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      Genetic Heterogeneity in Autosomal Dominant Pseudohypoaldosteronism Type I: Exclusion of Claudin-8 as a Candidate Gene


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          Background/Aims: Pseudohypoaldosteronism type I (PHAI) is an inherited disorder characterized by renal salt wasting, hyperkalemic metabolic acidosis, and hyperaldosteronism. Its known causes are mutations in the mineralocorticoid receptor and the epithelial sodium channel (ENaC), but there are reports of genetic heterogeneity. Claudin-8 is a tight junction protein that acts as a paracellular cation barrier in the distal nephron. The aim of this study was to test the hypothesis that mutations in claudin-8, which would be expected to induce a distal tubule cation leak, can be a cause of PHAI. Methods: We identified 10 patients with autosomal dominant PHAI in whom mutations in the mineralocorticoid receptor and ENaC had been excluded. The claudin-8 gene and upstream region was sequenced in all patients. Results: No disease-associated claudin-8 mutations were identified. A novel polymorphic allele in the 3′-untranslated region was identified in 2 patients, but was also found in 15% of individuals in a panel of normal controls. Conclusion: We present further evidence for locus heterogeneity in PHAI. Mutations in claudin-8 are unlikely to be a cause of PHAI. Further studies of other claudins in this disease are warranted.

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          Most cited references18

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          Claudin-2 expression induces cation-selective channels in tight junctions of epithelial cells.

          Tight junctions seal the paracellular pathway of epithelia but, in leaky tissues, also exhibit specific permeability. In order to characterize the contribution of claudin-2 to barrier and permeability properties of the tight junction in detail, we studied two strains of Madin-Darby canine kidney cells (MDCK-C7 and MDCK-C11) with different tight junctional permeabilities. Monolayers of C7 cells exhibited a high transepithelial resistance (>1 kOhms cm(2)), compared with C11 cells (<100 Ohms cm(2)). Genuine expression of claudin-1 and claudin-2, but not of occludin or claudin-3, was reciprocal to transepithelial resistance. However, confocal microscopy revealed a marked subjunctional localization of claudin-1 in C11 cells, indicating that claudin-1 is not functionally related to the low tight junctional resistance of C11 cells. Strain MDCK-C7, which endogenously does not express junctional claudin-2, was transfected with claudin-2 cDNA. In transfected cells, but not in vector controls, the protein was detected in colocalization with junctional occludin by means of immunohistochemical analyses. Overexpression of claudin-2 in the originally tight epithelium with claudin-2 cDNA resulted in a 5.6-fold higher paracellular conductivity and relative ion permeabilities of Na(+) identical with 1, K(+)=1.02, NMDG(+)=0.79, choline(+)=0.71, Cl(-)=0.12, Br(-)=0.10 (vector control, 1:1.04:0.95:0.94:0.85:0.83). By contrast, fluxes of (radioactively labeled) mannitol and lactulose and (fluorescence labeled) 4 kDa dextran were not changed. Hence, with regular Ringer's, Na(+) conductivity was 0.2 mS cm(-2) in vector controls and 1.7 mS cm(-2) in claudin-2-transfected cells, while Cl(-) conductivity was 0.2 mS cm(-2) in both cells. Thus, presence of junctional claudin-2 causes the formation of cation-selective channels sufficient to transform a 'tight' tight junction into a leaky one.
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            Conversion of Zonulae Occludentes from Tight to Leaky Strand Type by Introducing Claudin-2 into Madin-Darby Canine Kidney I Cells

            There are two strains of MDCK cells, MDCK I and II. MDCK I cells show much higher transepithelial electric resistance (TER) than MDCK II cells, although they bear similar numbers of tight junction (TJ) strands. We examined the expression pattern of claudins, the major components of TJ strands, in these cells: claudin-1 and -4 were expressed both in MDCK I and II cells, whereas the expression of claudin-2 was restricted to MDCK II cells. The dog claudin-2 cDNA was then introduced into MDCK I cells to mimic the claudin expression pattern of MDCK II cells. Interestingly, the TER values of MDCK I clones stably expressing claudin-2 (dCL2-MDCK I) fell to the levels of MDCK II cells (>20-fold decrease). In contrast, when dog claudin-3 was introduced into MDCK I cells, no change was detected in their TER. Similar results were obtained in mouse epithelial cells, Eph4. Morphometric analyses identified no significant differences in the density of TJs or in the number of TJ strands between dCL2-MDCK I and control MDCK I cells. These findings indicated that the addition of claudin-2 markedly decreased the tightness of individual claudin-1/4–based TJ strands, leading to the speculation that the combination and mixing ratios of claudin species determine the barrier properties of individual TJ strands.
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              Regulated expression of claudin-4 decreases paracellular conductance through a selective decrease in sodium permeability.

              Tight junctions regulate paracellular conductance and ionic selectivity. These properties vary among epithelia but the molecular basis of this variation remains unknown. To test whether members of the claudin family of tight junction proteins influence paracellular ionic selectivity, we expressed human claudin-4 in cultured MDCK cells using an inducible promoter. Overexpression increased the complexity of tight junction strands visible by freeze-fracture microscopy without affecting the levels of claudin-1, -2, or -3, occludin, or ZO-1. A decrease in conductance correlated directly with the kinetics of claudin-4 induction. Dilution potentials revealed that the decrease in paracellular conductance resulted from a selective decrease in Na(+) permeability without a significant effect on Cl(-) permeability. Flux for an uncharged solute, mannitol, and the rank order of permeabilities for the alkali metal cations were unchanged. A paracellular site for these effects was supported by the lack of apical/basal directionality of the dilution potentials, the linearity of current-voltage relationships, and the lack of influence of inhibitors of major transcellular transporters. These results provide, to our knowledge, the first direct demonstration of the ability of a claudin to influence paracellular ion selectivity and support a role for the claudins in creating selective channels through the tight-junction barrier.

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                October 2004
                01 December 2004
                : 24
                : 5
                : 483-487
                aDivision of Nephrology, Department of Medicine, and Department of Physiology and Biophysics, University of Southern California Keck School of Medicine, Los Angeles, Calif., USA; bDivision of Pediatric Endocrinology, Department of Pediatrics, Christian-Albrechts-Universität, Kiel, Germany
                80672 Am J Nephrol 2004;24:483–487
                © 2004 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                : 17 May 2004
                : 28 July 2004
                Page count
                Figures: 2, Tables: 3, References: 23, Pages: 5
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/80672
                Self URI (text/html): https://www.karger.com/Article/FullText/80672
                Self URI (journal page): https://www.karger.com/SubjectArea/Nephrology
                Original Report: Laboratory Investigation

                Cardiovascular Medicine,Nephrology
                Distal renal tubular acidosis,Claudin-8,Genetic heterogeneity,Pseudohypoaldosteronismtype I,Hyperkalemia,Renal salt wasting


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