BACKGROUND: Andersen-Tawil syndrome (ATS) is a rare inherited disorder, 
characterised by periodic paralysis, cardiac dysarrhythmias, and dysmorphic 
features, and is caused by mutations in the gene KCNJ2, which encodes the inward 
rectifier potassium channel, Kir2.1. This study sought to analyse KCNJ2 in 
patients with familial ATS and to determine the functional characteristics of 
the mutated gene.
METHODS AND RESULTS: We screened a family with inherited ATS for the mutation in 
KCNJ2, using direct DNA sequencing. A missense mutation (T75R) of Kir2.1, 
located in the highly conserved cytoplasmic N-terminal domain, was identified in 
three affected members of this family. Using the Xenopus oocyte expression 
system and whole cell voltage clamp analyses, we found that the T75R mutant was 
non-functional and possessed a strong dominant negative effect when co-expressed 
with the same amount of wild type Kir2.1. Transgenic (Tg) mice expressing the 
mutated form of Kir2.1 in the heart had prolonged QTc intervals compared with 
mice expressing the wild type protein. Ventricular tachyarrhythmias were 
observed in 5 of 14 T75R-Tg mice compared with 1 of 7 Wt-Tg and none of 6 
non-transgenic littermates. In three of five T75R-Tg mice with ventricular 
tachycardia, their ECG disclosed bidirectional tachycardia as in our proband.
CONCLUSIONS: The in vitro studies revealed that the T75R mutant of Kir2.1 had a 
strong dominant negative effect in the Xenopus oocyte expression system. It 
still preserved the ability to co-assemble and traffic to the cell membrane in 
mammalian cells. For in vivo studies, the T75R-Tg mice had bidirectional 
ventricular tachycardia after induction and longer QT intervals.