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Michael Ludwig - One of the best experts on this subject based on the ideXlab platform.
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a case of type 1 Dent Disease presenting with isolated persistent proteinuria
Turk Pediatri Arsivi-turkish Archives of Pediatrics, 2018Co-Authors: Tulin Gungor, Michael Ludwig, Fehime Kara Eroglu, Fatma Yazilitas, Evrim Kargin Cakici, Mehmet BulbulAbstract:Dent Disease is a rare X-linked recessive tubular disorder, characterized by the triad of low molecular-weight proteinuria, hypercalciuria, nephrocalcinosis and/or nephrolithiasis. It is caused by mutations in the CLCN5 gene or OCRL gene. Thirty to 80% of affected males develop end-stage kidney Disease between the ages of 30 and 50 years. Some children were reported to present with isolated persistent proteinuria and a part of these patients were diagnosed as having focal segmental glomerulosclerosis with kidney biopsy. Although there is no specific treatment, treatment of proteinuria and hypercalciuria is thought to delay the progression of the Disease. For this reason, awareness of the Disease findings and early diagnosis are important. In this case report, we present a boy followed-up with isolated persistent proteinuria and then diagnosed as having Dent Disease with mutation analysis that showed c.328_330delT (p.Phe110Trpfs27*) in the CLCN5 gene. The importance of researching low-molecular- weight proteinuria and considering Dent Disease in the differential diagnosis of children presenting with isolated persistent proteinuria has been emphasized.
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proteinuria in Dent Disease a review of the literature
Pediatric Nephrology, 2017Co-Authors: Youri Van Berkel, Michael Ludwig, Joanna A E Van Wijk, Arend BokenkampAbstract: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, Michael Ludwig, Joanna A E Van Wijk, Arend BokenkampAbstract: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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The oculocerebrorenal syndrome of Lowe: an update
Pediatric Nephrology, 2016Co-Authors: Arend Bokenkamp, Michael LudwigAbstract:The oculocerebrorenal syndrome of Lowe is a rare X-linked multisystemic disorder characterized by the triad of congenital cataracts, intellectual disability, and proximal renal tubular dysfunction. Whereas the ocular manifestations and severe muscular hypotonia are the typical first diagnostic clues apparent at birth, the manifestations of incomplete renal Fanconi syndrome are often recognized only later in life. Other characteristic features are progressive severe growth retardation and behavioral problems, with tantrums. Many patients develop a debilitating arthropathy. Treatment is symptomatic, and the life span rarely exceeds 40 years. The causative oculocerebrorenal syndrome of Lowe gene ( OCRL ) encodes the inositol polyphosphate 5-phosphatase OCRL-1. OCRL variants have not only been found in classic Lowe syndrome, but also in patients with a predominantly renal phenotype classified as Dent Disease type 2 (Dent-2). Recent data indicate that there is a phenotypic continuum between Dent-2 Disease and Lowe syndrome, suggesting that there are individual differences in the ability to compensate for the loss of enzyme function. Extensive research has demonstrated that OCRL-1 is involved in multiple intracellular processes involving endocytic trafficking and actin skeleton dynamics. This explains the multi-organ manifestations of the Disease. Still, the mechanisms underlying the wide phenotypic spectrum are poorly understood, and we are far from a causative therapy. In this review, we provide an update on clinical and molecular genetic findings in Lowe syndrome and the cellular and physiological functions of OCRL-1.
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Dent Disease in children diagnostic and therapeutic considerations
Clinical Nephrology, 2015Co-Authors: Maria Szczepanska, Marcin Zaniew, Florian Recker, Malgorzata Mizerskawasiak, I Zaluskalesniewska, Katarzyna Kilispstrusinska, Piotr Adamczyk, J Zawadzki, Krzysztof Pawlaczyk, 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.
Hae Il Cheong - One of the best experts on this subject based on the ideXlab platform.
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muscle involvement in Dent Disease 2
Pediatric Nephrology, 2014Co-Authors: Eujin Park, Hyun Jin Choi, Il Soo Ha, Hae Il Cheong, Hee Gyung Kang, Yoo Mee Choi, Se Jin Park, Yonghoon ParkAbstract:Background Dent Disease, an X-linked recessive renal tubulopathy, is caused by mutations in either CLCN5 (Dent Disease 1) or OCRL (Dent Disease 2). OCRL mutations can also cause Lowe syndrome. In some cases it is difficult to differentiate Dent Disease 1 and 2 on the basis of clinical features only without genetic tests. Several studies have shown differences in serum levels of muscle enzymes between these Diseases. The aim of our study was to test the validity of these findings.
