@article{25182b227e824a0e8420dbbc0fd42772,
title = "Embryonic type Na + channel β-subunit, SCN3B masks the disease phenotype of Brugada syndrome",
abstract = "SCN5A is abundant in heart and has a major role in I Na. 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 I Na of mutated SCN5A is decreased and SCN3B augmented I Na of 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.",
author = "Shinichiro Okata and Shinsuke Yuasa and Tomoyuki Suzuki and Shogo Ito and Naomasa Makita and Tetsu Yoshida and Min Li and Junko Kurokawa and Tomohisa Seki and Toru Egashira and Yoshiyasu Aizawa and Masaki Kodaira and Chikaaki Motoda and Gakuto Yozu and Masaya Shimojima and Nozomi Hayashiji and Hisayuki Hashimoto and Yusuke Kuroda and Atsushi Tanaka and Mitsushige Murata and Takeshi Aiba and Wataru Shimizu and Minoru Horie and Kaichiro Kamiya and Tetsushi Furukawa and Keiichi Fukuda",
note = "Funding Information: The authors thank all the laboratory members for their critical comments and helpful discussions. The authors thank Drs. I. Komuro, H. Morita and A. Naito (University of Tokyo) for helpful discussions. This study was supported, in part, by research grants from the Program for Intractable Diseases Research utilizing Diseasespecific iPS cells from Japan Agency for Medical Research and development, AMED, Grants-in-Aid for Scientific Research (JSPS KAKENHI Grant Number: 26670408, 15H01521, 16H050304, 16K15415), a Health Labour Sciences Research Grant, the New Energy and Industrial Technology Development Organization, and the Program for Promotion of Fundamental Studies in Health Science of the National Institute of Biomedical Innovation, Suzuken Memorial Foundation and Keio University Medical Science Fund, and the Joint Usage/Research Program of Medical Research Institute, Tokyo Medical and Dental University. Publisher Copyright: {\textcopyright} The Author(s) 2016.",
year = "2016",
month = sep,
day = "28",
doi = "10.1038/srep34198",
language = "English",
volume = "6",
journal = "Scientific reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
}