Embryonic type Na+channel β-subunit, SCN3B masks the disease phenotype of Brugada syndrome.
SCN5A is abundant in heart and has a major role in INa. Loss-of-function mutation in SCN5A results in Brugada syndrome (BrS), which causes sudden death in adults. It remains unclear why disease phenotype does not manifest in the young even though mutated SCN5A is expressed in the young. The aim of the present study is to elucidate the timing of the disease manifestation in BrS. A gain-of-function mutation in SCN5A also results in Long QT syndrome type 3 (LQTS3), leading to sudden death in the young. Induced pluripotent stem cells (iPSCs) were generated from a patient with a mixed phenotype of LQTS3 and BrS with the E1784K SCN5A mutation. Here we show that electrophysiological analysis revealed that LQTS3/BrS iPSC-derived cardiomyocytes recapitulate the phenotype of LQTS3 but not BrS. Each β-subunit of the sodium channel is differentially expressed in embryonic and adult hearts. SCN3B is highly expressed in embryonic hearts and iPSC-derived cardiomyocytes. A heterologous expression system revealed that INaof mutated SCN5A is decreased and SCN3B augmented INaof mutated SCN5A. Knockdown of SCN3B in LQTS3/BrS iPSC-derived cardiomyocytes successfully unmasked the phenotype of BrS. Isogenic control of LQTS3/BrS (corrected-LQTS3/BrS) iPSC-derived cardiomyocytes gained the normal electrophysiological properties.
Department of Cardiology, Keio University School of Medicine, Japan.|Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Japan.
Shinichiro
S
Okata
Department of Cardiology, Keio University School of Medicine, Japan.
Shinsuke
S
Yuasa
Department of Cardiology, Keio University School of Medicine, Japan.|Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Japan.
Tomoyuki
T
Suzuki
Department of Cardiology, Keio University School of Medicine, Japan.
Shogo
S
Ito
Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Naomasa
N
Makita
Division of Gene Therapy, Research Center of Genome Medicine, Saitama Medical University, Japan.
Tetsu
T
Yoshida
Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Japan.
Min
M
Li
Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Japan.
Junko
J
Kurokawa
Department of Cardiology, Keio University School of Medicine, Japan.
Tomohisa
T
Seki
Department of Cardiology, Keio University School of Medicine, Japan.
Toru
T
Egashira
Department of Cardiology, Keio University School of Medicine, Japan.
Yoshiyasu
Y
Aizawa
Department of Cardiology, Keio University School of Medicine, Japan.
Masaki
M
Kodaira
Department of Cardiology, Keio University School of Medicine, Japan.
Chikaaki
C
Motoda
Department of Cardiology, Keio University School of Medicine, Japan.
Gakuto
G
Yozu
Department of Cardiology, Keio University School of Medicine, Japan.
Masaya
M
Shimojima
Department of Cardiology, Keio University School of Medicine, Japan.
Nozomi
N
Hayashiji
Department of Cardiology, Keio University School of Medicine, Japan.
Hisayuki
H
Hashimoto
Department of Cardiology, Keio University School of Medicine, Japan.|Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Japan.
Yusuke
Y
Kuroda
Department of Cardiology, Keio University School of Medicine, Japan.
Atsushi
A
Tanaka
Department of Cardiology, Keio University School of Medicine, Japan.|Department of Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan.
Mitsushige
M
Murata
Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan.
Takeshi
T
Aiba
Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan.|Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.
Wataru
W
Shimizu
Department of Cardiovascular Medicine, Shiga University of Medical Science, Shiga, Japan.
Minoru
M
Horie
Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Japan.
Kaichiro
K
Kamiya
Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Japan.
Tetsushi
T
Furukawa
Department of Cardiology, Keio University School of Medicine, Japan.
Keiichi
K
Fukuda
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