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      Polycystin Expression in the Kidney and Other Tissues: Complexity, Consensus and Controversy

      review-article
      Cardiorenal Medicine
      S. Karger AG
      ADPKD, Western analysis, PKD1, Immunohistochemistry, Polycystin

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          Abstract

          PKD1, the major gene mutated in autosomal dominant polycystic kidney disease, was identified in 1994, and fully sequenced in 1995. The protein which it encodes, polycystin-1, is the first member of a new family of proteins, whose functions presently remain unclear. This review seeks to highlight the difficulties researchers studying polycystin-1 have faced and to summarize the current areas of consensus and controversy between different groups, particularly with regard to the expression pattern, subcellular location and biochemical characterization of polycystin-1. Where relevant, more recent data regarding polycystin-2, the protein encoded by PKD2, will also be discussed.

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          Most cited references6

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          Somatic inactivation of Pkd2 results in polycystic kidney disease.

          Germline mutations in PKD2 cause autosomal dominant polycystic kidney disease. We have introduced a mutant exon 1 in tandem with the wild-type exon 1 at the mouse Pkd2 locus. This is an unstable allele that undergoes somatic inactivation by intragenic homologous recombination to produce a true null allele. Mice heterozygous and homozygous for this mutation, as well as Pkd+/- mice, develop polycystic kidney and liver lesions that are indistinguishable from the human phenotype. In all cases, renal cysts arise from renal tubular cells that lose the capacity to produce Pkd2 protein. Somatic loss of Pkd2 expression is both necessary and sufficient for renal cyst formation in ADPKD, suggesting that PKD2 occurs by a cellular recessive mechanism.
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            Homo- and heterodimeric interactions between the gene products of PKD1 and PKD2.

            PKD1 and PKD2 are two recently identified genes that are responsible for the vast majority of autosomal polycystic kidney disease, a common inherited disease that causes progressive renal failure. PKD1 encodes polycystin, a large glycoprotein that contains several extracellular motifs indicative of a role in cell-cell or cell-matrix interactions, and the PKD2 encodes a protein with homology to a voltage-activated calcium channel and to PKD1. It is currently unknown how mutations of either protein functionally cause autosomal polycystic kidney disease. We show that PKD1 and PKD2 interact through their C-terminal cytoplasmic tails. This interaction resulted in an up-regulation of PKD1 but not PKD2. Furthermore, the cytoplasmic tail of PKD2 but not PKD1 formed homodimers through a coiled-coil domain distinct from the region required for interaction with PKD1. These interactions suggest that PKD1 and PKD2 may function through a common signaling pathway that is necessary for normal tubulogenesis and that PKD1 may require the presence of PKD2 for stable expression.
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              Perinatal lethality with kidney and pancreas defects in mice with a targetted Pkd1 mutation.

              PKD1 is the most common site for mutations in human autosomal dominant polycystic kidney disease (ADPKD). ADPKD is characterized by progressive replacement of kidney tissue by epithelial cysts and eventual renal failure. Hepatic and pancreatic cysts are also common. The PKD1 protein, polycystin, is a cell-surface protein of unknown function that is widely expressed in epithelia and in vascular smooth muscle and myocardium. None of the genetic forms of murine polycystic disease map to the murine Pkd1 locus. We introduced into mice by homologous recombination a Pkd1 truncation mutation, Pkd1-, that mimics a mutation found in ADPKD. Pkd1- heterozygotes have no discernible phenotype, whereas homozygotes die during the perinatal period with massively enlarged cystic kidneys, pancreatic ductal cysts and pulmonary hypoplasia. Renal cyst formation begins at embryonic day 15.5 (E15.5) in proximal tubules and progresses rapidly to replace the entire renal parenchyma. The timing of cyst formation indicates that full-length polycystin is required for normal morphogenesis during elongation and maturation of tubular structures in the kidney and pancreas.
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                Author and article information

                Journal
                EXN
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                2000
                October 2000
                31 July 2000
                : 8
                : 4-5
                : 208-214
                Affiliations
                MRC Molecular Haematology Unit, Institute of Molecular Medicine, University of Oxford, Headington, Oxon., UK
                Article
                20670 Exp Nephrol 2000;8:208–214
                10.1159/000020670
                10940718
                a77379cf-5823-44b5-afc2-907216f80d05
                © 2000 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.

                History
                Page count
                Figures: 1, Tables: 3, References: 22, Pages: 7
                Categories
                Minireview

                Cardiovascular Medicine,Nephrology
                ADPKD,Western analysis,PKD1,Polycystin,Immunohistochemistry
                Cardiovascular Medicine, Nephrology
                ADPKD, Western analysis, PKD1, Polycystin, Immunohistochemistry

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