ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene

Dan Hu, Hector Barajas-Martínez, Andre Terzic, Sungjo Park, Ryan Pfeiffer, Elena Burashnikov, Yuesheng Wu, Martin Borggrefe, Christian Veltmann, Rainer Schimpf, John J. Cai, Gi Byong Nam, Pramod Deshmukh, Melvin Scheinman, Mark Preminger, Jonathan Steinberg, Angélica López-Izquierdo, Daniela Ponce-Balbuena, Christian Wolpert, Michel HaïssaguerreJosé Antonio Sánchez-Chapula, Charles Antzelevitch

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)431-442
Number of pages12
JournalInternational Journal of Cardiology
Volume171
Issue number3
DOIs
StatePublished - Feb 15 2014

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Adenosine Triphosphate
Genes
Mutation
Inhibitory Concentration 50
Brugada Syndrome
ATP-Binding Cassette Transporters
Fathers
Mothers
Phenotype

Keywords

  • ATP-sensitive potassium channel
  • J wave syndromes
  • Mutation
  • Sodium channel
  • Sudden cardiac death

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Hu, D., Barajas-Martínez, H., Terzic, A., Park, S., Pfeiffer, R., Burashnikov, E., ... Antzelevitch, C. (2014). ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene. International Journal of Cardiology, 171(3), 431-442. https://doi.org/10.1016/j.ijcard.2013.12.084

ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene. / Hu, Dan; Barajas-Martínez, Hector; Terzic, Andre; Park, Sungjo; Pfeiffer, Ryan; Burashnikov, Elena; Wu, Yuesheng; Borggrefe, Martin; Veltmann, Christian; Schimpf, Rainer; Cai, John J.; Nam, Gi Byong; Deshmukh, Pramod; Scheinman, Melvin; Preminger, Mark; Steinberg, Jonathan; López-Izquierdo, Angélica; Ponce-Balbuena, Daniela; Wolpert, Christian; Haïssaguerre, Michel; Sánchez-Chapula, José Antonio; Antzelevitch, Charles.

In: International Journal of Cardiology, Vol. 171, No. 3, 15.02.2014, p. 431-442.

Research output: Contribution to journalArticle

Hu, D, Barajas-Martínez, H, Terzic, A, Park, S, Pfeiffer, R, Burashnikov, E, Wu, Y, Borggrefe, M, Veltmann, C, Schimpf, R, Cai, JJ, Nam, GB, Deshmukh, P, Scheinman, M, Preminger, M, Steinberg, J, López-Izquierdo, A, Ponce-Balbuena, D, Wolpert, C, Haïssaguerre, M, Sánchez-Chapula, JA & Antzelevitch, C 2014, 'ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene', International Journal of Cardiology, vol. 171, no. 3, pp. 431-442. https://doi.org/10.1016/j.ijcard.2013.12.084
Hu, Dan ; Barajas-Martínez, Hector ; Terzic, Andre ; Park, Sungjo ; Pfeiffer, Ryan ; Burashnikov, Elena ; Wu, Yuesheng ; Borggrefe, Martin ; Veltmann, Christian ; Schimpf, Rainer ; Cai, John J. ; Nam, Gi Byong ; Deshmukh, Pramod ; Scheinman, Melvin ; Preminger, Mark ; Steinberg, Jonathan ; López-Izquierdo, Angélica ; Ponce-Balbuena, Daniela ; Wolpert, Christian ; Haïssaguerre, Michel ; Sánchez-Chapula, José Antonio ; Antzelevitch, Charles. / ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene. In: International Journal of Cardiology. 2014 ; Vol. 171, No. 3. pp. 431-442.
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abstract = "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.",
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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

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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