A sodium-channel mutation causes isolated cardiac conduction disease

Cardiac conduction disorders slow the heart rhythm and cause disability in millions of people worldwide. Inherited mutations in SCN5A, the gene encodi ng the human cardiac sodium (Na+) channel, have been associated with rapid heart rhythms that occur suddenly and are life-threatening(1-3); however, a chief function of the Na+ channel is to initiate cardiac impulse conductio n. Here we provide the first functional characterization of an SCN5A mutati on that causes a sustained, isolated conduction defect with pathological sl owing of the cardiac rhythm. By analysing the SCN5A coding region, we have identified a single mutation in five affected family members; this mutation results in the substitution of cysteine 514 for glycine (G514C) in the cha nnel protein. Biophysical characterization of the mutant channel shows that there are abnormalities in voltage-dependent 'gating' behaviour that can b e partially corrected by dexamethasone, consistent with the salutary effect s of glucocorticoids on the clinical phenotype. Computational analysis pred icts that the gating defects of G514C selectively slow myocardial conductio n, but do not provoke the rapid cardiac arrhythmias associated previously w ith SCN5A mutations.