2 research outputs found
A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene.
Abstract—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 channels to mimic the heterozygous condition of the proband
yielded an outward current that was intermediate betweenWTand D172N. In computer simulations using a human ventricular
myocyte model the increased outward IK1 greatly accelerated the final phase of repolarization and shortened the action
potential duration. Hence, unlike the known mutations in the two other SQTS forms (N588K in HERG and V307L in
KvLQT1), simulations using the D172N and WT/D172N mutations fully accounted for the ECG phenotype of tall and
asymmetrically shaped T waves. Although we were unable to test for inducibility of arrhythmia susceptibility due to lack of
patients’ consent, our computer simulations predict a steeper steady-state restitution curve for the D172N and WT/D172N
mutation, compared with WT or to HERG or KvLQT1 mutations, which may predispose SQT3 patients to a greater risk of
reentrant arrhythmia