Pathophysiological mechanisms of dominant and recessive KVLQT1 K+ channel mutations found in inherited cardiac arrhythmias

The inherited long QT syndrome (LQTS), characterized by a prolonged QT interval in the electrocardiogram and cardiac arrhythmia, is caused by mutations in at least four different genes, three of which have been identified and encode cardiac ion channels, The most common form of LQTS is due to mutations in the potassium channel gene KVLQT1, but their effects on associated currents are still unknown, Different mutations in KVLQT1 cause the dominant Romano-Ward (RW) syndrome and the recessive Jervell and Lange-Nielsen (JLN) syndrome, which, in addition to cardiac abnormalities, includes congenital deafness, Coexpression of K(V)LQT1 with the IsK protein elicits slowly activating potassium currents resembling the cardiac I-ks current, We now show that IsK not only changes the kinetics of K(V)LQT1 currents, but also its ion selectivity, Several mutations found in RW, including a novel mutation (D222N) in the putative channel pore, abolish channel activity and reduce the activity of wild-type K(V)LQT1 by a dominant-negative mechanism, By contrast, a JLN mutation truncating the carboxy-terminus of the K(V)LQT1 channel protein abolishes channel function without having a dominant-negative effect, This fully explains the different patterns of inheritance, Further, we identified a novel splice variant of the K(V)LQT1 gene, but could not achieve functional expression of this nor of a previously described heart-specific isoform.