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

Hereditary long QT syndrome (hLQTS) is a heterogeneous genetic disease char acterized by prolonged QT interval in the electrocardiogram, recurrent sync ope, and sudden cardiac death. Mutations in the cardiac potassium channel H ERG (KCNH2) are the second most common form of hLQTS and reduce the delayed rectifier K+ currents, thereby prolonging repolarization. We studied a nov el COOH-terminal missense mutation, HERG R752W, which segregated with the d isease in a family of 101 genotyped individuals. When the mutant cRNA was e xpressed in Xenopus oocytes it produced enhanced rather than reduced curren ts. Simulations using the Luo-Rudy model predicted minimal shortening rathe r than prolongation of the cardiac action potential. Consequently, a normal or shortened QT interval would be expected in contrast to the long QT obse rved clinically. This anomaly was resolved by our observation that the muta nt protein was not delivered to the plasma membrane of mammalian cells but was retained intracellularly. We found that this trafficking defect was cor rected at lower incubation temperatures and that functional channels were n ow delivered to the plasma membrane. However, trafficking could not be rest ored by chemical chaperones or E-4031, a specific blocker of HERG channels. Therefore, HERG R752W represents a new class of trafficking mutants in hLQ TS. The occurrence of different classes of misprocessed channels suggests t hat a unified therapeutic approach for altering HERG trafficking will not b e possible and that different treatment modalities will have to be matched to the different classes of trafficking mutants.