Abstract 15636: NFATC1 Modulates Atrial Excitability and Arrhythmogenesis

Abstract

Transcription factors have emerged as important loci for atrial fibrillation (AF) susceptibility. We identified a novel mutation (M527L) in a conserved site of the transcription factor NFATC1 in a multigenerational family with an autosomal dominant young onset AF (<40 years old) phenotype. M527L reduces NFATC1 nuclear translocation (nuclear/total cellular ratio: M527L 0.50±0.02; WT 0.64±0.04, p<1E-5; n=10/each), DNA binding (M527L 0.69±0.02; WT 0.83±0.01, p=0.02; n=3/ each), and transcriptional activity (M527L 0.0003±0.00005; WT 0.0009±0.0002, p=0.01; n=5/each) in expression systems, underscoring the functional consequences of this mutation. To study the broader role of NFATC1 in atrial excitability we employed a CRISPR/Cas9 strategy to create an nfatc1 null (KO) zebrafish. KO fish exhibited reduced survival, with ~80% of juvenile fish succumbing to sudden death (log rank test p=0.0001), with no observable change in body or heart gross morphology. Explanted juvenile atria displayed spontaneous tachyarrhythmias or irregular rhythm (29 /40 KO atria vs 11/28 WT atria; Chi-Squared, p=0.0013) accompanied by irregular Ca 2+ handling (10/11 KO atria vs 5/16 WT atria). Furthermore, we found an abbreviated action potential duration in KO atrium (80±1 ms in KO (n=607) vs 91±1 ms in WT (n=441), p=0.0001), but not ventricle (186±3 ms in KO (n=109) vs 191±2 ms in WT (n=160), p=0.8). Taken together, our data suggests that NFATC1 is a modulator of atrial excitability and plays a role in AF susceptibility. Experiments are ongoing to further define the mechanisms underlying arrhythmia susceptibility and to identify the gene networks downstream of NFATC1 in the atria.