Ion channel messenger RNA processing defects and arrhythmia

Abstract:

Messenger RNA (mRNA) processing is an essential step for the expression of most eukaryote genes. Ion channels are critical for proper electrical activity in the heart, and perturbations of these channels are known to cause arrhythmia. Recently, mRNA processing defects have been shown to contribute to altered ion channel activity and arrhythmogenesis. Abnormal pre-mRNA splicing of cardiac ion channels, including the cardiac sodium channel, potassium channels, and calcium channels, because of mutations of the cis-elements within the RNA or abnormal expression of splicing factors, has been documented to contribute to arrhythmic risk. In addition to pre-mRNA splicing, other mRNA processing events, such as 3′-end formation and mRNA turnover, are also disrupted in cardiac diseases, such as congenital heart disease caused by mutation at the 3′-untranslated region of GATA4. mRNA stability is also dysregulated by altered expression of microRNAs in atrial fibrillation. In this review, we discuss our current understanding of how mRNA processing defects contribute to the risk of arrhythmias and how monitoring the products of abnormal processing may lead to diagnostic tests for arrhythmic risk.

Keywords::

• messenger RNA
• arrhythmia
• sudden death
• ion channels
• biomarkers

Acknowledgments

This work was funded by National Institutes of Health grants RO1 HL104025 (SCD) and HL106592 (SCD), and a Veterans Affairs MERIT grant BX000859 (SCD).

Disclosure

SCD is the inventor in the following patent applications: SCN5A Splice Variants for Use in Methods Relating to Sudden Cardiac Death and Need for Implanted Cardiac Defibrillators, PCT/US2012/20564 and SCN5A Splicing Factors and Splice Variants for Use in Diagnostic and Prognostic Methods, 13/291,826. The authors declare no other conflicts of interest in this work.