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Abstract
Patients with short QT syndrome (SQTS) may present with syncope, ventricular fibrillation or sudden cardiac death. Six SQTS susceptibility genes, encoding cation channels, explain <25% of SQTS cases. Here we identify a missense mutation in the anion exchanger (AE3)-encoding SLC4A3 gene in two unrelated families with SQTS. The mutation causes reduced surface expression of AE3 and reduced membrane bicarbonate transport. Slc4a3 knockdown in zebrafish causes increased cardiac pHi, short QTc, and reduced systolic duration, which is rescued by wildtype but not mutated SLC4A3. Mechanistic analyses suggest that an increase in pHi and decrease in [Cl−]i shortened the action potential duration. However, other mechanisms may also play a role. Altered anion transport represents a mechanism for development of arrhythmia and may provide new therapeutic possibilities.
Highlights
Patients with short QT syndrome (SQTS) may present with syncope, ventricular fibrillation or sudden cardiac death
Disease-causing mutations have been identified in the cardiac potassium ion channels KCNH26,7, KCNQ18 and KCNJ29 leading to gain of channel function and causing action potential duration (APD) shortening and elevated risk of cardiac arrhythmia
L-type calcium channels CACNA1C, CACNB2 and CACNA2D1, have recently been identified as separate genetic causes of SQTS10,11. Only these six cation channels have been implicated in SQTS, and most expanded genetic screening focuses on cation channel genes
Summary
Patients with short QT syndrome (SQTS) may present with syncope, ventricular fibrillation or sudden cardiac death. The short QT syndrome (SQTS), first recognized in 20001, is a rare, genetically determined, severe arrhythmogenic disease with a high risk of syncope, atrial and ventricular fibrillation, and sudden cardiac death (SCD)[2]. Considering that identified cation channel mutations explain
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