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

Abstract

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 (I Kr ) channel, and SQT2, caused by a gain of function substitution in the KvLQT1 (I Ks ) 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 (I K1 ) 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 I K1 than the wild-type (PϽ0.05) at potentials between Ϫ75 mV and Ϫ45 mV, with the peak current being shifted in the former with respect to the latter (WT, Ϫ75 mV; D172N, Ϫ65 mV). Coexpression of WT and mutant channels to mimic the heterozygous condition of the proband yielded an outward current that was intermediate between WT and D172N. In computer simulations using a human ventricular myocyte model the increased outward I K1 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 arrhythmias. (Circ Res. 2005;96:800-807.)

KCNJ2 mutation in short QT syndrome 3 results in atrial fibrillation and ventricular proarrhythmia

“…Mutations found in SQTS patients in the genes encoding potassium channels cause "gain of function," whereas mutations found in the alpha 1C subunit of the voltage-dependent L-type Ca + channel (CACNA1C), the beta 2b subunit of the voltage dependent Ca 2+ channel (CACNB2B) and the alpha2/delta subunit 1 of the voltage dependent Ca 2+ channel (CACNA2D1) cause "loss of function" (1,2). In 2005, we reported a mutation (D172N) in the strong inward rectifier K + channel protein (Kir2.1), which is coded by KCNJ2, in an SQTS patient: Functional characterization revealed that D172N shows an increased outward component of the inward rectifier current I K1 (3). Computer simulation demonstrated that D172N leads to a shortening of the QT interval and predisposes the heart to develop reentrant arrhythmias.…”

Turbulent electrical activity at sharp-edged inexcitable obstacles in a model for human cardiac tissue

“…These currents are major determinants of action potential shape and are targets of antiarrhythmic drugs of class I (Na ϩ channel blockers), class III (K ϩ channel blockers), and class IV (Ca 2ϩ channel blockers) (75). These currents are also changed during various cardiac pathologies, e.g., long and short QT syndromes (30,41,52). Figure 4, A-E, illustrate the dependence of T critical and T spiral on the values of G Na , G Ca , G K1 , G Kr , and G Ks , respectively, expressed as percentages of their original values.…”

Pharmacological approach to the treatment of long and short QT syndromes

“…SQT2 is a mirror image of LQT1, with the mutation in KCNQ1 leading to a gain of function of I Ks in SQT2, but to a loss of function in LQT1. Similarly, a gain of function mutation in KCNJ2 was identified by Priori et al (2005) in a familial setting in an asymptomatic 5 year old child and 35 year old father who showed extremely short QT interval on ECG. Heterologous expression of the mutant channel showed that the genetic mutation caused a significant augmentation of I K1 responsible for abbreviation of action potential and QT interval.…”

“…Similar to LQTS, SQTS is also genetically heterogeneous disease and thus far mutations in five different genes (Table 1) encoding different cardiac ion channels located on chromosome 7, 10, 11, 12 and 17 have been identified, and the corresponding syndromes have been termed SQT1 to SQT5 depending of chronology of discovery (Brugada et al, 2004;Bellocq et al, 2004;Priori et al, 2005;Antzelevitch et al, 2007). Interestingly, four of those genes are the same as those involved in LQTS; however mutations leading to SQTS have the net effect of increasing rather than decreasing depolarizing forces.…”