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 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.
| Original language | English (US) |
|---|---|
| Article number | 10370 |
| Journal | Nature Communications |
| Volume | 7 |
| DOIs | |
| State | Published - Jan 29 2016 |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Chemistry(all)
- Physics and Astronomy(all)
Cite this
Arrhythmogenesis in Timothy Syndrome is associated with defects in Ca2+-dependent inactivation. / Dick, Ivy E.; Joshi-Mukherjee, Rosy; Yang, Wanjun; Yue, David T.
In: Nature Communications, Vol. 7, 10370, 29.01.2016.Research output: Contribution to journal › Article
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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.
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.
UR - http://www.scopus.com/inward/record.url?scp=84956601375&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84956601375&partnerID=8YFLogxK
U2 - 10.1038/ncomms10370
DO - 10.1038/ncomms10370
M3 - Article
C2 - 26822303
AN - SCOPUS:84956601375
VL - 7
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 10370
ER -