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

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

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Article number34198
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 2016 Sep 28

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Brugada Syndrome
Masks
Induced Pluripotent Stem Cells
Phenotype
Cardiac Myocytes
Sudden Death
Mutation
Sodium Channels
Long QT syndrome type 3
Cause of Death

ASJC Scopus subject areas

  • General

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

In: Scientific Reports, Vol. 6, 34198, 28.09.2016.

Research output: Contribution to journalArticle

Okata, S, Yuasa, S, Suzuki, T, Ito, S, Makita, N, Yoshida, T, Li, M, Kurokawa, J, Seki, T, Egashira, T, Aizawa, Y, Kodaira, M, Motoda, C, Yozu, G, Shimojima, M, Hayashiji, N, Hashimoto, H, Kuroda, Y, Tanaka, A, Murata, M, Aiba, T, Shimizu, W, Horie, M, Kamiya, K, Furukawa, T & Fukuda, K 2016, 'Embryonic type Na + channel β-subunit, SCN3B masks the disease phenotype of Brugada syndrome', Scientific Reports, vol. 6, 34198. https://doi.org/10.1038/srep34198
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. / Embryonic type Na + channel β-subunit, SCN3B masks the disease phenotype of Brugada syndrome. In: Scientific Reports. 2016 ; Vol. 6.
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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.",
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AU - Okata, Shinichiro

AU - Yuasa, Shinsuke

AU - Suzuki, Tomoyuki

AU - Ito, Shogo

AU - Makita, Naomasa

AU - Yoshida, Tetsu

AU - Li, Min

AU - Kurokawa, Junko

AU - Seki, Tomohisa

AU - Egashira, Toru

AU - Aizawa, Yoshiyasu

AU - Kodaira, Masaki

AU - Motoda, Chikaaki

AU - Yozu, Gakuto

AU - Shimojima, Masaya

AU - Hayashiji, Nozomi

AU - Hashimoto, Hisayuki

AU - Kuroda, Yusuke

AU - Tanaka, Atsushi

AU - Murata, Mitsushige

AU - Aiba, Takeshi

AU - Shimizu, Wataru

AU - Horie, Minoru

AU - Kamiya, Kaichiro

AU - Furukawa, Tetsushi

AU - Fukuda, Keiichi

PY - 2016/9/28

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N2 - 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.

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