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Arrhythmogenesis in Timothy Syndrome is associated with defects in Ca(2+)-dependent inactivation
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Arrhythmogenesis in Timothy Syndrome is associated with defects in Ca(2+)-dependent inactivation
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Journal Article
Arrhythmogenesis in Timothy Syndrome is associated with defects in Ca(2+)-dependent inactivation
2016
Overview
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.
Subject
/ Arrhythmias, Cardiac - genetics
/ Arrhythmias, Cardiac - metabolism
/ Autistic Disorder - genetics
/ Autistic Disorder - metabolism
/ Calcium Channels, L-Type - genetics
/ Calcium Channels, L-Type - metabolism
/ Female
/ Humans
/ Long QT Syndrome - metabolism
/ Male
