Pathogenic mechanism and gene correction for LQTS-causing double mutations in KCNQ1 using a pluripotent stem cell...

Area of Science:

• Cardiovascular Research
• Stem Cell Biology
• Genetics

Background:

• Inherited long QT syndrome (LQTS) is a cardiac arrhythmia disorder.
• KCNQ1 gene mutations are a common cause of LQTS.
• Understanding KCNQ1 mutation pathogenesis is crucial for developing effective treatments.

Purpose of the Study:

• To establish a patient-specific induced pluripotent stem cell (iPSC) model for Chinese inherited LQTS.
• To investigate the pathogenic mechanisms of KCNQ1 mutations using this iPSC model.

Main Methods:

• Generated patient-specific iPSC lines from an LQTS proband.
• Differentiated iPSCs into spontaneously beating cardiomyocytes (CMs).
• Utilized CRISPR-Cas9 gene editing for correction.

Main Results:

• KCNQ1 splicing mutations in iPSC-derived CMs led to exon skipping, mirroring findings in patient leukocytes.
• Patient-derived CMs exhibited prolonged action potential duration (APD) and early afterdepolarizations (EADs).
• CRISPR-Cas9 successfully corrected the mutation in a generated iPSC line.

Conclusions:

• Patient-specific iPSC-derived CMs effectively model KCNQ1-related LQTS.
• KCNQ1 splicing mutations likely decrease Iks current, causing APD prolongation and triggered arrhythmias.
• CRISPR-Cas9 gene editing presents a potential therapeutic strategy for LQTS.