Genetic basis and molecular mechanism for idiopathic ventricular fibrillation (original) (raw)

Nature volume 392, pages 293–296 (1998)Cite this article

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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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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Author notes

  1. Qiuyun Chen, Glenn E. Kirsch and Jeffrey A. Towbin: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics (Cardiology), Baylor College of Medicine, Houston, 77030, Texas, USA
    Qiuyun Chen, Danmei Zhang, Rocio Ortiz-Lopez, Richard E. O'Brien, Jeffrey A. Towbin & Qing Wang
  2. Medicine (Cardiology), Baylor College of Medicine, Houston, 77030, Texas, USA
    Ramon Brugada
  3. Cardiovasascular Sciences, Baylor College of Medicine, Houston, 77030, Texas, USA
    Zhiqing Wang & Jeffrey A. Towbin
  4. Molecular and Human Genetics, Baylor College of Medicine, Houston, 77030, Texas, USA
    Jeffrey A. Towbin
  5. The Rammelkamp Center for Research, MetroHealth Campus, Case Western Reserve University, Cleveland, 44109, Ohio, USA
    Glenn E. Kirsch
  6. Arrhythmia Unit, Cardiovascular Institute, Hospital Clinic, University of Barcelona, 08036, Barcelona, Spain
    Josep Brugada
  7. The Cardiovascular Center, OLV Hospital, 9300, Aalst, Belgium
    Pedro Brugada
  8. Cardiology Department, IRCCS Casa Sollievo della Sofferenza, S. Giovanni, Rotondo, Italy
    Domenico Potenza
  9. Department of Cardiology, Hospital Vall d'Hebron, 08020, Barcelona, Spain
    Angel Moya
  10. Department of Cardiology and Angiology, Institute of Arteriosclerosis Research, Hospital of the University of Munster, D48129, Munster, Germany
    Martin Borggrefe, Günter Breithardt & Eric Schulze-Bahr
  11. Masonic Medical Research Laboratory, Utica, 13504, New York, USA
    Charles Antzelevitch
  12. Department of Human Genetics and Medicine, Howard Hughes Medical Institute, University of Utah, Salt Lake City, 84112, Utah, USA
    Mark T. Keating

Authors

  1. Qiuyun Chen
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  2. Glenn E. Kirsch
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  3. Danmei Zhang
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  4. Ramon Brugada
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  5. Josep Brugada
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  6. Pedro Brugada
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  7. Domenico Potenza
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  8. Angel Moya
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  9. Martin Borggrefe
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  10. Günter Breithardt
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  11. Rocio Ortiz-Lopez
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  12. Zhiqing Wang
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  13. Charles Antzelevitch
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  14. Richard E. O'Brien
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  15. Eric Schulze-Bahr
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  16. Mark T. Keating
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  17. Jeffrey A. Towbin
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  18. Qing Wang
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Corresponding author

Correspondence toQing 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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