Rescue of Mutated Cardiac Ion Channels in Inherited Arrhythmia Syndromes

Abstract

Inherited arrhythmia syndromes comprise an increasingly complex group of diseases involving mutations in multiple genes encoding ion channels, ion channel accessory subunits and channel interacting proteins, and various regulatory elements. These mutations serve to disrupt normal electrophysiology in the heart, leading to increased arrhythmogenic risk and death. These diseases have added impact as they often affect young people, sometimes without warning. Although originally thought to alter ion channel function, it is now increasingly recognized that mutations may alter ion channel protein and messenger RNA processing, to reduce the number of channels reaching the surface membrane. For many of these mutations, it is also known that several interventions may restore protein processing of mutant channels to increase their surface membrane expression toward normal. In this article, we reviewed inherited arrhythmia syndromes, focusing on long QT syndrome type 2, and discuss the complex biology of ion channel trafficking and pharmacological rescue of disease-causing mutant channels. Pharmacological rescue of misprocessed mutant channel proteins, or their transcripts providing appropriate small molecule drugs can be developed, has the potential for novel clinical therapies in some patients with inherited arrhythmia syndromes.