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 IC50 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 IK-ATP with a shift of ATP IC50 from 8.5 卤 2 mM to 13.4 卤 5 渭M (p < 0.05). The SCN5A mutation reduced peak INa to 39% of WT (p < 0.01), shifted steady-state inactivation by 鈭?#xA0;18.0 mV (p < 0.01) and increased late INa from 0.14% to 2.01% of peak INa (p < 0.01).
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 IK-ATP when coupled with a loss-of-function in SCN5A may underlie type 3 ERS, which is associated with a severe arrhythmic phenotype.
