TY - JOUR
T1 - Arrhythmogenesis in Timothy Syndrome is associated with defects in Ca2+-dependent inactivation
AU - Dick, Ivy E.
AU - Joshi-Mukherjee, Rosy
AU - Yang, Wanjun
AU - Yue, David T.
N1 - Funding Information:
We have had the incredible fortune to have worked under the caring guidance of Dr David T. Yue. David was an exceptional teacher, a thoughtful advisor and a true friend. His passion and excitement for science was infectious and he inspired each of us to always search for truth. The loss of our beloved mentor has left an immense hole in our hearts and in the ion channel field. We will cherish the memories, wisdom and wonder of David Yue for the rest of our lives. We thank Dr Ye Chen-Izu (UC Davis) for generously loaning the flash lamp and Dr Leslie Tung for kind support and use of his optical mapping setup. We also thank Dr Gordon Tomaselli for generously providing the lentiviral vectors as well as for helpful discussion and feedback throughout the project and Dr Brian O’Rourke for assistance and use of his laboratory for myocyte isolations. We thank Dr Michael Tadross and members of the CSL lab for helpful feedback and comments. This work was supported by NHLBI and NIMH (to DTY), and a Kirchstein NRSA Fellowship (to IED).
PY - 2016/1/29
Y1 - 2016/1/29
N2 - 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 Ca V 1.2 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.
AB - 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 Ca V 1.2 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.
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U2 - 10.1038/ncomms10370
DO - 10.1038/ncomms10370
M3 - Article
C2 - 26822303
AN - SCOPUS:84956601375
SN - 2041-1723
VL - 7
JO - Nature communications
JF - Nature communications
M1 - 10370
ER -