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

Nature volume 400, pages 566–569 (1999)Cite this article

Abstract

Advances in genetics and molecular biology have provided an extensive body of information on the structure and function of the elementary building blocks 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 function1,2,3. As ion-channel defects are typically studied in isolated expression systems, away from the cellular environment where they function physiologically, a connection between molecular findings and the physiology and pathophysiology of the cell is rarely established. Here we describe a single-channel-based Markovian modelling approach that bridges this gap. We achieve this by determining the cellular arrhythmogenic consequences of a mutation in the cardiac sodium channel that can lead to a clinical arrhythmogenic disorder (the long-QT syndrome) and sudden cardiac death.

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Figure 1: Markovian models of sodium channels.
Figure 2: Single-channel properties of WT and mutant I Na.
Figure 3: Macroscopic WT and mutant I Na.
Figure 4: Effect of ΔKPQ mutation on the whole-cell action potential.

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Acknowledgements

We thank P. Bennett and A. Grant for providing us with original figures from their experimental publications. This work was supported by the NIH-National Heart, Lung and Blood Institute and The Whitaker Foundation.

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Authors and Affiliations

  1. Cardiac Bioelectricity Research and Training Center,

    Colleen E. Clancy & Yoram Rudy

  2. Department of Biomedical Engineering,

    Yoram Rudy

  3. Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, 44106-7207, Ohio, USA

    Colleen E. Clancy & Yoram Rudy

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  1. Colleen E. Clancy
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  2. Yoram Rudy
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Correspondence to Yoram Rudy.

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Clancy, C., Rudy, Y. Linking a genetic defect to its cellular phenotype in a cardiac arrhythmia. Nature 400, 566–569 (1999). https://doi.org/10.1038/23034

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