SCN5A

SCN5A is the gene that encodes the alpha subunit of the cardiac voltage-gated sodium channel Nav1.5. This channel underlies the fast inward sodium current essential for the initiation and propagation of action potentials in cardiac muscle. The SCN5A gene is located on chromosome 3p21 and is most highly expressed in the heart, especially in atrial and ventricular myocytes, with lower levels in skeletal muscle and in the conducting system of the heart.

Nav1.5 consists of four homologous domains (DI–DIV), each with six transmembrane segments (S1–S6). The S4 segments act as voltage sensors and the loop between S5 and S6 forms the channel pore. Upon depolarization, sodium ions rapidly enter the cell, producing the upstroke of the cardiac action potential and influencing conduction velocity and excitability. The channel associates with beta subunits and other regulatory proteins that modulate trafficking, gating, and expression.

Pathogenic variants in SCN5A are linked to several inherited arrhythmia syndromes. Loss-of-function mutations reduce the sodium current and are associated with Brugada syndrome type 1, progressive conduction disease, and sick sinus syndrome. Gain-of-function mutations increase late or persistent sodium current, prolonging repolarization and causing long QT syndrome type 3. SCN5A variants have also been implicated in atrial fibrillation, dilated cardiomyopathy, and sudden cardiac death, with clinical presentation influenced by genetic and environmental factors.

Diagnosis often involves genetic testing in individuals with suspected channelopathies or related cardiomyopathies. Management depends on the condition and may include antiarrhythmic drugs, implantable devices, and lifestyle considerations. Ongoing research seeks to clarify genotype–phenotype correlations and develop targeted therapies.