April 1, 1999Cell1,359 citationsOpen Access
MiRP1 Forms IKr Potassium Channels with HERG and Is Associated with Cardiac Arrhythmia
Key Result
Missense mutations in the MiRP1 gene diminish potassium currents and are associated with long QT syndrome and ventricular fibrillation, revealing a mechanism for acquired arrhythmia.
Structured PICO
P
Population
Preclinical models studying the MiRP1 gene, which encodes a small integral membrane subunit that assembles with HERG, and its mutations associated with long QT syndrome and ventricular fibrillation.
E
Exposure
Expression of mutant MiRP1 (three missense mutations) and exposure to clarithromycin or E-4031.
C
Comparator
Expression of wild-type MiRP1 with HERG, or HERG alone.
O
Outcome
Electrophysiological properties of the potassium channels (gating, unitary conductance, regulation by potassium, and inhibition by E-4031 or clarithromycin).surrogate
The discovery of MiRP1 and its mutations provides a genetic mechanism for both congenital and acquired (drug-induced) cardiac arrhythmias via reduced potassium currents.
Abstract
A novel potassium channel gene has been cloned, characterized, and associated with cardiac arrhythmia. The gene encodes MinK-related peptide 1 (MiRP1), a small integral membrane subunit that assembles with HERG, a pore-forming protein, to alter its function. Unlike channels formed only with HERG, mixed complexes resemble native cardiac IKr channels in their gating, unitary conductance, regulation by potassium, and distinctive biphasic inhibition by the class III antiarrhythmic E-4031. Three missense mutations associated with long QT syndrome and ventricular fibrillation are identified in the gene for MiRP1. Mutants form channels that open slowly and close rapidly, thereby diminishing potassium currents. One variant, associated with clarithromycin-induced arrhythmia, increases channel blockade by the antibiotic. A mechanism for acquired arrhythmia is revealed: genetically based reduction in potassium currents that remains clinically silent until combined with additional stressors.