GENETIC-BASIS AND MOLECULAR MECHANISM FOR IDIOPATHIC - VENTRICULAR-FIBRILLATION

Ventricular fibrillation causes more than 300,000 sudden deaths each y ear in the USA alone(1,2). In approximately 5-12% of these cases, ther e are no demonstrable cardiac or non-cardiac causes to account for the episode, which is therefore classified as idiopathic ventricular fibr illation (IVF)(3-6). A distinct group of IVF patients has been found t o present with a characteristic electrocardiographic pattern(7-15). Be cause of the small size of most pedigrees and the high incidence of su dden death, however, molecular genetic studies of NF have not yet been done. Because IVF causes cardiac rhythm disturbance, we investigated whether malfunction of ion channels could cause the disorder by studyi ng mutations in the cardiac sodium channel gene SCN5A. We have now ide ntified a missense mutation, a splice-donor mutation, and a frameshift mutation in the coding region of SCN5A in three IVF families. We show that sodium channels with the missense mutation recover from inactiva tion more rapidly than normal and that the frameshift mutation causes the sodium channel to be non-functional. Our results indicate that mut ations in cardiac ion-channel genes contribute to the risk of developi ng IVF.