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Genetic basis and molecular mechanism for idiopathic ventricular fibrillation

Abstract

Ventricular fibrillation causes more than 300, 000 sudden deaths each year in the USA alone1,2. In approximately 5–12% of these cases, there are no demonstrable cardiac or non-cardiac causes to account for the episode, which is therefore classified as idiopathic ventricular fibrillation (IVF)3,4,5,6. A distinct group of IVF patients has been found to present with a characteristic electrocardiographic pattern7,8,9,10,11,12,13,14,15. Because of the small size of most pedigrees and the high incidence of sudden death, however, molecular genetic studies of IVF have not yet been done. Because IVF causes cardiac rhythm disturbance, we investigated whether malfunction of ion channels could cause the disorder by studying mutations in the cardiac sodium channel gene SCN5A. We have now identified 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 inactivation more rapidly than normal and that the frameshift mutation causes the sodium channel to be non-functional. Our results indicate that mutations in cardiac ion-channel genes contribute to the risk of developing IVF.

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Figure 1: SCN5A missense mutation co-segregating with IVF in family K005.
Figure 2: SCN5A splicing mutation in K007 and intragenic deletion in K2823.
Figure 3: Voltage-dependence of activation and inactivation, and time course of recovery from inactivation.
Figure 4: The predicted secondary structure of the cardiac sodium channel and locations of mutations causing IVF and chromosome-3-linked long-QT syn.

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Acknowledgements

We thank H. Hartmann for the wild-type SCN5A construct; M. Sanguinetti and P.Spector for help with electrophysiological analysis of the 1-bp deletion; and P. Szafranski, J. T. Bricker, M. Scheinman, A.L. Beaudet, A. Bradley and X. Qu for help and advice. This work ws supported by a Grant-In-Aid from the American Heart association, by the AHA, Northeast Ohio Affiliate (G.E.K.), and the Deutsche Forschungsgemeinschaft (E.S.-B.), and by grants from the NIH and Bristol-Myers Squibb (M.T.K.), The Texas Children's Hospital Foundation Chair in Pediatric Cardiac Research and NIH grants (J.A.T.), the Carolien Weiss Law Grant for Research in Molecular Medicine (Q.W.), the Abercrombie Cardiology Fund of Texas Children's Hospital (Q.W.), and a Scientist Development Award from the American Hearth Association (Q.W.).

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Correspondence to Qing Wang.

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Chen, Q., Kirsch, G., Zhang, D. et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 392, 293–296 (1998). https://doi.org/10.1038/32675

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