Dent disease with mutation in OCRL1

Department of Medicine, SUNY Upstate Medical University, Syracuse, NY, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 03/2005; 76(2):260-7. DOI: 10.1086/427887
Source: PubMed


Dent disease is an X-linked renal proximal tubulopathy associated with mutations in the chloride channel gene CLCN5. Lowe syndrome, a multisystem disease characterized by renal tubulopathy, congenital cataracts, and mental retardation, is associated with mutations in the gene OCRL1, which encodes a phosphatidylinositol 4,5-bisphosphate (PIP(2)) 5-phosphatase. Genetic heterogeneity has been suspected in Dent disease, but no other gene for Dent disease has been reported. We studied male probands in 13 families, all of whom met strict criteria for Dent disease but lacked mutations in CLCN5. Linkage analysis in the one large family localized the gene to a candidate region at Xq25-Xq27.1. Sequencing of candidate genes revealed a mutation in the OCRL1 gene. Of the 13 families studied, OCRL1 mutations were found in 5. PIP(2) 5-phosphatase activity was markedly reduced in skin fibroblasts cultured from the probands of these five families, and protein expression, measured by western blotting, was reduced or absent. Slit-lamp examinations performed in childhood or adulthood for all five probands showed normal results. Unlike patients with typical Lowe syndrome, none of these patients had metabolic acidosis. Three of the five probands had mild mental retardation, whereas two had no developmental delay or behavioral disturbance. These findings demonstrate that mutations in OCRL1 can occur with the isolated renal phenotype of Dent disease in patients lacking the cataracts, renal tubular acidosis, and neurological abnormalities that are characteristic of Lowe syndrome. This observation confirms genetic heterogeneity in Dent disease and demonstrates more-extensive phenotypic heterogeneity in Lowe syndrome than was previously appreciated. It establishes that the diagnostic criteria for disorders resulting from mutations in the Lowe syndrome gene OCRL1 need to be revised.

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    • "Dent's disease is caused by mutation of CLCN5 located on Xp11.22 and coding for the Cl − /H + exchanger channel ClC-5 [17] [18] [19]. Alternative to CLCN5, a few patients present specific mutations in OCRL1 at the 5′ region of the gene (exons 4–15) that are associated with a phenotype similar but less renal involving (Dent's 2) [20] [21]. Mechanisms for renal symptoms of Dents' disease had not received unequivocal explanations. "
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    ABSTRACT: Biological significance: Studying with new-generation techniques for proteomic analysis of the members of a large family with Dent's disease sharing the same molecular defect allowed highly repetitive results that justify conclusions. Identification in urine of proteins actively involved in interstitial matrix remodelling poses the question of active anti-fibrotic drugs in Dent's patients.
    Journal of proteomics 09/2015; DOI:10.1016/j.jprot.2015.08.024 · 3.89 Impact Factor
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    • "were elevated in most patients with Dent-2 disease and all cases with Lowe syndrome as well as in our 2 patients with Dent-1 disease. Although the elevation of serum LDH and/ or CK makes CLCN5 defect less likely [17], elevation of serum LDH and/or CK occurs in ~ 1/3 of CLCN5 mutation-positive patients [10], thus it should not preclude a CLCN5 analysis. "
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    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.
    Clinical nephrology 08/2015; 84(4). DOI:10.5414/CN108522 · 1.13 Impact Factor
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    • "The human genome contains 10 genes encoding inositol 5-phosphatases, a group of enzymes that dephosphorylate the inositol ring at the 5 position, nine of which act on inositol phospholipids (Dyson et al., 2012; Pirruccello and De Camilli, 2012). Mutations in one such gene, OCRL, give rise to Oculo-Cerebro-Renal syndrome of Lowe (Lowe syndrome) and type 2 Dent's disease, two X-linked diseases (Attree et al., 1992; Hoopes et al., 2005). Lowe syndrome is characterized by congenital cataracts, renal proximal tubule dysfunction, cognitive disabilities and developmental delay (Delleman et al., 1977; Kenworthy and Charnas, 1995; Böckenhauer et al., 2008). "
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    ABSTRACT: Mutations in the inositol 5-phosphatase OCRL cause Lowe syndrome and Dent's disease. Although OCRL, a direct clathrin interactor, is recruited to late-stage clathrin-coated pits, clinical manifestations have been primarily attributed to intracellular sorting defects. Here we show that OCRL loss in Lowe syndrome patient fibroblasts impacts clathrin-mediated endocytosis and results in an endocytic defect. These cells exhibit an accumulation of clathrin-coated vesicles and an increase in U-shaped clathrin-coated pits, which may result from sequestration of coat components on uncoated vesicles. Endocytic vesicles that fail to lose their coat nucleate the majority of the numerous actin comets present in patient cells. SNX9, an adaptor that couples late-stage endocytic coated pits to actin polymerization and which we found to bind OCRL directly, remains associated with such vesicles. These results indicate that OCRL acts as an uncoating factor and that defects in clathrin-mediated endocytosis likely contribute to pathology in patients with OCRL mutations. DOI:
    eLife Sciences 08/2014; 3:e02975. DOI:10.7554/eLife.02975 · 9.32 Impact Factor
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