Abstract 2926: A Novel Variant of Alpha-1-Syntrophin May Cause Long-QT Syndrome
Background: Long QT syndrome (LQTS) is an inherited disorder that can cause sudden cardiac death. It has been reported that alpha-1-syntrophin (SNTA1), a cytoarchitectural protein, can modify the cardiac sodium channel’s (hNav1.5) gating kinetics by protein-protein interaction. We hypothesized that SNTA mutations might cause LQTS.
Methods: PCR and direct sequencing of the open reading frame of SNTA1 was performed on 39 clinically-diagnosed LQTS patients (26 females; average age at diagnosis 23.6 ± 6.3 years; average QTc 537 ± 18.7 ms) whose genetic-screening was negative for the previously known LQTS-susceptibility genes. Using patch-clamp techniques, kinectics of hNav1.5 was studied in HEK293 cell line stably expressing hNav1.5 and transiently transfected with wild-type and mutant SNTA1.
Results: We identified a novel SNTA1 missense mutation (A257G) in 3 LQTS patients (2 females) but not in 400 ethnic-matched control alleles. The A257G mutation affects a highly conserved residue. The 2 unrelated females (QTc = 480ms) had no apparent family history, while the male subject (QTc = 550ms) was diagnosed at 3 years of age with familial LQTS. Electrophysiological analysis of INa demonstrated that A257G-SNTA1 showed significantly larger peak currents than WT (WT, 97.8 ± 35.1 pA/pF, n =15; A257G, 179.6 ± 66.2 pA/pF, n = 13, p<0.01) and shifted leftward the onset and peak current of the I-V relationships by 10 mV. The A257G also significantly shifted the voltage-dependent activation kinetics toward negative compared to the WT ( Vh: WT, -43.5 ± 5.9 mV, n = 15 vs. A257G, -51.7 ± 5.6 mV, n = 13, p<0.01). The voltage-dependent inactivation kinetics were not affected by A257G. The analysis of peak current decay during a 200 ms depolarization pulse demonstrated that A257G significantly delayed the fast component of the time constant but not the slow component (τf: WT, 0.92 0.15 ms, n =15; A257G, 1.06 ± 0.13 ms, n =13, p<0.05; τs: WT, 8.57 ± 3.84 ms, n =15; A257G, 8.97 ± 3.59 ms, n =13, NS).
Conclusion: We present the first evidence of SNTA1 as a new susceptibility gene for LQTS. The functional characterization of the A257G mutation demonstrated an increase of the total inward sodium current consistent with an LQT3-like electrophysiological phenotype.