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

Area of Science:

• Cardiovascular Science
• Genetics
• Stem Cell Biology

Background:

• KCNH2 mutations cause long QT syndrome type 2, a condition with variable patient risk.
• Predicting disease severity is challenging due to mutation location and type influencing KCNH2 channel function.

Purpose of the Study:

• To investigate phenotypic differences in cardiomyocytes harboring KCNH2 mutations.
• To assess the utility of isogenic human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for modeling KCNH2 channelopathies.

Main Methods:

• Genetically engineered isogenic hiPSC-CMs with KCNH2 mutations in pore or tail regions.
• Performed electrophysiological analysis on monolayer hiPSC-CM cultures.
• Utilized hERG channel blockade to assess susceptibility to arrhythmias.

Main Results:

• hiPSC-CMs exhibited prolonged repolarization due to KCNH2 mutations, with distinct differences between mutation sites.
• The pore-loop mutation demonstrated increased susceptibility to arrhythmias upon hERG channel blockade.
• Subtle phenotypic variations were discernible in genetically matched hiPSC-CMs.

Conclusions:

• hiPSC-CMs effectively capture distinct phenotypes of KCNH2 mutations.
• This model system supports the evaluation of individual KCNH2 mutation severity.
• Findings facilitate improved patient risk stratification for long QT syndrome type 2.