Muations in protein can contribute to human disease through mechanims that either involve loss of function (LOF) or aberrant gain-of-function (GOF). Known GOF function mutations in the human KCNQ1 potassium channel are a cause of certain cardiac arrhythmias, such as atrial fibrillation (AF) and short QT syndrome (SQTS). It was demonstrated that 7 out of 15 known GOF disease mutant forms of KCNQ1 cause the channel to traffic to the membrane surface more efficiently than the wild type (WT) protien, a property we refer to as "super-trafficking". One of these GOF mutants, R231C, traffics tto the cell surface 5 times more efficiently that WT. Follow-up studies revealed the molecular biophysical mechanisms that result in this surper-trafficking trait and also revealed that channel GOF caused by supertrafficking is partially offset by mutation-induced defects in channel functionality. These results establish super-trafficking as a human disease mechanism and also reveal how a single mutation can lead to multiple and sometimes off-setting affects on overall channel function.

Super-trafficking of a membrane protein as a disease mechanism

ACS Spring Meeting 2021

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