The common African American polymorphism SCN5A-S1103Y interacts with mutation SCN5A-R680H to increase late Na current

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Electrophysiology

Background:

• The SCN5A-S1103Y polymorphism is linked to arrhythmia and sudden death, particularly in African Americans.
• A case of sudden unexplained death (SUD) in a young athlete prompted investigation into SCN5A variant interactions.

Purpose of the Study:

• To investigate the hypothesis that SCN5A-S1103Y interacts with other SCN5A variants to alter sodium current (I(Na)).
• To determine the functional impact of combined SCN5A-R680H and SCN5A-S1103Y variants on cardiac sodium channel function.

Main Methods:

• Constructing and expressing SCN5A variants (R680H, S1103Y) separately and together in HEK293 cells.
• Measuring late sodium current (late I(Na)) using patch-clamp electrophysiology under normal and acidic conditions (pH 6.7).
• Analyzing variants on both the common SCN5A-Q1077del and less common SCN5A-Q1077 splice variant backgrounds.

Main Results:

• The SCN5A-R680H variant, alone and in combination with S1103Y, significantly increased late I(Na) in the SCN5A-Q1077del background.
• Coexpression of R680H and S1103Y (R680H+S1103Y) and variants on the same cDNA (R680H/S1103Y) resulted in 3.4- and 3.6-fold increases in late I(Na), respectively.
• Intracellular acidosis markedly potentiated the increase in late I(Na) caused by these SCN5A variants, with R680H/S1103Y showing a 5.5-fold increase.

Conclusions:

• This study provides the first evidence of a functional interaction between the common SCN5A-S1103Y polymorphism and the R680H mutation.
• The combined effect of these variants, particularly under acidic conditions, can significantly enhance late I(Na), potentially leading to fatal arrhythmias.
• A 'double hit' genetic mechanism combined with an environmental factor like acidosis may explain sudden arrhythmic death in cases involving these SCN5A variants.