Referenced in: none

Automatically associated channels: Cav1.2

Title: Arrhythmogenesis in Timothy Syndrome is associated with defects in Ca(2+)-dependent inactivation.

Authors: Ivy E Dick, Rosy Joshi-Mukherjee, Wanjun Yang, David T Yue

Journal, date & volume: Nat Commun, 2016 , 7, 10370

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/26822303

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.