Isogenic Sets of hiPSC-CMs Harboring Distinct KCNH2 Mutations Differ Functionally and in Susceptibility to Drug-Induced Arrhythmias

Karina O. Brandão, Lettine van den Brink, Duncan C. Miller, Catarina Grandela, Berend J. van Meer, Mervyn P.H. Mol, Tessa de Korte, Leon G.J. Tertoolen, Christine L. Mummery, Luca Sala, Arie O. Verkerk, Richard P. Davis

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations in KCNH2 can lead to long QT syndrome type 2. Variable disease manifestation observed with this channelopathy is associated with the location and type of mutation within the protein, complicating efforts to predict patient risk. Here, we demonstrated phenotypic differences in cardiomyocytes derived from isogenic human induced pluripotent stem cells (hiPSC-CMs) genetically edited to harbor mutations either within the pore or tail region of the ion channel. Electrophysiological analysis confirmed that the mutations prolonged repolarization of the hiPSC-CMs, with differences between the mutations evident in monolayer cultures. Blocking the hERG channel revealed that the pore-loop mutation conferred greater susceptibility to arrhythmic events. These findings showed that subtle phenotypic differences related to KCNH2 mutations could be captured by hiPSC-CMs under genetically matched conditions. Moreover, the results support hiPSC-CMs as strong candidates for evaluating the underlying severity of individual KCNH2 mutations in humans, which could facilitate patient risk stratification.

Original languageEnglish
Pages (from-to)1127-1139
Number of pages13
JournalStem Cell Reports
Volume15
Issue number5
DOIs
Publication statusPublished - Nov 10 2020

Keywords

  • arrhythmia
  • disease modeling
  • electrophysiology
  • genome editing
  • induced pluripotent stem cells
  • isogenic
  • long QT syndrome 2
  • risk stratification

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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