 51%, rickets in 2% and nephrocalcinosis in 35%. Although the patients were relatively young, six patients (8%) showed apparent renal dysfunction. Japanese Dent disease has a wider clinical spectrum than Dent disease in Europe and the USA.
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Molecular and clinical studies of Dent's disease in Japan: biochemical examination and renal ultrasonography do not predict carrier state.
Clinical nephrology, 2004Co-Authors: Takeshi Matsuyama, Jun Inatomi, Takashi Sekine, Midori Awazu, T. Oikawa, Takashi IgarashiAbstract:BACKGROUND Dent's disease is an X-linked renal tubular disorder characterized by low-molecular-weight-proteinuria, hypercalciuria, nephrolithiasis and renal failure. The disease is due to inactivation of a renal chloride channel gene, CLCN5. We have investigated 3 unrelated Japanese families for CLCN5 mutations and assessed the carrier mothers biochemically and ultrasonogaraphically to ascertain whether these clinical examinations can predict the carrier state of the disease. MATERIAL AND METHODS Twelve members from these families were studied biochemically and ultrasonographically. Leukocyte DNA from probands was used with CLCN5-specific primers for PCR amplification of the coding region and exon-intron boundaries, and the DNA sequences of the products determined to identify abnormalities in the gene. RESULTS Three novel CLCN5 mutations consisting of a single base "A" insertion between nucleotides 590 and 591, a nonsense mutation (R28X) and a missense mutation (G506R) were exhibited. Hypophosphatemia was detected in 2 patients, beta2-microglobulinuria, alpha1-microglobulinuria, and hyperretinol binding proteinuria in 6 patients, hypercalciuria in 5 patients, decreased urine osmolality in 3 patients, and nephrocalcinosis or nephrolithiasis in 4 patients. Biochemical analysis of the urine and the renal ultrasonography in each carrier mother were completely normal. CONCLUSIONS Neither urinary low-molecular-weight-proteins, urinary calcium to creatinine ratio, nor renal ultrasonography was predictive of carrier state in the 3 families with this disease, although each carrier mother had CLCN5 mutation. Hypophosphatemia and decreased urine osmolality might be a hint to suspect the carrier state of Dent's disease, although these findings are not found frequently.
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functional characterization of renal chloride channel CLCN5 mutations associated with dent sjapan disease
Kidney International, 1998Co-Authors: Takashi Igarashi, Willy Gunther, Jun Inatomi, Junzou Suzuki, Noboru Tsuru, Toshio Yanagihara, Hiroshi Shiraga, Takashi Sekine, Shouri Takahashi, Mitsunobu ShimazuAbstract:Functional characterization of renal chloride channel, CLCN5, mutations associated with Dent's Japan disease. Background The annual urinary screening of Japanese children above three years of age has identified a progressive renal tubular disorder characterized by low molecular weight proteinuria, hypercalciuria and nephrocalcinosis, and this represents a variant of Dent's disease. Hitherto, 12 mutations of the X-linked renal specific chloride channel, CLCN5, have been reported in the Dent’s Japan variant. To further identify such CLCN5 mutations and to define the structure-function relationships of this channel, we have investigated five unrelated, non-consanguinous Japanese families with this disorder. Methods Leukocyte DNA from probands was used with CLCN5 primers for PCR amplification of the coding region, and the DNA sequences of the products determined. Functional studies were performed by expressing the mutants in Xenopus oocytes. Results Five CLCN5 mutations consisting of two nonsense (R648X and R704X), two missense (S270R and L278F) and one acceptor splice site mutation (ag→cg) in intron 4 were identified. The missense and splice site mutations represent novel abnormalities. Heterologous expression in Xenopus oocytes of wild-type and the missense mutants demonstrated that the mutations, which were translated, either abolished or markedly reduced chloride conductance. Conclusions These results expand the spectrum of CLCN5 mutations associated with this renal disorder and provide insight into possible structure-function relationships. For example, both the missense mutations are located within a short putative loop between two transmembrane domains, and our results suggest that this region may have an important functional role in the regulation of channel activity.
