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Am J Physiol Heart Circ Physiol 279: H3003-H3011, 2000;
0363-6135/00 $5.00
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Vol. 279, Issue 6, H3003-H3011, December 2000

Mechanisms of IKs suppression in LQT1 mutants

Laura Bianchi1, Silvia G. Priori2, Carlo Napolitano2, Krystyna A. Surewicz1, Adrienne T. Dennis1, Mirella Memmi3, Peter J. Schwartz3, and Arthur M. Brown1

1 The Rammelkamp Center for Education and Research, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio 44109-1998; 2 Molecular Cardiology, Fondazione Salvatore Maugeri, Pavia; and 3 Department of Cardiology, University of Pavia and Policlinico S. Matteo Instituto di Ricovero e Cura a Carattene Scientifico, 27100 Pavia, Italy

Mutations in the cardiac potassium ion channel gene KCNQ1 (voltage-gated K+ channel subtype KvLQT1) cause LQT1, the most common type of hereditary long Q-T syndrome. KvLQT1 mutations prolong Q-T by reducing the repolarizing cardiac current [slow delayed rectifier K+ current (IKs )], but, for reasons that are not well understood, the clinical phenotypes may vary considerably even for carriers of the same mutation, perhaps explaining the mode of inheritance. At present, only currents expressed by LQT1 mutants have been studied, and it is unknown whether abnormal subunits are transported to the cell surface. Here, we have examined for the first time trafficking of KvLQT1 mutations and correlated the results with the IKs currents that were expressed. Two missense mutations, S225L and A300T, produced abnormal currents, and two others, Y281C and Y315C, produced no currents. However, all four KvLQT1 mutations were detected at the cell surface. S225L, Y281C, and Y315C produced dominant negative effects on wild-type IKs current, whereas the mutant with the mildest dysfunction, A300T, did not. We examined trafficking of a severe insertion deletion mutant Delta 544 and detected this protein at the cell surface as well. We compared the cellular and clinical phenotypes and found a poor correlation for the severely dysfunctional mutations.

KvLQT1 mutations; cellular processing; cellular phenotype; clinical phenotype; slow delayed rectifier potassium current; long Q-T syndrome


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