Linking a genetic defect to its cellular phenotype in a cardiac arrhythmia

Advances in genetics and molecular biology have provided an extensive body of information on the structure and function of the elementary building blo cks of living systems. Genetic defects in membrane ion channels can disrupt the delicate balance of dynamic interactions between the ion channels and the cellular environment, leading to altered cell function(1-3). As ion-cha nnel defects are typically studied in isolated expression systems, away fro m the cellular environment where they function physiologically, a connectio n between molecular findings and the physiology and pathophysiology of the cell is rarely established. Here we describe a single-channel-based Markovi an modelling approach that bridges this gap. We achieve this by determining the cellular arrhythmogenic consequences of a mutation in the cardiac sodi um channel that can lead to a clinical arrhythmogenic disorder (the long-QT syndrome) and sudden cardiac death.