Olivier Devuyst - One of the best experts on this subject based on the ideXlab platform.
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bone marrow transplantation improves proximal tubule dysfunction in a mouse model of dent disease
Kidney International, 2017Co-Authors: Sarah Sharon Gabriel, Alkaly Gassama, Huguette Debaix, Hendrica Belge, Thomas Fehr, Alessandro Luciani, Olivier DevuystAbstract:Dent disease is a rare X-linked tubulopathy caused by mutations in the endosomal chloride-proton exchanger (ClC-5) resulting in defective receptor-mediated endocytosis and severe proximal tubule dysfunction. Bone marrow transplantation has recently been shown to preserve kidney function in cystinosis, a lysosomal storage disease causing proximal tubule dysfunction. Here we test the effects of bone marrow transplantation in CLCN5 Y/- mice, a faithful model for Dent disease. Transplantation of wild-type bone marrow in CLCN5 Y/- mice significantly improved proximal tubule dysfunction, with decreased low-molecular-weight proteinuria, glycosuria, calciuria, and polyuria four months after transplantation, compared to CLCN5 Y/- mice transplanted with ClC-5 knockout bone marrow. Bone marrow–derived cells engrafted in the interstitium, surrounding proximal tubule cells, which showed a rescue of the apical expression of ClC-5 and megalin receptors. The improvement of proximal tubule dysfunction correlated with CLCN5 gene expression in kidneys of mice transplanted with wild-type bone marrow cells. Coculture of CLCN5 Y/- proximal tubule cells with bone marrow–derived cells confirmed rescue of ClC-5 and megalin, resulting in improved endocytosis. Nanotubular extensions between the engrafted bone marrow–derived cells and proximal tubule cells were observed in vivo and in vitro . No rescue was found when the formation of the tunneling nanotubes was prevented by actin depolymerization or when cells were physically separated by transwell inserts. Thus, bone marrow transplantation may rescue the epithelial phenotype due to an inherited endosomal defect. Direct contacts between bone marrow–derived cells and diseased tubular cells play a key role in the rescue mechanism.
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REVIEW Dent’s disease
2013Co-Authors: Olivier Devuyst, Rajesh V ThakkerAbstract:Dent’s disease is a renal tubular disorder characterized by manifestations of proximal tubule dysfunction, including low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis, and progressive renal failure. These features are generally found in males only, and may be present in early childhood, whereas female carriers may show a milder phenotype. Prevalence is unknown; the disorder has been reported in around 250 families to date. Complications such as rickets or osteomalacia may occur. The disease is caused by mutations in either the CLCN5 (Dent disease 1) or OCRL1 (Dent disease 2) genes that are located on chromosome Xp11.22 and Xq25, respectively. CLCN5 encodes the electrogenic Cl- /H + exchanger ClC-5, which belongs to the CLC family of Cl- channels/transporters. OCRL1 encodes a phosphatidylinositol bisphosphate (PIP2) 5-phosphatase and mutations are also associated with Lowe Syndrome. The phenotype of Dent’s disease is explained by the predominant expression of ClC-5 in the proximal tubule segments of the kidney. No genotype-phenotype correlation has been described thus far, and there is considerable intra-familial variability in disease severity. A few patients with Dent’s disease do not harbour mutations in CLCN5 and OCRL1, pointing to the involvement of other genes. Diagnosis is based on the presence of all three of the following criteria: low-molecular-weight proteinuria, hypercalciuria and at least one of the following: nephrocalcinosis, kidney stones, hematuria, hypophosphatemia or renal insufficiency. Molecula
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renal fanconi syndrome dent s disease and bartter s syndrome