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Dent 2 Disease a mild variant of lowe syndrome
The Journal of Pediatrics, 2009Co-Authors: Arend Bokenkamp, Hae Il Cheong, Bernd Hoppe, Velibor Tasic, Detlef Bockenhauer, R J Unwin, Michael LudwigAbstract:Objective To compare the renal and extra-renal phenotypes of patients classified as having Dent Disease, Dent-2 Disease, or Lowe syndrome. Study design Chart review of data from 93 patients with iDentified voltage-gated chloride channel and chloride/proton antiporter 5 gene and oculo-cerebro-renal syndrome of Lowe gene mutations observed by the authors, complemented with published data. Results There was a wide overlap of renal symptoms. Nephrocalcinosis was more prevalent in Dent-1 Disease, and renal tubular acidosis, aminoaciduria, and renal failure was more prevalent in patients with Lowe syndrome. Patients with Lowe syndrome were shorter than patients with Dent-1 Disease, and patients with Dent-2 Disease showed an intermediate phenotype. Three patients with Dent-2 Disease had mild peripheral cataract, and 9 patients were noted to have some degree of mental retardation. Conclusion There is a phenotypic continuum within patients with Dent-2 Disease and Lowe syndrome, suggesting that there are individual differences in the ability to compensate for loss of oculo-cerebro-renal syndrome of Lowe gene function.
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Renal manifestations of Dent Disease and Lowe syndrome
Pediatric Nephrology, 2008Co-Authors: Hyun Jin Choi, Il Soo Ha, Yong Choi, Hae Il CheongAbstract:To date, two responsible genes for the development of Dent Disease have been iDentified: CLCN5 and OCRL1 . In this study, genotype-phenotype correlations were studied in patients with Dent Disease and those with Lowe syndrome. Among the 12 boys with a phenotype typical of Dent Disease, nine had a mutation in CLCN5 (Dent Disease 1), two had a mutation in OCRL1 (Dent Disease 2), and one had no mutations in either gene. All seven boys with a clinical diagnosis of Lowe syndrome had a mutation in OCRL1 . Patients with Lowe syndrome showed more frequent hypophosphatemia/rickets and more prominent tubular proteinuria than patients with Dent Disease 1, and patients with Dent Disease 2 had higher degree of tubular proteinuria and hypercalciuria than patients with Dent Disease 1. Additionally, one patient with Dent Disease 2 showed a mild degree of developmental delay, elevated serum muscle enzyme levels, and cryptorchidism. In this study, the genetic heterogeneity in Dent Disease and the phenotypic heterogeneity in Lowe syndrome were confirmed. In patients with Dent Disease, the presence of the above-mentioned extrarenal manifestations indicates that it is more likely that the patient is affected by Dent Disease 2 than by Dent Disease 1.
Arend Bokenkamp - One of the best experts on this subject based on the ideXlab platform.
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Novel OCRL1 mutations in patients with the phenotype of Dent Disease.
American journal of kidney diseases : the official journal of the National Kidney Foundation, 2020Co-Authors: Boris Utsch, Bernd Hoppe, Arend Bokenkamp, Marcus R Benz, Nesrin Besbas, Jorg Dotsch, Ingo Franke, Stefan Frund, Stephanie M KarleAbstract:Dent Disease is an X-linked tubulopathy frequently caused by mutations affecting the voltage-gated chloride channel and chloride/proton antiporter ClC-5. A recent study showed that defects in OCRL1, encoding a phosphatidylinositol 4,5-bisphosphate 5-phosphatase (Ocrl) and usually found mutated in patients with Lowe syndrome, also can provoke a Dent-like phenotype (Dent 2 Disease). We investigated 20 CLCN5-negative males from 17 families with a phenotype resembling Dent Disease for defects in OCRL1. In our complete series of 35 families with a phenotype of Dent Disease, a mutation in the OCRL1 gene was detected in 6 kindreds. All were novel frameshift (Q70RfsX88 and T121NfsX122, detected twice) or missense mutations (I257T and R476W). None of our patients had cognitive or behavioral impairment or cataracts, 2 classic hallmarks of Lowe syndrome. All patients had mild increases in lactate dehydrogenase and/or creatine kinase levels, which rarely is observed in CLCN5-positive patients, but frequently found in patients with Lowe syndrome. To explain the phenotypic heterogeneity caused by OCRL1 mutations, we performed extensive data-bank mining and extended reverse-transcriptase polymerase chain reaction analysis, which provided no evidence for yet unknown (tissue-specific) alternative OCRL1 transcripts. Mutations in the OCRL1 gene are found in approximately 23% of kindreds with a Dent phenotype. Defective protein sorting/targeting of Ocrl might be the reason for mildly elevated creatine kinase and lactate dehydrogenase serum concentrations in these patients and a clue to suspect Dent Disease unrelated to CLCN5 mutations. It remains to be elucidated why the various OCRL1 mutations found in patients with Dent 2 Disease do not cause cataracts.
