ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene.

Abstract Background Genetic defects in KCNJ8 , encoding the Kir6.1 subunit of the ATP-sensitive K + channel (I K-ATP ), have previously been associated with early repolarization (ERS) and Brugada (BrS) syndromes. Here we test the hypothesis that genetic variants in ABCC9 , encoding the ATP-binding cassette transporter of I K-ATP (SUR2A), are also associated with both BrS and ERS. Methods and results Direct sequencing of all ERS/BrS susceptibility genes was performed on 150 probands and family members. Whole-cell and inside-out patch-clamp methods were used to characterize mutant channels expressed in TSA201-cells. Eight ABCC9 mutations were uncovered in 11 male BrS probands. Four probands, diagnosed with ERS, carried a highly-conserved mutation, V734I- ABCC9 . Functional expression of the V734I variant yielded a Mg-ATP IC 50 that was 5-fold that of wild-type (WT). An 18-y/o male with global ERS inherited an SCN5A -E1784K mutation from his mother, who displayed long QT intervals, and S1402C- ABCC9 mutation from his father, who displayed an ER pattern. ABCC9 -S1402C likewise caused a gain of function of I K-ATP with a shift of ATP IC 50 from 8.5±2mM to 13.4±5μM (p SCN5A mutation reduced peak I Na to 39% of WT (p Na from 0.14% to 2.01% of peak I Na (p Conclusion Our study is the first to identify ABCC9 as a susceptibility gene for ERS and BrS. Our findings also suggest that a gain-of-function in I K-ATP when coupled with a loss-of-function in S CN5A may underlie type 3 ERS, which is associated with a severe arrhythmic phenotype.