Development of a Patient-Derived Induced Pluripotent Stem Cell Model for the Investigation of SCN5A-D1275N-Related Cardiac Sodium Channelopathy
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- Hayano Mamoru
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
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- Makiyama Takeru
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
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- Kamakura Tsukasa
- Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center
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- Watanabe Hiroshi
- Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences
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- Sasaki Kenichi
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
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- Funakoshi Shunsuke
- Center for iPS Cell Research and Application (CiRA), Kyoto University
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- Wuriyanghai Yimin
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science
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- Nishiuchi Suguru
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
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- Harita Takeshi
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
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- Yamamoto Yuta
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
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- Kohjitani Hirohiko
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
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- Hirose Sayako
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
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- Yokoi Fumika
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
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- Chen Jiarong
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
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- Baba Osamu
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
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- Horie Takahiro
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
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- Chonabayashi Kazuhisa
- Center for iPS Cell Research and Application (CiRA), Kyoto University
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- Ohno Seiko
- Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science
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- Toyoda Futoshi
- Department of Physiology, Shiga University of Medical Science
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- Yoshida Yoshinori
- Center for iPS Cell Research and Application (CiRA), Kyoto University
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- Ono Koh
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
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- Horie Minoru
- Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science
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- Kimura Takeshi
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
書誌事項
- タイトル別名
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- Development of a Patient-Derived Induced Pluripotent Stem Cell Model for the Investigation of <i>SCN5A</i>-D1275N-Related Cardiac Sodium Channelopathy
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<p>Background:TheSCN5Agene encodes the α subunit of the cardiac voltage-gated sodium channel, NaV1.5. The missense mutation, D1275N, has been associated with a range of unusual phenotypes associated with reduced NaV1.5 function, including cardiac conduction disease and dilated cardiomyopathy. Curiously, the reported biophysical properties ofSCN5A-D1275N channels vary with experimental system.</p><p>Methods and Results:First, using a human embryonic kidney (HEK) 293 cell-based heterologous expression system, theSCN5A-D1275N channels showed similar maximum sodium conductance but a significantly depolarizing shift of activation gate (+10 mV) compared to wild type. Second, we generated human-induced pluripotent stem cells (hiPSCs) from a 24-year-old female who carried heterozygousSCN5A-D1275N and analyzed the differentiated cardiomyocytes (CMs). AlthoughSCN5Atranscript levels were equivalent between D1275N and control hiPSC-CMs, both the total amount of NaV1.5 and the membrane fractions were reduced approximately half in the D1275N cells, which were rescued by the proteasome inhibitor MG132 treatment. Electrophysiological assays revealed that maximum sodium conductance was reduced to approximately half of that in control hiPSC-CMs in the D1275N cells, and maximum upstroke velocity of action potential was lower in D1275N, which was consistent with the reduced protein level of NaV1.5.</p><p>Conclusions:This study successfully demonstrated diminished sodium currents resulting from lower NaV1.5 protein levels, which is dependent on proteasomal degradation, using a hiPSC-based model forSCN5A-D1275N-related sodium channelopathy.</p>
収録刊行物
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- Circulation Journal
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Circulation Journal 81 (12), 1783-1791, 2017
一般社団法人 日本循環器学会
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詳細情報 詳細情報について
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- CRID
- 1390282680083442816
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- NII論文ID
- 130006219109
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- NII書誌ID
- AA11591968
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- ISSN
- 13474820
- 13469843
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- NDL書誌ID
- 028673735
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- PubMed
- 28637969
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- 本文言語コード
- en
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- NDL
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- PubMed
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