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proteinuria in Dent Disease a review of the literature
Pediatric Nephrology, 2017Co-Authors: Youri Van Berkel, Michael Ludwig, Joanna A E Van Wijk, Arend BokenkampAbstract: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, Michael Ludwig, Joanna A E Van Wijk, Arend BokenkampAbstract: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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The oculocerebrorenal syndrome of Lowe: an update
Pediatric Nephrology, 2016Co-Authors: Arend Bokenkamp, Michael LudwigAbstract:The oculocerebrorenal syndrome of Lowe is a rare X-linked multisystemic disorder characterized by the triad of congenital cataracts, intellectual disability, and proximal renal tubular dysfunction. Whereas the ocular manifestations and severe muscular hypotonia are the typical first diagnostic clues apparent at birth, the manifestations of incomplete renal Fanconi syndrome are often recognized only later in life. Other characteristic features are progressive severe growth retardation and behavioral problems, with tantrums. Many patients develop a debilitating arthropathy. Treatment is symptomatic, and the life span rarely exceeds 40 years. The causative oculocerebrorenal syndrome of Lowe gene ( OCRL ) encodes the inositol polyphosphate 5-phosphatase OCRL-1. OCRL variants have not only been found in classic Lowe syndrome, but also in patients with a predominantly renal phenotype classified as Dent Disease type 2 (Dent-2). Recent data indicate that there is a phenotypic continuum between Dent-2 Disease and Lowe syndrome, suggesting that there are individual differences in the ability to compensate for the loss of enzyme function. Extensive research has demonstrated that OCRL-1 is involved in multiple intracellular processes involving endocytic trafficking and actin skeleton dynamics. This explains the multi-organ manifestations of the Disease. Still, the mechanisms underlying the wide phenotypic spectrum are poorly understood, and we are far from a causative therapy. In this review, we provide an update on clinical and molecular genetic findings in Lowe syndrome and the cellular and physiological functions of OCRL-1.
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novel ocrl mutations in patients with Dent 2 Disease
Journal of pediatric genetics, 2015Co-Authors: Detlef Bockenhauer, Arend Bokenkamp, Matti Nuutinen, Robert J Unwin, William Vant Hoff, Tony Sirimanna, Kristina Vrljicak, 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.
Takashi Sekine - One of the best experts on this subject based on the ideXlab platform.
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Electrophoretic analysis of various urinary proteins in Japanese patients with Dent Disease
Journal of Electrophoresis, 2020Co-Authors: Kumiko Sawada, Takashi Sekine, Takeshi Matsuyama, Kiyoko Shiba, Kenji SatoAbstract:Patients with Dent Disease excrete high amounts of urinary α1-microglobulin (α1-m), β2-microglobulin (β2-m), and retinol-binding protein (RBP). We found that the levels of α1-m, β2-m, and RBP in patients with Dent Disease were higher than those in healthy subjects by 20 times, 130 times, and 200 times, respectively. These results confirmed the results of previous studies. The cellulose acetate membrane electrophoresis (CAE) showed that the characteristics of the urinary protein fraction in patients with Dent Disease included appearance of pre-albumin, low albumin value, equal α1-globulin (α1-G) and α2-globulin (α2-G) values, disappearance of β-globulin (β-G), and appearance of slow α2-G (RBP) and slow β-G (β2-m). Urinary albumin (ALB), α1-m, β2-m, and RBP of patients with Dent Disease 1 (mutation of CLCN 5) and Dent Disease 2 (mutation of OCRL 1) and of healthy subjects were iDentified using western blot analysis after sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Six bands from 84 kDa to 130 kDa were detected in addition to a main band of ALB (67 kDa). Seven bands from 51 kDa to 92 kDa were detected in addition to a main band of α1-m (34 kDa). A 17-kDa band was detected in addition to a main band of β2-m (14 kDa). RBP was detected only in the main band (17 kDa). The ALB and α1-m bands, which were in the high molecular weight range in addition to the main band, were densely stained in Dent Disease 2.
