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      Call for Papers: Green Renal Replacement Therapy: Caring for the Environment

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      Modifier Effect of the Glu298Asp Polymorphism of Endothelial Nitric Oxide Synthase Gene in Autosomal-Dominant Polycystic Kidney Disease

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          Abstract

          Autosomal-dominant polycystic kidney disease (ADPKD) is one of the most common monogenic diseases. It is characterized by a substantial variability in the severity of renal phenotype, primarily assessed by the age at end-stage renal disease (ESRD). The role of modifier genes has been shown in various hereditary diseases, including ADPKD. The gene coding for the endothelial nitric oxide synthase (NOS3) is considered to have a modifier effect on the severity of ADPKD, even if there are studies among different populations that have shown contradictory results. In this study, we investigated the influence of one of the most studied polymorphisms of the NOS3 gene, the Glu298Asp polymorphism, on the age at ESRD in ADPKD. We analyzed a total of 100 ADPKD unrelated patients and 107 healthy cohorts from the Greek population. ADPKD patients were classified into two subgroups: patients with early (rapid progressors) and late (slow progressors) age at ESRD. The results suggested that the Glu298Asp polymorphism of NOS3 gene is associated with the onset age of ESRD. The distribution of C/T alleIes is significantly different between rapid and slow ADPKD progressors leading to the conclusion that the T allele of the Glu298Asp polymorphism of NOS3 gene is associated with earlier progression to ESRD in ADPKD patients.

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          Modifier genes in mice and humans.

          J Nadeau (2001)
          An emerging theme of studies with spontaneous, engineered and induced mutant mice is that phenotypes often depend on genetic background, implying that genetic modifiers have a role in guiding the functional consequences of genetic variation. Understanding the molecular and cellular basis by which modifier genes exert their influence will provide insights into developmental and physiological pathways that are critical to fundamental biological processes, as well as into novel targets for therapeutic interventions in human diseases.
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            Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: cleavage of proteins with aspartate vs. glutamate at position 298.

            M. Tesauro, W. Thompson, P Rogliani … (2000)
            An endothelial nitric oxide synthase (eNOS) polymorphism in exon 7 (894 G/T) resulting in glutamate or aspartate, respectively, at position 298 on the protein is correlated with severity of cardiopulmonary diseases. Because glutamate and aspartate are considered to be conservative replacements, the polymorphism was thought to be a marker for a functional locus elsewhere in the gene. We now show in transfected cells, primary human endothelial cells, and human hearts, that eNOS with aspartate, but not glutamate, at position 298 is cleaved, resulting in the generation of 100-kDa and 35-kDa products. Recombinant or native eNOS was examined by immunoblotting either in lysates (COS7) or after partial purification over 2',5'-ADP-Sepharose and calmodulin-Sepharose. Immunoblotting after SDS/PAGE with a carboxyl-terminal antibody showed a single major protein band in the predicted position for eNOS at 135 kDa. An additional band at approximately 100 kDa was present only in the recombinant 298Asp eNOS and in the eNOS synthesized by primary cells and heart tissue with a G/T genotype. Using an eNOS amino-terminal-specific antibody, an immunoreactive band at approximately 35 kDa, corresponding to the residual N-terminal cleavage fragment, was observed in those cells with a T genotype. Thus, eNOS with aspartate but not glutamate at position 298 is cleaved, resulting in the generation of N-terminal 35-kDa and C-terminal 100-kDa fragments. Thus, the eNOS gene with polymorphisms at nucleotide 894 generates protein products with differing susceptibility to cleavage, suggesting that, in contrast to prior predictions, this polymorphism has a functional effect on the eNOS protein.
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              Evidence of association of the ecNOS gene polymorphism with plasma NO metabolite levels in humans.

              T Tsukada, Kathryn Yamada, S Hara … (1998)
              Nitric oxide (NO) synthesized by the vascular endothelium regulates mammalian blood vessels and other systems in humans. Recently, an endothelial nitric oxide synthase (ecNOS) gene polymorphism, the 27-bp repeat in intron 4 (ecNOS4), was reported to be related to the pathogenesis of coronary heart disease and terminal renal failure. We analyzed this polymorphism in a group of 413 healthy subjects, and measured their plasma nitrite and nitrate (NOx) levels. The frequency of the b allele was 89.8% , and the frequency of the a allele was 10.2%. The frequency of ecNOS4 b/b, ecNOS4 b/a, and ecNOS4 a/a in the healthy subjects in this study was 0.814 (n=336), 0.169 (n=70) and 0.017 (n=7), respectively. Using this polymorphism as a DNA marker, we found a strong association between the alleles of the ecNOS gene polymorphism and the plasma NOx levels. The basal NO metabolite levels were 28.8 micromol/L in subjects with ecNOS4 a/a, 31.4 micromol/L in those with ecNOS4 b/a, and 35.5 micromol/L in those with ecNOS4 b/b. The mean plasma NOx level of the subjects who were homozygous for the a allele was nearly 20% lower than in the subjects with the b allele. The plasma NOx level of the subjects with the a allele was 31.2+/-2.00 micromol/L, and significantly lower than the 35.5+/-0.93 micromol/L in those without the a allele (P <0.05). The results of this study indicate that the ecNOS4 gene locus may be responsible for variations in the genetic control of plasma NOx and that analysis of ecNOS4 gene polymorphism may be a useful tool for studying the relation between NO and diseases. Copyright 1998 Academic Press.
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                Author and article information

                Journal
                Journal ID (publisher-id): NEC
                Journal ID (nlm-ta): Nephron Clin Pract
                Journal ID (doi): 10.1159/issn.1660-2110
                Title: Nephron Clinical Practice
                Publisher: S. Karger AG
                ISSN (Electronic): 1660-2110
                Publication date Subscription-year: 2008
                Publication date (Print): November 2008
                Publication date (Electronic): 25 September 2008
                Volume: 110
                Issue: 2
                Pages: c101-c106
                Affiliations
                aDivision of Genetics, Department of Biology, University of Athens, and bDepartment of Nephrology, ‘G. Gennimatas’ Hospital, Athens, Greece
                Article
                Publisher ID: 157623 Other ID: Nephron Clin Pract 2008;110:c101
                DOI: 10.1159/000157623
                PubMed ID: 18815450
                SO-VID: e2867e68-daf1-4a6e-bcc2-0372144ce8ca
                Copyright © © 2008 S. Karger AG, Basel
                License:

                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
                Date received : 07 December 2007
                Date accepted : 24 June 2008
                Page count
                Tables: 5, References: 36, Pages: 1
                Categories
                Subject: Original Paper

                ScienceOpen disciplines: Cardiovascular Medicine,Nephrology
                Keywords: Autosomal-dominant polycystic kidney disease,End-stage renal disease,<italic>NOS3</italic> gene polymorphism
                Data availability:
                ScienceOpen disciplines: Cardiovascular Medicine, Nephrology
                Keywords: Autosomal-dominant polycystic kidney disease, End-stage renal disease, <italic>NOS3</italic> gene polymorphism

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