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(Circulation. 2001;104:1071.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Long-QT Syndrome-Associated Missense Mutations in the Pore Helix of the HERG Potassium Channel

Fu-De Huang, MD; Jun Chen, PhD; Monica Lin, MD; Mark T. Keating, MD; Michael C. Sanguinetti, PhD

From the Department of Medicine, Division of Cardiology (F.-D.H., J.C., M.L., M.C.S.), and the Eccles Program in Human Molecular Biology and Genetics (M.C.S.), University of Utah, Salt Lake City; and the Howard Hughes Medical Institute, Department of Cell Biology, Harvard Medical School and Department of Cardiology, Children’s Hospital, Boston, Mass (M.T.K.).

Correspondence to Michael C. Sanguinetti, Eccles Institute of Human Genetics, University of Utah, 15 N 2030 East, Room 4220, Salt Lake City, UT 84112. E-mail michael.sanguinetti@ hmbg.utah.edu

Background— Mutations in the human ether-à-go-go-related gene (HERG) cause chromosome 7-linked long-QT syndrome (LQTS), an inherited disorder of cardiac repolarization that predisposes affected individuals to arrhythmia and sudden death.

Methods and Results— Here, we characterize the physiological consequences of 3 LQTS-associated missense mutations (V612L, T613M, and L615V) located in the pore helix of the HERG channel subunit. Mutant HERG subunits were heterologously expressed in Xenopus oocytes alone or in combination with wild-type HERG subunits. Two-microelectrode voltage-clamp techniques were used to record currents, and a single oocyte chemiluminescence assay was used to assay surface expression of epitope-tagged subunits. When expressed alone, V612L and T613M HERG subunits did not induce detectable currents, and L615V induced very small currents. Coexpression of mutant and wild-type HERG subunits caused a dominant-negative effect that varied for each mutation.

Conclusions— These findings define the physiological consequences of mutations in HERG that cause LQTS and indicate the importance of the pore helix of HERG for normal channel function.

Key Words: arrhythmia • long-QT syndrome • ion channels

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