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Arrhythmogenesis in Timothy Syndrome is associated with defects in Ca2+-dependent inactivation

Author

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  • Ivy E. Dick

    (Calcium Signals Laboratory, The Johns Hopkins University School of Medicine)

  • Rosy Joshi-Mukherjee

    (Calcium Signals Laboratory, The Johns Hopkins University School of Medicine)

  • Wanjun Yang

    (Calcium Signals Laboratory, The Johns Hopkins University School of Medicine)

  • David T. Yue

    (Calcium Signals Laboratory, The Johns Hopkins University School of Medicine)

Abstract

Timothy Syndrome (TS) is a multisystem disorder, prominently featuring cardiac action potential prolongation with paroxysms of life-threatening arrhythmias. The underlying defect is a single de novo missense mutation in CaV1.2 channels, either G406R or G402S. Notably, these mutations are often viewed as equivalent, as they produce comparable defects in voltage-dependent inactivation and cause similar manifestations in patients. Yet, their effects on calcium-dependent inactivation (CDI) have remained uncertain. Here, we find a significant defect in CDI in TS channels, and uncover a remarkable divergence in the underlying mechanism for G406R versus G402S variants. Moreover, expression of these TS channels in cultured adult guinea pig myocytes, combined with a quantitative ventricular myocyte model, reveals a threshold behaviour in the induction of arrhythmias due to TS channel expression, suggesting an important therapeutic principle: a small shift in the complement of mutant versus wild-type channels may confer significant clinical improvement.

Suggested Citation

  • Ivy E. Dick & Rosy Joshi-Mukherjee & Wanjun Yang & David T. Yue, 2016. "Arrhythmogenesis in Timothy Syndrome is associated with defects in Ca2+-dependent inactivation," Nature Communications, Nature, vol. 7(1), pages 1-12, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10370
    DOI: 10.1038/ncomms10370
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