Mission possible: RNA interference rescues the hERG current

Abstract

The congenital long QT syndrome (LQTS) is an inherited disease that causes cardiac arrhythmias and sudden cardiac death in the absence of evident structural heart defects. It is mainly attributed to genetic mutations that affect the function of ion channels that regulate the action potential waveform. LQTS is characterized by an abnormal prolongation of cardiac repolarization, leading to an increased QT interval, notched or biphasic T waves, and T-wave alternans. Affected patients are at a higher risk for developing arrhythmias, including polymorphic ventricular tachycardia, torsades de pointes, and ventricular fibrillation. The estimated prevalence of LQTS (based on electrocardiographic-guided identification of disease-causing mutations among whites) is approximately 1:2500 in apparently healthy live births. LQTS was initially described in the Jervell and Lange-Nielsen syndrome, where QT prolongation and deafness were present. A few years later, an autosomal dominant form of LQTS, in the absence of deafness, was reported. During the last decade, 13 LQTS variants have been described. Mutations in KCNQ1, KCNH2, and SCN5A genes account for approximately 90% of the positivegenotype cases of LQTS and underlie LQTS1, LQTS2, and LQTS3. Those genes encode Kv7.1, Kv11.1, and Nav1.5, respectively. Genetic analyses have identified more than 200 LQTS2causing mutations in KCNH2. Missense mutations leading to single amino acid substitutions in hERG (human ethera-gogo-related gene) protein—the alpha subunit of the rapid delayed rectifier current (IKr)—are the predominant abnormality. At the functional level, these mutations result in a decreased IKr. 11 It has been shown that LQTS2 mutations reduce IKr through a variety of mechanisms including aberrant hERG protein folding, trafficking, or ion-channel gating. Although not all identified mutations have been investigated, the majority of the mutations produce failure of the hERG subunits to exit the endoplasmic