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      The Curious Genomic Path from Leaky Red Cell to Nephrotic Kidney

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          Abstract

          The human red cell has proved to be an invaluable model cell for the study of many aspects of membrane structure and function. It has a series of transport pathways which mediate the movements of the univalent cations Na and K, which are either identical or similar to systems in other human tissues, including the human kidney. The balance between the energy-consuming NaK pump and a ‘passive leak’ component maintains a net deficit of cations within the cell, which defends the cell volume against osmotic swelling. There exist a series of dominantly inherited human red cell conditions, gathered under the generic title ‘hereditary stomatocytoses’, in which the so-called ‘passive leak’ to Na and K is pathologically increased. In the more severe variants this compromises the integrity of the cell and the patients suffer haemolytic anaemia. Some less severe variants present with pseudohyperkalaemia caused by loss of K from red cells on storage of blood at room temperature. The most severe variants show a deficiency in a widely distributed ‘raft’ protein known as stomatin. The stomatin protein is homologous to the ‘podocin’ protein, the gene for which is mutated in a recessively inherited form of nephrotic syndrome. Among other possible functions, both proteins could be involved in the trafficking of membrane proteins to and from the plasma membrane.

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          Most cited references 7

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          NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome.

          Familial idiopathic nephrotic syndromes represent a heterogeneous group of kidney disorders, and include autosomal recessive steroid-resistant nephrotic syndrome, which is characterized by early childhood onset of proteinuria, rapid progression to end-stage renal disease and focal segmental glomerulosclerosis. A causative gene for this disease, NPHS2, was mapped to 1q25-31 and we report here its identification by positional cloning. NPHS2 is almost exclusively expressed in the podocytes of fetal and mature kidney glomeruli, and encodes a new integral membrane protein, podocin, belonging to the stomatin protein family. We found ten different NPHS2 mutations, comprising nonsense, frameshift and missense mutations, to segregate with the disease, demonstrating a crucial role for podocin in the function of the glomerular filtration barrier.
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            Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK.

            Mutations in the Na-K-2Cl cotransporter (NKCC2), a mediator of renal salt reabsorption, cause Bartter's syndrome, featuring salt wasting, hypokalaemic alkalosis, hypercalciuria and low blood pressure. NKCC2 mutations can be excluded in some Bartter's kindreds, prompting examination of regulators of cotransporter activity. One regulator is believed to be ROMK, an ATP-sensitive K+ channel that 'recycles' reabsorbed K+ back to the tubule lumen. Examination of the ROMK gene reveals mutations that co-segregate with the disease and disrupt ROMK function in four Bartter's kindreds. Our findings establish the genetic heterogeneity of Bartter's syndrome, and demonstrate the physiologic role of ROMK in vivo.
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              A stomatin-like protein necessary for mechanosensation in C. elegans.

              The mec-2 gene is required for the function of a set of six touch receptor neurons in the nematode Caenorhabditis elegans; mec-2 mutants, which are touch-insensitive, have touch cells that appear morphologically normal. Gene interaction studies suggest that mec-2 positively regulates the activity of the putative mechanosensory transduction channel (and the present paper), comprised in part of proteins encoded by the two degenerin genes mec-4 and mec-10 The central region of the mec-2 protein (MEC-2) is very similar to stomatin, an integral membrane protein (band 7.2b) in human red blood cells that is thought to regulate cation conductance. MEC-2-LacZ fusions are distributed along the touch receptor axons. This axonal distribution, which is mediated by the mec-2-specific amino terminus, is disrupted by mutations in mec-12, an alpha-tubulin gene needed for touch cell function. Our results indicate that MEC-2 links the mechanosensory channel and the microtubule cytoskeleton of the touch receptor neurons. Such linkage provides the basis for a mechanism of mechanosensation whereby microtubule displacement leads to channel opening.
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                Author and article information

                Journal
                NEP
                Nephron Physiol
                10.1159/issn.1660-2137
                Nephron Physiology
                S. Karger AG
                1660-2137
                2003
                February 2003
                20 February 2003
                : 93
                : 2
                : p29-p33
                Affiliations
                aDepartment of Medicine, University College London, Rayne Institute, London, UK; bAbteilung für Neuroanatomie, Institut für Anatomie MA 6/152, Ruhr-Universität, Bochum, Germany
                Article
                68527 Nephron Physiol 2003;93:p29–p33
                10.1159/000068527
                12629268
                © 2003 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.

                Page count
                Figures: 2, References: 16, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/68527
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