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Vol. 119, No. 3, 2011
Issue release date: October 2011
Section title: Original Paper
Nephron Physiol 2011;119:p40–p48
(DOI:10.1159/000330250)

KCNJ10 Mutations Disrupt Function in Patients with EAST Syndrome

Freudenthal B.a · Kulaveerasingam D.b · Lingappa L.c · Shah M.A.c · Brueton L.d · Wassmer E.e · Ognjanovic M.f · Dorison N.g · Reichold M.h · Bockenhauer D.a, i, j · Kleta R.a, b, i, j · Zdebik A.A.a, b
aCentre for Nephrology, University College London, Royal Free Hospital, and bDepartment of Neuroscience, Physiology and Pharmacology, University College London, London, UK; cRainbow Children‘s Hospital and Perinatal Centre, Hyderabad, India; dClinical Genetics Unit, Birmingham Women’s Hospital, eBirmingham Children’s Hospital, Birmingham, and fGreat North Children‘s Hospital, Newcastle upon Tyne, UK; gNeuropédiatrie, Hôpital Trousseau, Paris, France; hMedical Cell Biology, University of Regensburg, Regensburg, Germany; iInstitute of Child Health, University College London, and jGreat Ormond Street Hospital for Children, London, UK

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Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: 4/3/2011 8:54:10 AM
Accepted: 6/17/2011 12:23:53 PM
Published online: 8/18/2011
Issue release date: October 2011

Number of Print Pages: 9
Number of Figures: 3
Number of Tables: 2

ISSN: (Print)
eISSN: 1660-2137 (Online)

For additional information: http://www.karger.com/NEP

Abstract

Background/Aims: Mutations in the inwardly-rectifying K+ channel KCNJ10/Kir4.1 cause an autosomal recessive disorder characterized by epilepsy, ataxia, sensorineural deafness and tubulopathy (EAST syndrome). KCNJ10 is expressed in the kidney distal convoluted tubule, cochlear stria vascularis and brain glial cells. Patients clinically diagnosed with EAST syndrome were genotyped to identify and study mutations in KCNJ10. Methods: Patient DNA was sequenced and new mutations identified. Mutant and wild-type KCNJ10 constructs were cloned and heterologously expressed in Xenopus oocytes. Whole-cell K+ currents were measured by two-electrode voltage clamping. Results: Three new mutations in KCNJ10 (p.R65C, p.F75L and p.V259fs259X) were identified, and mutation p.R297C, previously only seen in a compound heterozygous patient, was found in a homozygous state. Wild-type human KCNJ10-expressing oocytes showed strongly inwardly-rectified currents, which by comparison were significantly reduced in all the mutants (p < 0.001). Specific inhibition of KCNJ10 currents by Ba2+ demonstrated residual function in all mutant channels (p < 0.05) but V259X. Conclusion: This study confirms that EAST syndrome can be caused by many different mutations in KCNJ10 that significantly reduce K+ conductance. EAST syndrome should be considered in any patient with a renal Gitelman-like phenotype with additional neurological signs and symptoms like ataxia, epilepsy or sensorineural deafness.

© 2011 S. Karger AG, Basel


  

Author Contacts

Anselm A. Zdebik
University College London
Royal Free Hospital Medical School, 1-702
Rowland Hill Street, London NW3 2PF (UK)
Tel. +44 75 3432 9860, E-Mail a.zdebik@ucl.ac.uk

  

Article Information

Received: April 3, 2011
Accepted: June 17, 2011
Published online: August 18, 2011
Number of Print Pages : 9
Number of Figures : 3, Number of Tables : 2, Number of References : 41

  

Publication Details

Nephron Physiology

Vol. 119, No. 3, Year 2011 (Cover Date: October 2011)

Journal Editor: Kleta R. (London)
ISSN: 1660-2137 (Print), eISSN: 1660-2137 (Online)

For additional information: http://www.karger.com/NEP


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: 4/3/2011 8:54:10 AM
Accepted: 6/17/2011 12:23:53 PM
Published online: 8/18/2011
Issue release date: October 2011

Number of Print Pages: 9
Number of Figures: 3
Number of Tables: 2

ISSN: (Print)
eISSN: 1660-2137 (Online)

For additional information: http://www.karger.com/NEP


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