Computational Study on Effect of KCNQ1 P535T Mutation in a Cardiac Ventricular Tissue

• Published in: The Journal of membrane biology 2023-06, Vol.256 (3), p.287-297
• Main Authors: Satish, Helan, Machireddy, Ramasubba Reddy
• Format: Article
• Language: English
• Subjects: Action potential; Arrhythmia; Biochemistry; Biomedical and Life Sciences; Cardiac arrhythmia; Chemical damage; Coronary artery disease; EKG; Genes; Genotypes; Heart diseases; Human Physiology; Humans; Ion channels; Jervell and Lange-Nielsen syndrome; Jervell-Lange Nielsen Syndrome - genetics; KCNQ Potassium Channels - genetics; KCNQ1 Potassium Channel - genetics; KCNQ1 protein; Life Sciences; Long QT syndrome; Long QT Syndrome - genetics; Mutation; Point mutation; Potassium; Potassium Channels; Potassium channels (voltage-gated); Romano-Ward Syndrome - genetics; Torsades de pointes; Ventricle
• ISSN: 0022-2631; 1432-1424
• DOI: 10.1007/s00232-023-00287-9

Heart diseases such as arrhythmia are the main causes of sudden death. Arrhythmias are typically caused by mutations in specific genes, damage in the cardiac tissue, or due to some chemical exposure. Arrhythmias caused due to mutation is called inherited arrhythmia. Induced arrhythmias are caused due to tissue damage or chemical exposure. Mutations in genes that encode ion channels of the cardiac cells usually result in (dysfunction) improper functioning of the channel. Improper functioning of the ion channel may lead to major changes in the action potential (AP) of the cardiac cells. This further leads to distorted electrical activity of the heart. Distorted electrical activity will affect the ECG that results in arrhythmia. KCNQ1 P535T mutation is one such gene mutation that encodes the potassium ion channel (KV7.1) of the cardiac ventricular tissue. Its clinical significance is not known. This study aims to perform a simulation study on P535T mutation in the KCNQ1 gene that encodes the potassium ion channel KV7.1 in the ventricular tissue grid. The effect of P535T mutation on transmural tissue grids for three genotypes (wild type, heterozygous, and homozygous) of cells are studied and the generated pseudo-ECGs are compared. Results show the delayed repolarization in the cells of ventricular tissue grid. Slower propagation of action potential in the transmural tissue grid is observed in the mutated (heterozygous and homozygous) genotypes. Longer QT interval is also observed in the pseudo-ECG of heterozygous and homozygous genotype tissue grids. From the pseudo-ECGs, it is observed that KCNQ1 P535T mutation leads to Long QT Syndrome (LQTS) which may result in life-threatening arrhythmias, such as Torsade de Pointes (TdP), Jervell and Lange–Nielsen syndrome (JLNS), and Romano–Ward syndrome (RWS). Graphical abstract