Functional Suppression of Sodium Channels by β1-Subunits as a Molecular Mechanism of Idiopathic Ventricular Fibrillation

Ventricular fibrillation leading to sudden cardiac death can occur even in the absence of structural heart disease. One form of this so-called idiopathic ventricular fibrillation (IVF) is characterized by ST segment elevation (STE) in the electrocardiogram. Recently we found that IVF with STE is linked to mutations of SCN5A, the gene encoding the cardiac sodium channel α -subunit. Two types of defects were identified: loss-of-function mutations that severely truncate channel proteins and missense mutations (e.g. a double mutation, R1232W and T1620M) that cause only minor changes in channel gating. Here we show that co-expression of the R1232W+T1620M missense mutant α -subunits in a mammalian cell line stably transfected with human sodium channel β1-subunits results in a phenotype similar to that of the truncation mutants. In the presence of β1subunits the expression of both ionic currents andα -subunit-specific, immunoreactive protein was markedly suppressed after transfection of mutant, but not wild-typeα -subunits when cells were incubated at physiological temperature. Expression was partially restored by incubation at reduced temperatures. Our results reconcile two classes of IVF mutations and support the notion that a reduction in the amplitude of voltage-gated sodium conductance is the primary cause of IVF.