Mechanisms of KCNQ1 Channel Dysfunction in Long QT Syndrome Involving Voltage Sensor Domain Mutations

Loss-of-function (LOF) mutations in human KCNQ1 are responsible for susceptibility to a life-threatening heart rhythm disorder, the congenital long-QT syndrome (LQTS). Hundreds of KCNQ1 mutations have been identified, but the molecular mechanisms responsible for impaired function are poorly understood. Here, we investigated the impact of 51 KCNQ1 variants located within the voltage sensor domain (VSD), with an emphasis on elucidating effects on cell surface expression, protein folding and structure. For each variant, the efficiency of trafficking to the plasma membrane, the impact of proteasome inhibition, and protein stability were assayed. The results of these experiments, combined with channel functional data, provided the basis for classifying each mutation into one of 6 mechanistic categories. More than half of the KCNQ1 LOF mutations destabilize the structure of the VSD, resulting in mistrafficking and degradation by the proteasome, an observation that underscores the growing appreciation that mutation-induced destabilization of membrane proteins may be a common human disease mechanism. Finally, we observed that 5 of the folding-defective LQTS mutants are located in the VSD S0 helix, where they interact with a number of other LOF mutation sites in other segments of the VSD. These observations reveal a critical role for the S0 helix as a central scaffold to help organize and stabilize the KCNQ1 VSD and, most likely, the corresponding domain of many other ion channels.\n\nOne Sentence SummaryLong QT syndrome-associated mutations in KCNQ1 most often destabilize the protein, leading to mistrafficking and degradation.