Relevance of the KCNH2 protein stoichiometry to pathological conditions underlying QT abnormality

Genetic defects in the KCNH2 gene are a primary cause of instable cardiac ventricular repolarization. The aim of this work has been to assess the functional implication of the stoichiometric properties of the mutated KCNH2 protein complex. We have developed both homotetrameric and heterotetrameric kinetic models based on the heterologous expression of wild-type KCNH2 and/or C-terminus mutants in HEK293 cells, and incorporated defined deterministic and stochastic tetramerizations into the Luo-Rudy dynamic model. In comparison with WT homomeric channels, homomeric mutated channels showed a propensity to develop a shorter action potential duration (APD). As a consequence of the interplay between trafficking deficiency and altered kinetics a random tetramerization of WT and mutant subunits resulted in a marked prolongation of APD. These results suggest that stoichiometry of the KCNH2 channel protein complex may be a substrate for variable genetic penetrance in long QT syndrome.