R222Q Nav1.5 Mutation Associated with a New SCN5A-Related Cardiac Arrhythmia

Using a candidate-gene approach, we detected a variant of SCN5A, encoding the cardiac Na+ channel Nav1.5, by screening a family with cardiac arrhythmia resulting in frequent premature ventricular contractions (PVCs) and non-sustained ventricular tachycardia. Arrhythmia mechanism involved ectopic foci originating from the His-Purkinje system. The same mutation, leading to the R222Q substitution, was present in two additional unrelated families with the same associated cardiac phenotype. Exercise or hydroquinidine dramatically decreased the number of PVCs. To evaluate the functional incidence of this substitution, whole-cell patch-clamp experiments were performed on transfected COS-7 cells. The activation and inactivation curves were negatively shifted in the presence of the mutation (V1/2act, WT: −30.6±2.1 mV, n=9; heterozygous: −37.2±1.6 mV, n=9; p