Devuyst Olivier; Igarashi Takashi (2012). Renal Fanconi syndrome dent's disease and bartter's syndrome. In: Thakker Rajesh V; Whyte Michael P; Eisman , 2013Co-Authors: Olivier Devuyst, Takashi IgarashiAbstract:Renal Fanconi syndrome is characterized by a generalized dysfunction of the proximal renal tubule (PT) and a metabolic bone disease (rickets or osteomalacia). Renal Fanconi syndrome is associated with various inborn errors of metabolism, immunological or hematological disorders, and through exposure to various toxic agents. Dent’s disease (X-linked recessive nephrolithiasis, or X-linked recessive hypercalciuric hypophosphatemic rickets) is a renal tubular disorder caused by mutations in either the CLCN5 or OCRL genes. CLCN5 encodes the electrogenic Cl − /H + exchanger ClC-5, which is primarily located in the endosomes of the PT cells. The pathophysiology of the disease is essentially due to defective receptor-mediated endocytosis causing a generalized dysfunction of PT cells. OCRL encodes a PIP 2 5-phosphatase and mutations are also associated with the oculo-cerebro-renal syndrome of Lowe, characterized by bilateral congenital cataract, severe mental retardation, and renal Fanconi syndrome. A few patients harboring CLCN5 mutations may present with a Bartter-like syndrome, and some forms of Bartter syndrome may be associated with hypercalciuria. The care of patients with Dent’s disease is supportive, focusing on the prevention of nephrolithiasis. The cautious use of thiazide diuretics has been suggested to treat the associated hypercalciuria.
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Renal Fanconi Syndrome, Dent’s Disease and Bartter’s Syndrome
Genetics of Bone Biology and Skeletal Disease, 2013Co-Authors: Olivier Devuyst, Takashi IgarashiAbstract:Renal Fanconi syndrome is characterized by a generalized dysfunction of the proximal renal tubule (PT) and a metabolic bone disease (rickets or osteomalacia). Renal Fanconi syndrome is associated with various inborn errors of metabolism, immunological or hematological disorders, and through exposure to various toxic agents. Dent’s disease (X-linked recessive nephrolithiasis, or X-linked recessive hypercalciuric hypophosphatemic rickets) is a renal tubular disorder caused by mutations in either the CLCN5 or OCRL genes. CLCN5 encodes the electrogenic Cl − /H + exchanger ClC-5, which is primarily located in the endosomes of the PT cells. The pathophysiology of the disease is essentially due to defective receptor-mediated endocytosis causing a generalized dysfunction of PT cells. OCRL encodes a PIP 2 5-phosphatase and mutations are also associated with the oculo-cerebro-renal syndrome of Lowe, characterized by bilateral congenital cataract, severe mental retardation, and renal Fanconi syndrome. A few patients harboring CLCN5 mutations may present with a Bartter-like syndrome, and some forms of Bartter syndrome may be associated with hypercalciuria. The care of patients with Dent’s disease is supportive, focusing on the prevention of nephrolithiasis. The cautious use of thiazide diuretics has been suggested to treat the associated hypercalciuria.
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The transcription factor HNF1α regulates expression of chloride-proton exchanger ClC-5 in the renal proximal tubule
American journal of physiology. Renal physiology, 2010Co-Authors: Karo Tanaka, Sara Terryn, Lars Geffers, Serge Garbay, Marco Pontoglio, Olivier DevuystAbstract:The Cl(-)/H(+) exchanger ClC-5 is essential for the endocytic activity of the proximal tubule cells and the tubular clearance of proteins filtered in the glomeruli. The mechanisms that regulate the expression of ClC-5 in general and its specific expression in the proximal tubule are unknown. In this study, we investigated the hypothesis that the hepatocyte nuclear transcription factor HNF1α, which is predominantly expressed in proximal tubule segments, may directly regulate the expression of ClC-5. In situ hybridization demonstrated that the expression of CLCN5 overlaps with that of Hnf1α in the developing kidney as well as in absorptive epithelia, including the digestive tract and yolk sac. Multiple binding sites for HNF1 were mapped in the 5'-regulatory sequences of the mouse and human CLCN5/CLCN5 genes. The transactivation of the CLCN5/CLCN5 promoter by HNF1α was verified in vitro, and the binding of HNF1α to the CLCN5 promoter in vivo was confirmed by chromatin immunoprecipitation in mouse kidney. The expression of CLCN5 was reduced in the proximal tubule segments of HNF1α-null kidneys, and it was rescued upon transfection of HNF1α-null cells with wild-type but not with mutant HNF1α. These data demonstrate that HNF1α directly regulates the expression of ClC-5 in the renal proximal tubule and yield insights into the mechanisms governing epithelial differentiation and specialized transport activities in the kidney.
