Electrophysiological characterization of a novel mutation R863X in HERG C-terminus associated with long QT syndrome

Objective Molecular mechanism underlying long QT syndrome (LQTS) by mutations in C-terminus of HERG has not been fully characterized. We found a novel nonsense mutation in HERG in a four generation Chinese family with LQTS, the molecular mechanism of the mutation was investigated in vitro. Methods The mutation was constructed by PCR. Whole cell patch clamp studies were conducted in CHO cells by transfecting wild type and /or the mutant R863X HERG. Results In the cell transfected with R863X HERG, no time-dependent current was recorded. Whereas coexpression of wild-type HERG with R863X HERG significantly reduced the amplitude of HERG currents and resulted in currents with altered voltage-dependent inactivation. Conclusions Functional analysis suggests that the single mutation can not form the functional channel, but it can coassemble with the wild-type HERG and change its kinetics. These functional alterations may contribute to a prolongation of QT intervals and arrhythmias.