Published online before print March 10, 2005, doi: 10.1161/01.RES.0000162101.76263.8c
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Submitted on November 17, 2004
Revised on February 7, 2005
Accepted on March 2, 2005
A Novel Form of Short QT Syndrome (SQT3) Is Caused by a Mutation in the KCNJ2 Gene
Silvia G. Priori *;
From the Molecular Cardiology (S.G.P., I.R., E.R., C.N., M.R.d.B.), IRCCS Fondazione Maugeri, Pavia, Italy; University of Pavia (S.G.P.), Pavia, Italy; Pediatric Cardiology Unit (G.B.), Department of Clinical and Experimental Medicine, University of Ferrara, Ferrara, Italy; Pediatric Arrhythmias Center (M.S.-B.), Istituto Auxologico Italiano IRCCS, Milan, Italy; and the Department of Pharmacology and Institute for Cardiovascular Research (S.V.P., O.B., A.D., J.A., S.G., J.J.), SUNY Upstate Medical University, Syracuse, NY.
* To whom correspondence should be addressed. E-mail: spriori{at}fsm.it.
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 between WT and 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 arrhythmias.
Key words: genetics • arrhythmias • ion channels • cellular electrophysiology
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