Clinical and Molecular Features of Type 1 Pseudohypoaldosteronism

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Abstract

Pseudohypoaldosteronism (PHA) is a rare heterogeneous syndrome of mineralocorticoid resistance causing insufficient potassium and hydrogen secretion. PHA type 1 (PHA1) causes neonatal salt loss, failure to thrive, dehydration and circulatory shock. Two different forms of PHA1 can be distinguished on the clinical and genetic level, showing either a systemic or a renal form of mineralocorticoid resistance. This review provides an overview on transepithelial sodium reabsorption and on clinical features and the underlying molecular pathology of systemic and renal PHA1 caused by mutations in the subunit genes (SCNN1A, SCNN1B, SCNN1G) of the epithelial sodium channel (ENaC) and the mineralocorticoid receptor coding gene NR3C2. The in vitro investigation of several mutants has resulted in important progress in the understanding of the physiology of ENaC and the mineralocorticoid receptor. Some mutations are discussed in more detail to demonstrate some of these findings. A better clinical work-up of the patients suffering from PHA1 may delineate additional associations between the genotype and phenotype in the future.

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Most cited references 50

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Human hypertension caused by mutations in WNK kinases.

F. Wilson, S Disse-Nicodème, K A Choate … (2001)

Hypertension is a major public health problem of largely unknown cause. Here, we identify two genes causing pseudohypoaldosteronism type II, a Mendelian trait featuring hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion. Both genes encode members of the WNK family of serine-threonine kinases. Disease-causing mutations in WNK1 are large intronic deletions that increase WNK1 expression. The mutations in WNK4 are missense, which cluster in a short, highly conserved segment of the encoded protein. Both proteins localize to the distal nephron, a kidney segment involved in salt, K+, and pH homeostasis. WNK1 is cytoplasmic, whereas WNK4 localizes to tight junctions. The WNK kinases and their associated signaling pathway(s) may offer new targets for the development of antihypertensive drugs.

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Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits.

C M Canessa, L Schild, G. Buell … (1994)

The amiloride-sensitive epithelial sodium channel constitutes the rate-limiting step for sodium reabsorption in epithelial cells that line the distal part of the renal tubule, the distal colon, the duct of several exocrine glands, and the lung. The activity of this channel is upregulated by vasopressin and aldosterone, hormones involved in the maintenance of sodium balance, blood volume and blood pressure. We have identified the primary structure of the alpha-subunit of the rat epithelial sodium channel by expression cloning in Xenopus laevis oocytes. An identical subunit has recently been reported. Here we identify two other subunits (beta and gamma) by functional complementation of the alpha-subunit of the rat epithelial Na+ channel. The ion-selective permeability, the gating properties and the pharmacological profile of the channel formed by coexpressing the three subunits in oocytes are similar to that of the native channel.

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Early death due to defective neonatal lung liquid clearance in alpha-ENaC-deficient mice.

C Verdumo, Michael Schmidt, E Hummler … (1996)

The amiloride-sensitive epithelial sodium channel, ENaC, is a heteromultimeric protein made up of three homologous subunits (alpha, beta and gamma) (1,2). In vitro, assembly and expression of functional active sodium channels in the Xenopus oocyte is strictly dependent on alpha-ENaC--the beta and gamma subunits by themselves are unable to induce an amiloride-sensitive sodium current in this heterologous expression system (2). In vivo, ENaC constitutes the limiting step for sodium absorption in epithelial cells that line the distal renal tubule, distal colon and the duct of several exocrine glands. The adult lung expresses alpha, beta and gamma ENaC (3,4), and an amiloride-sensitive electrogenic sodium reabsorption has been documented in upper and lower airways (3-7), but it is not established whether this sodium transport is mediated by ENaC in vivo. We inactivated the mouse alpha-ENaC gene by gene targeting. Amiloride-sensitive electrogenic Na+ transport was abolished in airway epithelia from alpha-ENaC(-/-) mice. Alpha-ENaC(-/-) neonates developed respiratory distress and died within 40 h of birth from failure to clear their lungs of liquid. This study shows that ENaC plays a critical role in the adaptation of the newborn lung to air breathing.

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Author and article information

Journal

Journal ID (publisher-id): HRE

Journal ID (nlm-ta): Horm Res Paediatr

Journal ID (doi): 10.1159/issn.1663-2818

Title: Hormone Research in Paediatrics

Publisher: S. Karger AG

ISSN (Print): 1663-2818

ISSN (Electronic): 1663-2826

Publication date Subscription-year: 2009

Publication date (Print): June 2009

Publication date (Electronic): 30 June 2009

Volume: 72

Issue: 1

Pages: 1-9

Affiliations

Division of Paediatric Endocrinology, Department of Paediatrics, Christian Albrechts University, Kiel, Germany

Article

Publisher ID: 224334 Other ID: Horm Res 2009;72:1–9

DOI: 10.1159/000224334

PubMed ID: 19571553

SO-VID: 995b183b-bbfb-461a-9bed-dcc4355bbcd0

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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 : 20 March 2009

Date accepted : 27 April 2009

Page count

Figures: 3, Tables: 1, References: 63, Pages: 9

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