Michael Ludwig - One of the best experts on this subject based on the ideXlab platform.
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proteinuria in dent disease a review of the literature
Pediatric Nephrology, 2017Co-Authors: Youri Van Berkel, Joanna A E Van Wijk, Michael Ludwig, Arend BökenkampAbstract:Background Dent disease is a rare X-linked recessive proximal tubulopathy caused by mutations in CLCN5 (Dent-1) or OCRL (Dent-2). As a rule, total protein excretion (TPE) is low in tubular proteinuria compared with glomerular disease. Several authors have reported nephrotic-range proteinuria (NP) and glomerulosclerosis in Dent disease. Therefore, we aimed to analyze protein excretion in patients with documented CLCN5 or OCRL mutations in a systematic literature review.
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Proteinuria in Dent disease: a review of the literature
Pediatric Nephrology, 2017Co-Authors: Youri Van Berkel, Joanna A E Van Wijk, Michael Ludwig, Arend BökenkampAbstract:Background Dent disease is a rare X-linked recessive proximal tubulopathy caused by mutations in CLCN5 (Dent-1) or OCRL (Dent-2). As a rule, total protein excretion (TPE) is low in tubular proteinuria compared with glomerular disease. Several authors have reported nephrotic-range proteinuria (NP) and glomerulosclerosis in Dent disease. Therefore, we aimed to analyze protein excretion in patients with documented CLCN5 or OCRL mutations in a systematic literature review. Design PubMed and Embase were searched for cases with documented CLCN5 or OCRL mutations and (semi-)quantitative data on protein excretion. The most reliable data (i.e., TPE > protein–creatinine ratio > Albustix) was used for NP classification. Results Data were available on 148 patients from 47 reports: 126 had a CLCN5 and 22 an OCRL mutation. TPE was not significantly different between both forms ( p = 0.11). Fifty-five of 126 (43.7 %) Dent-1 vs 13/22 (59.1 %) Dent-2 patients met the definition of NP ( p = 0.25). Serum albumin was normal in all reported cases (24/148). Glomerulosclerosis was noted in 20/32 kidney biopsies and was strongly related to tubulointerstitial fibrosis, but not to kidney function or proteinuria. Conclusion More than half of the patients with both forms of Dent disease have NP, and the presence of low molecular weight proteinuria in a patient with NP in the absence of edema and hypoalbuminemia should prompt genetic testing. Even with normal renal function, glomerulosclerosis and tubulointerstitial fibrosis are present in Dent disease. The role of proteinuria in the course of the disease needs to be examined further in longitudinal studies.
