Abstract 17754: Human iPSC-Derived Myocyte Mmodel of SCN5A-D1275N-Related Cardiac Sodium Channelopathy Reveals Diminished Sodium Currents Resulting From Enhanced Protein Degradation

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 NaV1.5 function, including cardiac conduction disease and dilated cardiomyopathy. Curiously, the reported biophysical properties of SCN5A-D1275N channels vary with experimental system. This study aimed to investigate the biophysical properties of SCN5A-D1275N channels using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Methods u0026 Results: First, using a HEK 293 cell-based heterologous expression system, 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...