4.6 Article

hiPSC-Derived Cardiomyocyte Model of LQT2 Syndrome Derived from Asymptomatic and Symptomatic Mutation Carriers Reproduces Clinical Differences in Aggregates but Not in Single Cells

期刊

CELLS
卷 9, 期 5, 页码 -

出版社

MDPI
DOI: 10.3390/cells9051153

关键词

HERG; LQT2; channelopathies; in vitro electrophysiology; arrhythmia; induced pluripotent stem cells; in-silico modeling

资金

  1. Finnish National Agency for Education
  2. Pirkanmaa regional fund of the Finnish Cultural Foundation
  3. Aarne Koskelo foundation
  4. Paavo Nurmi foundation
  5. Paivikki, Sakari Sohlberg foundation
  6. Yrjo Jahnsson foundation
  7. Finnish Cardiovascular foundation
  8. Academy of Finland
  9. Pirkanmaa Hospital District
  10. Sigrid Juselius Foundation

向作者/读者索取更多资源

Mutations in the HERG gene encoding the potassium ion channel HERG, represent one of the most frequent causes of long QT syndrome type-2 (LQT2). The same genetic mutation frequently presents different clinical phenotypes in the family. Our study aimed to model LQT2 and study functional differences between the mutation carriers of variable clinical phenotypes. We derived human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) from asymptomatic and symptomatic HERG mutation carriers from the same family. When comparing asymptomatic and symptomatic single LQT2 hiPSC-CMs, results from allelic imbalance, potassium current density, and arrhythmicity on adrenaline exposure were similar, but a difference in Ca2+ transients was observed. The major differences were, however, observed at aggregate level with increased susceptibility to arrhythmias on exposure to adrenaline or potassium channel blockers on CM aggregates derived from the symptomatic individual. The effect of this mutation was modeled in-silico which indicated the reactivation of an inward calcium current as one of the main causes of arrhythmia. Our in-vitro hiPSC-CM model recapitulated major phenotype characteristics observed in LQT2 mutation carriers and strong phenotype differences between LQT2 asymptomatic vs. symptomatic were revealed at CM-aggregate level.

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