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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: Takashi Sekine, Fusako Komoda, Kenichiro Miura, Junko Takita, Mitsunobu Shimadzu, Takeshi Matsuyama, Akira Ashida, 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, Kenichiro Miura, Junko Takita, Mitsunobu Shimadzu, Takeshi Matsuyama, Akira Ashida, 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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OCRL1 mutations in patients with Dent Disease phenotype in Japan
Pediatric Nephrology, 2007Co-Authors: Takashi Sekine, Kandai Nozu, Rashmi Iyengar, Xue Jun Fu, Masafumi Matsuo, Ryojiro Tanaka, Kazumoto Iijima, Emiko Matsui, Yutaka Harita, Jun InatomiAbstract:Three distinct OCRL1 mutations in three patients with the Dent Disease phenotype are described. All the patients manifested an extremely high degree of low-molecular-weight proteinuria and showed no ocular abnormalities or apparent mental retardation. Urinalysis and blood chemistry showed no findings suggestive of Fanconi syndrome with renal tubular acidosis. Mutations in CLCN5 were ruled out. The mutations iDentified in OCRL1 are one frame-shift mutation (I127stop) and two missense mutations (R301C and R476W). R301C and R476W mutations might be hot spots in OCRL1 , which develop very similar phenotypes as Dent-2.
Olivier Devuyst - One of the best experts on this subject based on the ideXlab platform.
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the 5 phosphatase ocrl in lowe syndrome and Dent Disease 2
Nature Reviews Nephrology, 2017Co-Authors: Maria Antonietta De Matteis, Leopoldo Staiano, Francesco Emma, Olivier DevuystAbstract:Dysfunction of endolysosomal pathways can lead to generalized dysfunction of the proximal tubule. Here, De Matteis and colleagues describe the role of the inositol polyphosphate 5-phosphatase, OCRL, in the endolysosomal pathway and how mutations in the encoding gene lead to the clinical manifestations of Lowe syndrome and Dent Disease 2. Lowe syndrome is an X-linked Disease that is characterized by congenital cataracts, central hypotonia, intellectual disability and renal Fanconi syndrome. The Disease is caused by mutations in OCRL, which encodes an inositol polyphosphate 5-phosphatase (OCRL) that acts on phosphoinositides — quantitatively minor constituents of cell membranes that are nonetheless pivotal regulators of intracellular trafficking. In this Review we summarize the considerable progress made over the past decade in understanding the cellular roles of OCRL in regulating phosphoinositide balance along the endolysosomal pathway, a fundamental system for the reabsorption of proteins and solutes by proximal tubular cells. We discuss how studies of OCRL have led to important discoveries about the basic mechanisms of membrane trafficking and describe the key features and limitations of the currently available animal models of Lowe syndrome. Mutations in OCRL can also give rise to a milder pathology, Dent Disease 2, which is characterized by renal Fanconi syndrome in the absence of extrarenal pathologies. Understanding how mutations in OCRL give rise to two clinical entities with differing extrarenal manifestations represents an opportunity to iDentify molecular pathways that could be targeted to develop treatments for these conditions.
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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, Alessandro Luciani, Hendrica Belge, Huguette Debaix, Thomas Fehr, 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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renal fanconi syndrome Dent Disease and bartter syndrome
Genetics of Bone Biology and Skeletal Disease (Second Edition), 2017Co-Authors: Olivier Devuyst, Takashi IgarashiAbstract:Renal Fanconi syndrome is characterized by a generalized dysfunction of the proximal renal tubule and a metabolic bone Disease (rickets or osteomalacia). Renal Fanconi syndrome is associated with various inherited tubulopathies and inborn errors of metabolism, immunological, or hematological disorders, and through exposure to various toxic agents. Dent 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 proximal tubule cells. The pathophysiology of the Disease is essentially due to defective receptor-mediated endocytosis causing a generalized dysfunction of the cells. OCRL encodes a PIP2 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. The care of patients with Dent 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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Dent s Disease
Orphanet Journal of Rare Diseases, 2010Co-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. Molecular genetic testing confirms the diagnosis. The differential diagnosis includes other causes of generalized dysfunction of the proximal tubules (renal Fanconi syndrome), hereditary, acquired, or caused by exogenous substances. Antenatal diagnosis and pre-implantation genetic testing is not advised. The care of patients with Dent's Disease is supportive, focusing on the treatment of hypercalciuria and the prevention of nephrolithiasis. The vital prognosis is good in the majority of patients. Progression to end-stage renal failure occurs between the 3rd and 5th decades of life in 30-80% of affected males.