Abstract 17754: Human iPSC-Derived Myocyte Mmodel of SCN5A-D1275N-Related Cardiac Sodium Channelopathy Reveals Diminished Sodium Currents Resulting From Enhanced Protein Degradation
2017
Introduction: The SCN5A gene encodes the α subunit of the cardiac sodium (Na+) channel,
NaV1.5. The
missense mutation, D1275N, has been associated with a range of unusual phenotypes associated with reduced
NaV1.5function, including cardiac conduction disease and
dilated cardiomyopathy. Curiously, the reported
biophysicalproperties of SCN5A-D1275N channels vary with experimental system. This study aimed to investigate the
biophysicalproperties of SCN5A-D1275N
channels usinghuman-
induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Methods & Results: First, using a
HEK 293 cell-based
heterologous expressionsystem, the SCN5A-D1275N channels showed similar maximum Na+ conductance but a significantly depolarizing shift of activation gate (+10 mV) compared to wild type. Second, we generated hiPSCs from a 24-year-old female who carried heterozygous SCN5A-D1275N and analyzed the differentiated CMs. Although SCN5A transcript levels were equivalent between D1275N and control hiPSC-CMs, both the to...
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