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

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

Research output: Contribution to journalArticle

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 languageEnglish (US)
Article number10370
JournalNature Communications
Volume7
DOIs
StatePublished - Jan 29 2016

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deactivation
Defects
defects
arrhythmia
muscle cells
Muscle Cells
Calcium
Cardiac Arrhythmias
mutations
calcium
Missense Mutation
guinea pigs
prolongation
Action Potentials
Guinea Pigs
complement
Electric potential
induction
divergence
Mutation

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 journalArticle

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