Embryonic type Na+ channel beta-subunit, SCN3B masks the disease phenotype of Brugada syndrome

作者：Okata Shinichiro; Yuasa Shinsuke^*; Suzuki Tomoyuki; Ito Shogo; Makita Naomasa; Yoshida Tetsu; Li Min; Kurokawa Junko; Seki Tomohisa; Egashira Toru; Aizawa Yoshiyasu; Kodaira Masaki; Motoda Chikaaki; Yozu Gakuto; Shimojima Masaya; Hayashiji Nozomi; Hashimoto Hisayuki; Kuroda Yusuke; Tanaka Atsushi; Murata Mitsushige; Aiba Takeshi; Shimizu Wataru; Horie Minoru; Kamiya Kaichiro; Furukawa Tetsushi; Fukuda Keiichi

来源：Scientific Reports, 2016, 6(1): 34198.

DOI：10.1038/srep34198

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 beta-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 INa 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.

• 出版日期2016-9-28