期刊
INTERNATIONAL JOURNAL OF CARDIOLOGY
卷 171, 期 3, 页码 431-442出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.ijcard.2013.12.084
关键词
Mutation ATP; sensitive potassium channel; Sodium channel; Sudden cardiac death; J wave syndromes
资金
- National Institutes of Health [HL47678]
- NYSTEM [C026424]
- SEP-CONACYT [CB-2008-01-105941]
- CONACYT [FM (201866)]
- Mason of New York
- Mason of Florida
- Mason of Massachusetts
- Mason of Connecticut
- Mason of Maryland
- Mason of Rhode Island
- Mason of Wisconsin
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/omale 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 mu M (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 I-Na from 0.14% to 2.01% of peak I-Na (p b 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. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
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