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Multiple mechanisms underlie increased cardiac late sodium current.

Brett M Kroncke1, Tao Yang2, Dan M Roden3

  • 1Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Heart Rhythm
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PubMed
Summary

The SCN5A R1193Q variant generates a late sodium current (INa-L) in human cardiomyocytes, but its mechanism differs from type 3 long QT syndrome mutations. This suggests that in vitro late current findings do not always predict severe arrhythmia phenotypes.

Keywords:
GeneticsHuman-induced pluripotent stem cell cardiomyocytesLQT3Late/persistent currentSCN5A/Na(V)1.5hiPSC-CMs

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Area of Science:

  • Cardiovascular Genetics
  • Molecular Cardiology
  • Ion Channel Physiology

Background:

  • SCN5A variants are linked to arrhythmia phenotypes, with some common variants like R1193Q showing functional perturbations.
  • Previously, a quantitative relationship was established between SCN5A variant functional perturbation and arrhythmia penetrance.

Purpose of the Study:

  • To compare the functional properties of the SCN5A R1193Q variant with the established type 3 long QT syndrome mutation, ΔKPQ.
  • To investigate the role of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) in modulating the late sodium current (INa-L) produced by these variants.

Main Methods:

  • Functional comparison of SCN5A R1193Q and ΔKPQ in Chinese hamster ovary (CHO) cells, with and without PIP3.
  • Generation of R1193Q variants in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) using CRISPR/Cas9 editing.

Main Results:

  • Both R1193Q and ΔKPQ produced significant late sodium current (INa-L) in CHO cells.
  • PIP3 abolished the INa-L in R1193Q cells but not in ΔKPQ cells.
  • Homozygous R1193Q hiPSC-CMs exhibited increased INa-L, prolonged action potentials, and triggered beats, which were reversed by PIP3.

Conclusions:

  • The late current observed for SCN5A R1193Q in vitro is consistent across different cell types, suggesting it's a feature of the variant in human cardiomyocytes.
  • The mechanism underlying the R1193Q-associated late current is distinct and indirect compared to the ΔKPQ mutation.
  • In vitro detection of a late current does not automatically equate to a highly pathogenic type 3 long QT syndrome phenotype; the underlying mechanism is critical.