ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene.
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 IK-ATP (SUR2A), are also associated with both BrS and ERS.


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 INa 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<0.01).


CONCLUSIONS
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 SCN5A may underlie type 3 ERS, which is associated with a severe arrhythmic phenotype.
Department of Molecular Genetics and Experimental Cardiology, Masonic Medical Research Laboratory, Utica, NY, USA. Electronic address: dianah@mmrl.edu.
Dan
D
Hu
Department of Molecular Genetics and Experimental Cardiology, Masonic Medical Research Laboratory, Utica, NY, USA.
Hector
H
Barajas-Martínez
Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
Andre
A
Terzic
Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
Sungjo
S
Park
Department of Molecular Genetics and Experimental Cardiology, Masonic Medical Research Laboratory, Utica, NY, USA.
Ryan
R
Pfeiffer
Department of Molecular Genetics and Experimental Cardiology, Masonic Medical Research Laboratory, Utica, NY, USA.
Elena
E
Burashnikov
Department of Molecular Genetics and Experimental Cardiology, Masonic Medical Research Laboratory, Utica, NY, USA.
Yuesheng
Y
Wu
1st Department of Medicine-Cardiology, University Medical Centre Mannheim, Mannheim, Germany.
Martin
M
Borggrefe
1st Department of Medicine-Cardiology, University Medical Centre Mannheim, Mannheim, Germany.
Christian
C
Veltmann
1st Department of Medicine-Cardiology, University Medical Centre Mannheim, Mannheim, Germany.
Rainer
R
Schimpf
Mercy Hospital, Buffalo, NY, USA.
John J
JJ
Cai
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Gi-Byong
GB
Nam
Guthrie Clinic, Sayre, PA, USA.
Pramod
P
Deshmukh
Department of Medicine, University of California, San Francisco, CA, USA.
Melvin
M
Scheinman
United Medical Practice Association, Ridgewood, NJ, USA.
Mark
M
Preminger
Arrhythmia Institute, Valley Health System, Columbia University College of Physicians & Surgeons, New York, NY, USA.
Jonathan
J
Steinberg
Unidad de Investigación, "Carlos Méndez" del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Colima, Mexico.
Angélica
A
López-Izquierdo
Unidad de Investigación, "Carlos Méndez" del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Colima, Mexico.
Daniela
D
Ponce-Balbuena
1st Department of Medicine-Cardiology, University Medical Centre Mannheim, Mannheim, Germany.
Christian
C
Wolpert
Hôspital Cardiologique du Haut Lévêque, Université Bordeaux II, Pessac cedex, France.
Michel
M
Haïssaguerre
Unidad de Investigación, "Carlos Méndez" del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Colima, Mexico.
José Antonio
JA
Sánchez-Chapula
Department of Molecular Genetics and Experimental Cardiology, Masonic Medical Research Laboratory, Utica, NY, USA. Electronic address: ca@mmrl.edu.
Charles
C
Antzelevitch
D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D053840:Brugada Syndrome / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology* / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D017433:Protein Structure, Secondary; D011817:Rabbits; D051381:Rats; D064233:Sulfonylurea Receptors / Q000737:chemistry / Q000235:genetics*; D055815:Young Adult
C577510:ABCC9 protein, human; D064233:Sulfonylurea Receptors
ATP-sensitive potassium channel; J wave syndromes; Mutation; Sodium channel; Sudden cardiac death