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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  • Hayano Mamoru
    Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
  • Makiyama Takeru
    Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
  • Kamakura Tsukasa
    Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center
  • Watanabe Hiroshi
    Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences
  • Sasaki Kenichi
    Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
  • Funakoshi Shunsuke
    Center for iPS Cell Research and Application (CiRA), Kyoto University
  • Wuriyanghai Yimin
    Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science
  • Nishiuchi Suguru
    Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
  • Harita Takeshi
    Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
  • Yamamoto Yuta
    Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
  • Kohjitani Hirohiko
    Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
  • Hirose Sayako
    Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
  • Yokoi Fumika
    Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
  • Chen Jiarong
    Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
  • Baba Osamu
    Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
  • Horie Takahiro
    Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
  • Chonabayashi Kazuhisa
    Center for iPS Cell Research and Application (CiRA), Kyoto University
  • Ohno Seiko
    Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science
  • Toyoda Futoshi
    Department of Physiology, Shiga University of Medical Science
  • Yoshida Yoshinori
    Center for iPS Cell Research and Application (CiRA), Kyoto University
  • Ono Koh
    Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
  • Horie Minoru
    Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science
  • Kimura Takeshi
    Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine

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Other Title
  • Development of a Patient-Derived Induced Pluripotent Stem Cell Model for the Investigation of SCN5A-D1275N-Related Cardiac Sodium Channelopathy
  • Cardiac Sodium Channel Disease Modeling Using Patient-Derived Induced Pluripotent Stem Cells

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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>

Journal

  • Circulation Journal

    Circulation Journal 81 (12), 1783-1791, 2017

    The Japanese Circulation Society

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