alpha-1-syntrophin mutation and the long-QT syndrome: a disease of sodium channel disruption.

Background —Long QT syndrome (LQTS) is an inherited disorder associated with sudden cardiac death. The cytoskeletal protein alpha-1-syntrophin (SNTA1) is known to interact with the cardiac sodium channel (hNa v 1.5) and we hypothesized that SNTA1 mutations might cause phenotypical LQTS in patients with genotypically normal hNa v 1.5 by secondarily disturbing sodium channel function. Methods and Results —Mutational analysis of SNTA1 was performed on 39 LQTS patients (QTc ≥ 480ms) with previously negative genetic-screening for the known LQTS-causing genes. We identified a novel A257G- SNTA1 missense mutation, which affects a highly conserved residue, in 3 unrelated LQTS probands but not in 400 ethnic-matched control alleles. Only one of these probands had a preexisting family history of LQTS and sudden death with an additional intronic variant in KCNQ1. Electrophysiological analysis was performed using HEK-293 cells stably expressing hNa v 1.5 and transiently transfected with either wild type (WT) or mutant SNTA1, and in neonatal rat cardiomyocytes transiently expressing with either WT or mutant SNTA1. In both HEK293 cells and neonatal rat cardiomyocytes increased peak sodium currents were noted along with a 10 mV negative shift of the onset and peak of currents of the I-V relationships. In addition, A257G-SNTA1 shifted the steady-state activation ( V h ) leftward by 9.4 mV, while the voltage-dependent inactivation kinetics and the late sodium currents were similar to WT-SNTA1. Conclusion — SNTA1 is a new susceptibility gene for LQTS. A257G- SNTA1 can cause gain-of-function of Na v 1.5 similar to the LQT3.