Loss-of-function mutation of the channel subunits underlying Ito have not been reported but gain-of-function mutation of KV4.3 results in Brugada syndrome128 and persistent lone atrial fibrillation.129 Mutations of MiRP2, a normally inhibitory β subunit that associates with KV4.3, are also linked with lone atrial fibrillation130 and Brugada syndrome.131 Consistent with this, exposure of ventricular myocytes and ventricular wedge preparations from normal canine heart to NeuroSearch’s KV4-selective activator NS5806 mimics the symptoms of Brugada syndrome.132. This evidence concerns the gene KCND3 and Brugada syndrome.