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Am J Physiol Heart Circ Physiol 279: H1748-H1756, 2000;
0363-6135/00 $5.00
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Vol. 279, Issue 4, H1748-H1756, October 2000

Novel characteristics of a misprocessed mutant HERG channel linked to hereditary long QT syndrome

Eckhard Ficker1, Dierk Thomas1, Prakash C. Viswanathan2, Adrienne T. Dennis1, Silvia G. Priori3, Carlo Napolitano3, Mirella Memmi3, Barbara A. Wible4, Elizabeth S. Kaufman5, Sudha Iyengar6, Peter J. Schwartz7, Yoram Rudy2, and Arthur M. Brown8

1 Rammelkamp Center for Education and Research, 5 Heart and Vascular Research Center, and 6 Department of Epidemiology and Biostatistics, MetroHealth Campus, Departments of 8 Physiology and Biophysics, 4 Biochemistry and 2 Cardiac Bioelectricity Research and Training Center, Case Western Reserve University, Cleveland, Ohio 44109; and 3 Molecular Cardiology Laboratories, Fondazione Salvatore Maugeri and 7 Department of Cardiology, University of Pavia, Policlinico San Matteo, Istituto di Ricovero e Cura a Carattere Scientifico, 27100 Pavia, Italy

Hereditary long QT syndrome (hLQTS) is a heterogeneous genetic disease characterized by prolonged QT interval in the electrocardiogram, recurrent syncope, and sudden cardiac death. Mutations in the cardiac potassium channel HERG (KCNH2) are the second most common form of hLQTS and reduce the delayed rectifier K+ currents, thereby prolonging repolarization. We studied a novel COOH-terminal missense mutation, HERG R752W, which segregated with the disease in a family of 101 genotyped individuals. When the mutant cRNA was expressed in Xenopus oocytes it produced enhanced rather than reduced currents. Simulations using the Luo-Rudy model predicted minimal shortening rather than prolongation of the cardiac action potential. Consequently, a normal or shortened QT interval would be expected in contrast to the long QT observed clinically. This anomaly was resolved by our observation that the mutant protein was not delivered to the plasma membrane of mammalian cells but was retained intracellularly. We found that this trafficking defect was corrected at lower incubation temperatures and that functional channels were now delivered to the plasma membrane. However, trafficking could not be restored by chemical chaperones or E-4031, a specific blocker of HERG channels. Therefore, HERG R752W represents a new class of trafficking mutants in hLQTS. The occurrence of different classes of misprocessed channels suggests that a unified therapeutic approach for altering HERG trafficking will not be possible and that different treatment modalities will have to be matched to the different classes of trafficking mutants.

human ether-á-go-go-related gene; trafficking; K+ channel; arrhythmia


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