Abstract 18645: Rare SCN10A Variants Associated With Lone Atrial Fibrillation Modulate Peak and Late Sodium Currents
Introduction: SCN10A encodes the sodium channel isoform Nav1.8, which is variably expressed in atria and has been linked to altered cardiac conduction and atrial fibrillation (AF). We resequenced SCN10A in 274 lone AF probands and identified 18 heterozygous rare variants (6.6% prevalence). Based on evidence of AF co-segregation, initial assessment of functional importance, and presence in ≥1 lone AF proband, four single variants (Y158D, 417delK, R814H, A1886V) and a compound one (Y158D-R814H) were selected for functional studies. We tested the hypothesis that rare SCN10A variants modulate biophysical properties of Nav1.8 channel, providing a mechanism for enhanced AF susceptibility.
Methods: SCN10A variants generated by site-directed mutagenesis were transiently expressed in ND7/23 cells. Macroscopic currents obtained using voltage-clamp protocols were measured after 48 hr incubation at 37°C.
Results: Variant 417delK showed near-total loss of current, and the remaining ones exhibited enhanced peak INa and late sodium current (INa-L) measured at 100 ms post-depolarization (gain-of-function). The magnitude of peak INa density of variants A1886V (103.3±16.6 pA/pF, n=10) and Y158D (-81.9±7.2 pA/pF, n = 7) was ~2-fold larger than WT (-42.8±4.9 pA/pF, n=9, P<0.01), while R814H variant generated peak INa density ~4 times larger than WT (-187±22.6 pA/pF, n=17, P<0.01). The effect of the compound variant was close to the average effect of both variants expressed independently (table).
Conclusion: Rare SCN10A variants associated with lone AF displayed strikingly altered functional properties. There was both enhanced peak INa and INa-L (Y158D, R814H, and A1886V) as well as near-absent SCN10A-mediated Nav1.8 current (417delK). By demonstrating that rare SCN10A variants identified in subjects with lone AF markedly perturb Nav1.8 function in vitro, these studies provide further support for the hypothesis that these variants contribute to AF susceptibility.
- © 2013 by American Heart Association, Inc.