Arrhythmogenic KCNE gene variants: current knowledge and future challenges

Abstract

There are twenty-five known inherited cardiac arrhythmia susceptibility genes, all of which encode either ion channel pore-forming subunits or proteins that regulate aspects of ion channel biology such as function, trafficking, and localization. The human KCNE gene family comprises five potassium channel regulatory subunits, sequence variants in each of which are associated with cardiac arrhythmias. KCNE gene products exhibit promiscuous partnering and in some cases ubiquitous expression, hampering efforts to unequivocally correlate each gene to specific native potassium currents. Likewise, deducing the molecular etiology of cardiac arrhythmias in individuals harboring rare KCNE gene variants, or more common KCNE polymorphisms, can be challenging. In this review we provide an update on putative arrhythmia-causing KCNE gene variants, and discuss current thinking and future challenges in the study of molecular mechanisms of KCNE-associated cardiac rhythm disturbances.

Keywords: Brugada Syndrome; Long QT Syndrome; MiRP; MinK-related peptide; atrial fibrillation.

Figure 1

KCNE subunits and the ventricular myocyte action potential. (A) Upper, transmembrane topology of Kv α and KCNE subunits with transmembrane segments numbered; lower, one suggested stoichiometry of a KCNE-containing Kv channel complex. Extracellular side is uppermost in each case. (B) Upper, a ventricular action potential waveform indicating the major ionic currents that contribute to its morphology and duration; lower, a human surface ECG waveform showing the QT interval.

Figure 2

Human KCNE1-KCNE5 protein sequence alignments and gene variants. Image of aligned sequences generated using http://www.uniprot.org/align. Colors highlight inherited or sporadic non-synonymous mutations or polymorphisms resulting in single amino acid changes (changes involving >1 amino acid are omitted). In cases where an amino acid substitution is associated with LQTS in addition to another arrhythmia, only the latter is color-coded (see Table S1 for full information). The predicted transmembrane domain for each subunit is outlined in red.