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J. Biol. Chem., Vol. 281, Issue 46, 35397-35403, November 17, 2006

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Skipping of Exon 1 in the KCNQ1 Gene Causes Jervell and Lange-Nielsen Syndrome^*

Joerg Zehelein¹², Sven Kathoefer¹, Markus Khalil^¶, Markus Alter, Dierk Thomas, Konrad Brockmeier^||, Herbert E. Ulmer^¶, Hugo A. Katus, and Michael Koenen³

From the Universitätsklinikum Heidelberg, Innere Medizin III, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany, the Max-Planck-Institut für Medizinische Forschung, Abteilung Zellphysiologie, Jahnstrasse 29, 69120 Heidelberg, Germany, the ^¶Universitätsklinikum Heidelberg, Kinderheilkunde II, Im Neuenheimer Feld 153, 69120 Heidelberg, Germany, and the ^||Klinikum der Universität zu Köln, Abteilung Kinderkardiologie, Joseph-Stelzmann-Strasse 9, 50931 Köln, Germany

The Jervell and Lange-Nielsen syndrome (JLNS) is a rare autosomal recessive form of the long QT syndrome linked with a profound hearing loss caused by mutations affecting both alleles of either the KCNQ1 or the KCNE1 gene. We carried out a mutant screening of the KCNQ1 and KCNE1 genes in a clinical diagnosed German family with JLNS. Family members were examined by single strand conformation polymorphism analysis and PCR and amplified products were characterized by DNA sequence analysis. We identified a splice donor mutation of exon 1 in the KCNQ1 gene (G477 + 1A). Analysis of lymphocyte RNA by RT-PCR revealed that two symptomatic patients, homozygous for the mutant allele, exclusively produce KCNQ1 transcripts lacking exon 1 leading to a frameshift that introduced a premature termination codon at exon 4. Mutant subunits, functionally characterized in Xenpous oocytes, were unable to form homomeric channels but strongly reduced I_Ks (slowly activating delayed rectifier potassium current) in vitro (mutant isoforms 1 and 2 by 62 and 86%, respectively), a fact supposed to lead to severely affected heterozygous individuals. However, individuals heterozygous for the mutant allele exhibit an asymptomatic cardiac phenotype. Thus, the observed dominant-negative effect of mutant subunits in vitro is absent in vivo leaving heterozygous individuals unaffected. These data suggest mechanisms that prevent production of truncated KCNQ1 channel subunits in cardiomyocytes of individuals heterozygous for the mutant allele.

Received for publication, April 10, 2006 , and in revised form, September 15, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Supported by a "Tandemprojekt" grant of the Max-Planck-Gesellschaft in cooperation with the Universitätsklinikum Heidelberg.

³ To whom correspondence should be addressed: Max-Planck-Institut für Medizinische Forschung, Abteilung Zellphysiologie, Jahnstrasse 29, D-69120 Heidelberg, Germany. Tel.: 49-6221-486-475; Fax: 49-6221-486-549; E-mail: koenen{at}mpimf-heidelberg.mpg.de.

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