A Novel Form of Short QT Syndrome (SQT3) Is Caused by a Mutation in the KCNJ2 Gene

Short QT syndrome (SQTS) leads to an abbreviated QTc interval and predisposes patients to life-threatening arrhythmias. To date, two forms of the disease have been identified: SQT1, caused by a gain of function substitution in the HERG (IKr) channel, and SQT2, caused by a gain of function substitution in the KvLQT1 (IKs) channel. Here we identify a new variant, “SQT3”, which has a unique ECG phenotype characterized by asymmetrical T waves, and a defect in the gene coding for the inwardly rectifying Kir2.1 (IK1) channel. The affected members of a single family had a G514A substitution in the KCNJ2 gene that resulted in a change from aspartic acid to asparagine at position 172 (D172N). Whole-cell patch-clamp studies of the heterologously expressed human D172N channel demonstrated a larger outward IK1 than the wild-type (P<0.05) at potentials between −75 mV and −45 mV, with the peak current being shifted in the former with respect to the latter (WT, −75 mV; D172N, −65 mV). Coexpression of WT and mutant chann...