Mutation location matters in long QT syndrome type 2 (but behavior matters more)

Abstract

The KCNH2 (hERG) gene is responsible for the major (a) protein subunit of the rapidly activating delayed rectifier K + current (IKr) channel, which provides an essential repolarizing current in cardiac myocytes. Patients with mutations in KCNH2 have long QT syndrome type 2 and, depending on the tremendous variability in expression resulting from the complex variations in the rest of their genome, may present as phenotypically normal or may have QT prolongation with or without symptoms of syncope or cardiac arrest from torsades de pointes ventricular tachycardia. In order to form a functional IKr channel, the protein subunits must undergo glycosylation in the endoplasmic reticulum, coassemble into tetramers, and traffic to the cell membrane. Intracellular “quality-control” machinery can recognize abnormally folded/glycosylated proteins and prevent trafficking to the cell membrane. For the most part, mutations in the nonpore part of KCNH2 cause failure of mutant subunits to coassemble and traffic to the membrane, leaving heterozygous individuals with half the usual number of IKr channels (haplotype insufficiency). 1 In contrast, patients with muta