Abstract 2569: The SCN5A Mutation R680H From Sudden Death Interacts With a Polymorphism SCN5A-S1103Y Common in African Americans to Increase Late Sodium Current
Background- The common polymorphism SCN5A-S1103Y (~13% allelic frequency in African Americans) has been implicated as a risk factor for arrhythmia, sudden unexplained death (SUD), and sudden infant death syndrome (SIDS). S1103Y increased arrhythmia susceptibility in the presence of environmental factors such as acidosis, medications, hypokalemia, or structural heart disease. Because possible interactions of S1103Y with other SCN5A variants was unknown, we studied the electrophysiology of two variants (SCN5A-S1103Y and -R680H) identified in a single SUD victim.
Methods and Results- Comprehensive mutational analysis by PCR, DHPLC, and direct DNA sequencing of the long QT syndrome associated genes, KCNQ1, KCNH2, and SCN5A revealed two SCN5A variants (R680H and S1103Y) in a 23 year-old black male who collapsed after playing football. SCN5A-R680H was absent in over 1300 reference alleles and was previously reported to have a latent dysfunctional phenotype. The mutations were engineered both separately and on the same cDNA construct, since cis or trans status could not be determined in the decedent. They were expressed in HEK293 cells and sodium current (INa) recorded using the whole-cell method. Compared to a wild type (WT) late INa of 0.17±.04 as % of peak, S1103Y by itself showed no significant difference but R680H, R680H+S1103Y (co-expressed), and R680H/S1103Y (on the same cDNA ) showed 2.1, 3.6, and 3.4 fold increases, respectively. When intracellular acidosis (pipette solution pH=6.7) was introduced, S1103Y, R680H, R680H+S1103Y, and R680H/S1103Y showed respectively 2.2, 2.4, 5.0, and 5.5 fold increase of late INa compared to WT (0.21±.06 %) at pH 6.7. At low pH a significant depolarizing shift (6 mV) in channel inactivation, faster recovery from inactivation, and slower decay of macroscopic INa were observed in R680H+S1103Y and also R680H/S1103Y. These data suggested acidosis may increase the interactive effect of S1103Y on R680H to increase late INa.
Conclusions- This is the first report to elucidate a functional interaction of the common polymorphism S1103Y with another mutation in cardiac sodium channel. S1103Y significantly increased the late INa of R680H and may account for pathogenicity in this case.