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

Ivy E. Dick (), Rosy Joshi-Mukherjee, Wanjun Yang and David T. Yue
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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

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10370

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