TY - JOUR
T1 - ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene
AU - Hu, Dan
AU - Barajas-Martínez, Hector
AU - Terzic, Andre
AU - Park, Sungjo
AU - Pfeiffer, Ryan
AU - Burashnikov, Elena
AU - Wu, Yuesheng
AU - Borggrefe, Martin
AU - Veltmann, Christian
AU - Schimpf, Rainer
AU - Cai, John J.
AU - Nam, Gi Byong
AU - Deshmukh, Pramod
AU - Scheinman, Melvin
AU - Preminger, Mark
AU - Steinberg, Jonathan
AU - López-Izquierdo, Angélica
AU - Ponce-Balbuena, Daniela
AU - Wolpert, Christian
AU - Haïssaguerre, Michel
AU - Sánchez-Chapula, José Antonio
AU - Antzelevitch, Charles
N1 - Funding Information:
This work was supported by the National Institutes of Health [ HL47678 ] to CA; NYSTEM [ C026424 ] to CA; SEP-CONACYT [ CB-2008-01-105941 ] to J.A.C.; CONACYT [ FM (201866) ] to HBM and DH; and the Masons of New York, Florida, Massachusetts, Connecticut, Maryland, Rhode Island and Wisconsin .
PY - 2014/2/15
Y1 - 2014/2/15
N2 - Background Genetic defects in KCNJ8, encoding the Kir6.1 subunit of the ATP-sensitive K+ channel (IK-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 IK-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 ± 2 mM to 13.4 ± 5 μM (p < 0.05). The SCN5A mutation reduced peak I Na to 39% of WT (p < 0.01), shifted steady-state inactivation by - 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.
AB - Background Genetic defects in KCNJ8, encoding the Kir6.1 subunit of the ATP-sensitive K+ channel (IK-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 IK-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 ± 2 mM to 13.4 ± 5 μM (p < 0.05). The SCN5A mutation reduced peak I Na to 39% of WT (p < 0.01), shifted steady-state inactivation by - 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.
KW - ATP-sensitive potassium channel
KW - J wave syndromes
KW - Mutation
KW - Sodium channel
KW - Sudden cardiac death
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U2 - 10.1016/j.ijcard.2013.12.084
DO - 10.1016/j.ijcard.2013.12.084
M3 - Article
C2 - 24439875
AN - SCOPUS:84893699480
SN - 0167-5273
VL - 171
SP - 431
EP - 442
JO - International Journal of Cardiology
JF - International Journal of Cardiology
IS - 3
ER -