Overlap Arrhythmia Syndromes Resulting from Multiple Genetic Variations Studied in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Int J Mol Sci. 2021 Jul 1;22(13):7108. doi: 10.3390/ijms22137108.


Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for genetic models of cardiac diseases. We report an arrhythmia syndrome consisting of Early Repolarization Syndrome (ERS) and Short QT Syndrome (SQTS). The index patient (MMRL1215) developed arrhythmia-mediated syncope after electrocution and was found to carry six mutations. Functional alterations resulting from these mutations were examined in patient-derived hiPSC-CMs. Electrophysiological recordings were made in hiPSC-CMs from MMRL1215 and healthy controls. ECG analysis of the index patient showed slurring of the QRS complex and QTc = 326 ms. Action potential (AP) recordings from MMRL1215 myocytes showed slower spontaneous activity and AP duration was shorter. Field potential recordings from MMRL1215 hiPSC-CMs lack a "pseudo" QRS complex suggesting reduced inward current(s). Voltage clamp analysis of ICa showed no difference in the magnitude of current. Measurements of INa reveal a 60% reduction in INa density in MMRL1215 hiPSC-CMs. Steady inactivation and recovery of INa was unaffected. mRNA analysis revealed ANK2 and SCN5A are significantly reduced in hiPSC-CM derived from MMRL1215, consistent with electrophysiological recordings. The polygenic cause of ERS/SQTS phenotype is likely due to a loss of INa due to a mutation in PKP2 coupled with and a gain of function in IK,ATP due to a mutation in ABCC9.

Keywords: action potentials; depolarization; electrophysiology; sodium current; stem cells.

MeSH terms

  • Action Potentials / genetics
  • Adenosine Triphosphate / metabolism
  • Ankyrins / genetics
  • Ankyrins / metabolism
  • Arrhythmias, Cardiac / genetics*
  • Arrhythmias, Cardiac / physiopathology
  • Electrophysiological Phenomena
  • Genetic Variation / genetics
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / physiology
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / physiology
  • NAV1.5 Voltage-Gated Sodium Channel / genetics
  • NAV1.5 Voltage-Gated Sodium Channel / metabolism
  • Patch-Clamp Techniques / methods
  • Plakophilins / genetics
  • Potassium / metabolism
  • Sodium / metabolism
  • Sulfonylurea Receptors / genetics


  • ABCC9 protein, human
  • ANK2 protein, human
  • Ankyrins
  • NAV1.5 Voltage-Gated Sodium Channel
  • PKP2 protein, human
  • Plakophilins
  • SCN5A protein, human
  • Sulfonylurea Receptors
  • Adenosine Triphosphate
  • Sodium
  • Potassium

Supplementary concepts

  • Short Qt Syndrome