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Proteinuria in Dent disease: a review of the literature
Pediatric nephrology (Berlin Germany), 2016Co-Authors: Youri Van Berkel, Michael Ludwig, Joanna A.e. Van Wijk, Arend BökenkampAbstract:Dent disease is a rare X-linked recessive proximal tubulopathy caused by mutations in CLCN5 (Dent-1) or OCRL (Dent-2). As a rule, total protein excretion (TPE) is low in tubular proteinuria compared with glomerular disease. Several authors have reported nephrotic-range proteinuria (NP) and glomerulosclerosis in Dent disease. Therefore, we aimed to analyze protein excretion in patients with documented CLCN5 or OCRL mutations in a systematic literature review. PubMed and Embase were searched for cases with documented CLCN5 or OCRL mutations and (semi-)quantitative data on protein excretion. The most reliable data (i.e., TPE > protein-creatinine ratio > Albustix) was used for NP classification. Data were available on 148 patients from 47 reports: 126 had a CLCN5 and 22 an OCRLmutation. TPE was not significantly different between both forms (p = 0.11). Fifty-five of 126 (43.7 %) Dent-1 vs 13/22 (59.1 %) Dent-2 patients met the definition of NP (p = 0.25). Serum albumin was normal in all reported cases (24/148). Glomerulosclerosis was noted in 20/32 kidney biopsies and was strongly related to tubulointerstitial fibrosis, but not to kidney function or proteinuria. More than half of the patients with both forms of Dent disease have NP, and the presence of low molecular weight proteinuria in a patient with NP in the absence of edema and hypoalbuminemia should prompt genetic testing. Even with normal renal function, glomerulosclerosis and tubulointerstitial fibrosis are present in Dent disease. The role of proteinuria in the course of the disease needs to be examined further in longitudinal studies.
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dent disease in children diagnostic and therapeutic considerations
Clinical Nephrology, 2015Co-Authors: Maria Szczepanska, Malgorzata Mizerskawasiak, Iga Zaluskaleśniewska, Joseph Zawadzki, Krzysztof Pawlaczyk, Katarzyna Kiliśpstrusinska, Florian Recker, Marcin Zaniew, Piotr Adamczyk, Michael LudwigAbstract:Abstract Dent disease (DD) is a rare X-linked tubulopathy characterized by a proximal tubular dysfunction leading to nephrocalcinosis/nephrolithiasis and progressive renal failure. The disease is associated with a mutation either in CLCN5 or OCRL genes. We aim to define clinical and genetic disease characteristics and summarize treatments of Polish patients with DD. The study cohort consists of 10 boys (aged 5 - 16.5 years) whose data were collected through POLtube Registry. All of the patients had tubular proteinuria, hypercalciuria, and nephrocalcinosis/nephrolithiasis. Renal impairment and growth deficiency were found in 3 patients and rickets in 2 patients. In total, 9 of 10 patients carried a mutation in the CLCN5 gene. Five of 9 detected mutations were novel. In 1 patient with a clinical phenotype of DD, no mutations in either CLCN5 or OCRL were discovered. Therapy consisted of thiazides in 7 patients, and phosphate supplements and enalapril in 3 cases. Growth hormone therapy was initiated in 3 patients and resulted in improved growth rate. We report clinical and molecular characterization of Polish children with DD. Our study suggests that this tubulopathy may be generally under-diagnosed in Poland. The study revealed variable treatments, demonstrating a need for therapeutic guidelines.
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novel ocrl mutations in patients with dent 2 disease
Journal of pediatric genetics, 2015Co-Authors: Detlef Böckenhauer, Kristina Vrljicak, Tony Sirimanna, Robert J Unwin, William Vant Hoff, Matti Nuutinen, Arend Bökenkamp, Michael LudwigAbstract:Dent disease is an X-linked tubulopathy frequently caused by mutations in the CLCN5 gene encoding the voltage-gated chloride channel and chloride/proton antiporter, ClC-5. About 15% of patients with a Dent' phenotype have mutations in the OCRL gene, which also causes Lowe oculocerebrorenal syndrome. To distinguish these patients from the more severe Lowe phenotype, they are diagnosed as having Dent-2 disease. We studied 14 CLCN5-negative patients from 12 families with a phenotype resembling Dent disease for defects in OCRL. In six of these kindreds three novel (c.149+1G>A, c.1126A>T, c.1547T>C) and three repeatedly observed mutations (c.166_167delTT, c.901C>T, c.1426C>T) were discovered. With the exception of a lower prevalence of nephrocalcinosis, the renal phenotype is identical with patients harboring a CLCN5 mutation. Affected children may have some of the extra-renal symptoms of Lowe syndrome, such as peripheral cataracts, mental impairment, stunted growth or elevation of creatine kinase/lactate dehydrogenase, blurring the distinction between those two clinical entities.