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Intragenic Suppression of Trafficking-Defective KCNH2 Channels Associated with Long QT Syndrome

Departments of Medicine and Physiology, University of Wisconsin, Madison, Wisconsin (B.P.D., J.K.S., J.A.K., C.L.A., B.D.A., R.C.B., T.J.K., C.T.J.); and Departments of Medicine, Pediatrics, and Molecular Pharmacology, Mayo Clinic College of Medicine, Rochester, Minnesota (D.J.T., M.J.A.)

Mutations in the KCNH2 or human ether-a-go-go–related gene-encoded K⁺ channel reduce functional KCNH2 current (I_KCNH2) to cause long QT syndrome (LQT2) by multiple mechanisms, including defects in intracellular transport (trafficking). Trafficking-deficient, or class 2, LQT2 mutations reduce the Golgi processing and surface membrane expression of KCNH2 channel proteins. Drugs that associate with pore-S6 intracellular drug binding domain of KCNH2 channel proteins to cause high-affinity block of I_KCNH2 also can increase the processing of class 2 LQT2 channel proteins through the secretory pathway. We used a strategy of intragenic suppression to test the hypothesis that amino acid substitutions in the putative drug binding domain at residue Y652 could compensate for protein folding abnormalities caused by class 2 LQT2 mutations. We found that the Y652C substitution, and to lesser extent the Y652S substitution, resulted in intragenic suppression of the class 2 LQT2 G601S phenotype; these substitutions increased Golgi processing of G601S channel proteins. The Y652C substitution also caused intragenic suppression of the class 2 LQT2 V612L and F640V phenotypes but not the LQT2 N470D or F805C phenotypes. These are the first findings to demonstrate that a single amino acid substitution in the putative KCNH2 drug binding domain can cause intragenic suppression of several LQT2 mutations.

Address correspondence to: Dr. Craig T. January, Room 24, SMI Bldg., 1300 University Ave., University of Wisconsin, Madison, WI 53706. E-mail: ctj{at}medicine.wisc.edu

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