HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 565/3/731    most recent jphysiol.2004.081620v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bendahhou, S. Articles by Barhanin, J. Search for Related Content PubMed PubMed Citation Articles by Bendahhou, S. Articles by Barhanin, J.

¹ Institut de Pharmacologie Moléculaire et Cellulaire, UMR 6097 CNRS, Sophia Antipolis, France
² Departments of Physiology
³ Biochemistry
⁸ INSERM UMR 546, Pitié-Salpêtrière Hospital, Paris, France
⁴ Department of Histology, Henri Mondor Hospital, Créteil, France
⁵ Explorations Fonctionnelles Neurologiques, Saint Brieuc Hospital, Saint Brieuc, France
⁶ Department of Neurology, Saint Joseph Hospital, Paris, France
⁷ Department of Neurology, Howard Hughes Medical Institute, University of Utah, Salt Lake City, UT, USA

The inward rectifier K⁺ channel Kir2.1 carries all Andersen's syndrome mutations identified to date. Patients exhibit symptoms of periodic paralysis, cardiac dysrhythmia and multiple dysmorphic features. Here, we report the clinical manifestations found in three families with Andersen's syndrome. Molecular genetics analysis identified two novel missense mutations in the KCNJ2 gene leading to amino acid changes C154F and T309I of the Kir2.1 open reading frame. Patch clamp experiments showed that the two mutations produced a loss of channel function. When co-expressed with Kir2.1 wild-type (WT) channels, both mutations exerted a dominant-negative effect leading to a loss of the inward rectifying K⁺ current. Confocal microscopy imaging in HEK293 cells is consistent with a co-assembly of the EGFP-fused mutant proteins with WT channels and proper traffick to the plasma membrane to produce silent channels alone or as hetero-tetramers with WT. Functional expression in C2C12 muscle cell line of newly as well as previously reported Andersen's syndrome mutations confirmed that these mutations act through a dominant-negative effect by altering channel gating or trafficking. Finally, in vivo electromyographic evaluation showed a decrease in muscle excitability in Andersen's syndrome patients. We hypothesize that Andersen's syndrome-associated mutations and hypokalaemic periodic paralysis-associated calcium channel mutations may lead to muscle membrane hypoexcitability via a common mechanism.

(Received 17 December 2004; accepted after revision 13 April 2005; first published online 14 April 2005)
Corresponding author S. Bendahhou: Université de Nice Sophia Antipolis, UMR 6097 CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, 660 Route des Lucioles, Sophia-Antipolis, 06560 Valbonne, France. Email: bendahhou{at}ipmc.cnrs.fr

This article has been cited by other articles:

				D. Heitzmann and R. Warth Physiology and Pathophysiology of Potassium Channels in Gastrointestinal Epithelia Physiol Rev, July 1, 2008; 88(3): 1119 - 1182. [Abstract] [Full Text] [PDF]

				S. Bendahhou, E. Fournier, S. Gallet, D. Menard, M.-M. Larroque, and J. Barhanin Corticosteroid-exacerbated symptoms in an Andersen's syndrome kindred Hum. Mol. Genet., April 15, 2007; 16(8): 900 - 906. [Abstract] [Full Text] [PDF]

				R. J. Sung, S.-N. Wu, J.-S. Wu, H.-D. Chang, and C.-H. Luo Electrophysiological mechanisms of ventricular arrhythmias in relation to Andersen-Tawil syndrome under conditions of reduced IK1: a simulation study Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2597 - H2605. [Abstract] [Full Text] [PDF]