Spectrum of HERG K+-channel dysfunction in an inherited cardiac arrhythmia.

TLDR

Long QT syndrome (LQT) is an autosomal dominant disorder that can cause sudden death from cardiac arrhythmias. The study aims to define the mechanism of LQT by injecting oocytes with mutant HERG cRNAs, alone or with wild-type cRNA. The authors used heterologous expression of HERG in Xenopus oocytes, showing HERG current resembles IKr, and injected mutant HERG cRNAs (alone or with wild-type) to test how mutations affect IKr and action potential duration. Mutations in HERG cause chromosome 7‑linked LQT, with some leading to loss of function and others to dominant‑negative suppression, producing a spectrum of reduced IKr and delayed ventricular repolarization that matches the prolonged QT interval seen in patients.

Abstract

Long QT syndrome (LQT) is an autosomal dominant disorder that can cause sudden death from cardiac arrhythmias. We recently discovered that mutations in HERG, a K+-channel gene, cause chromosome 7-linked LQT. Heterologous expression of HERG in Xenopus oocytes revealed that HERG current was similar to a well-characterized cardiac delayed rectifier K+ current, IKr, and led to the hypothesis that mutations in HERG reduced IKr, causing prolonged myocellular action potentials. To define the mechanism of LQT, we injected oocytes with mutant HERG complementary RNAs, either singly or in combination with wild-type complementary RNA. Some mutations caused loss of function, whereas others caused dominant negative suppression of HERG function. These mutations are predicted to cause a spectrum of diminished IKr and delayed ventricular repolarization, consistent with the prolonged QT interval observed in individuals with LQT.