The voltage-gated potassium channel KCNQ1 is critical for the cardiac action potential. Mutations in KCNQ1 are the most common cause of congenital long-QT syndrome (LQTS), an often-fatal arrhythmia. There are a variety of possible mechanisms by which a given mutation may cause KCNQ1 channel dysfunction and disease. We employed a multidisciplinary approach to systematically investigate the effects of 51 KCNQ1 voltage sensor domain (VSD) mutations on channel structure, stability, trafficking, and electrophysiological (functional) properties. Our results established that each disease mutation causes loss of change function and disease via one of a panel of possible mechanisms, but that by far the most common is destabilization of channel folding, leading to mistrafficking and proteasomal degradation.  Our studies also led to completion of the NMR-determined high resolution 3-D structure of the wild type human KCNQ1 VSD in intermediate activation and revealed a previously-unrecognized role for the channel S0 segment as a critical structural scaffold for stabilizing the remainder of the VSD.  This work is supported by NIH Grant RO1 HL122010. 

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