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: Definition of the urinary protein composition would represent a potential tool for diagnosis in many clinical conditions. The use of new proteomic technologies allows detection of genetic and post-trasductional variants that increase sensitivity of the approach but complicates comparison within a heterogeneous patient population. Overall, this limits research of urinary biomarkers. Studying monogenic diseases are useful models to address this issue since genetic variability is reduced among first- and second-degree relatives of the same family. We applied this concept to Dent's disease, a monogenic condition characterised by low-molecular-weight proteinuria that is inherited following an X-linked trait. Results are presented here on a combined proteomic approach (LC-mass spectrometry, Western blot and zymograms for proteases and inhibitors) to characterise urine proteins in a large family (18 members, 6 hemizygous patients, 6 carrier females, and 6 normals) with Dent's diseases due to the 1070G. >. T mutation of the CLCN5.Gene ontology analysis on more than 1000 proteins showed that several clusters of proteins characterised urine of affected patients compared to carrier females and normal subjects: proteins involved in extracellular matrix remodelling were the major group. Specific analysis on metalloproteases and their inhibitors underscored unexpected mechanisms potentially involved in renal fibrosis. 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.
    No preview · Article · Sep 2015 · Journal of proteomics
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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.
    Full-text · Article · Aug 2015 · Clinical nephrology
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    • "Another 5­phosphatase implicated in PI(4,5)P 2 dephos­ phorylation during endocytosis is OCRL, an enzyme whose loss of function results in Lowe syndrome and Dent's disease (Attree et al., 1992; Hoopes et al., 2005; Pirruccello and De Camilli, 2012; Mehta et al., 2014). OCRL, which is broadly distributed on organelles of the endocytic pathway, is thought to dephosphorylate PI(4,5)P 2 upon endocytosis and then to prevent its ectopic accumulation on downstream stations of the endocytic pathway (Hyvola et al., 2006; Erdmann et al., 2007; Mao et al., 2009; Vicinanza et al., 2011; Mehta et al., 2014; Nández et al., 2014). "
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    ABSTRACT: The recruitment of inositol phosphatases to endocytic membranes mediates dephosphorylation of PI(4,5)P2, a phosphoinositide concentrated in the plasma membrane, and prevents its accumulation on endosomes. The importance of the conversion of PI(4,5)P2 to PtdIns during endocytosis is demonstrated by the presence of both a 5-phosphatase and a 4-phosphatase (Sac domain) module in the synaptojanins, endocytic PI(4,5)P2 phosphatases conserved from yeast to humans and the only PI(4,5)P2 phosphatases in yeast. OCRL, another 5-phosphatase that couples endocytosis to PI(4,5)P2 dephosphorylation, lacks a Sac domain. Here we show that Sac2/INPP5F is a PI4P phosphatase that colocalizes with OCRL on endocytic membranes, including vesicles formed by clathrin-mediated endocytosis, macropinosomes, and Rab5 endosomes. An OCRL-Sac2/INPP5F interaction could be demonstrated by coimmunoprecipitation and was potentiated by Rab5, whose activity is required to recruit Sac2/INPP5F to endosomes. Sac2/INPP5F and OCRL may cooperate in the sequential dephosphorylation of PI(4,5)P2 at the 5 and 4 position of inositol in a partnership that mimics that of the two phosphatase modules of synaptojanin. © 2015 Nakatsu et al.
    Full-text · Article · Apr 2015 · The Journal of Cell Biology
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