The KCNQ1/KCNE1 channel conducts the slow delayed rectifier K⁺ current, IKs, in the heart. Many loss-of-functions mutations have been described in human that cause the long QT syndrome associated with predisposition to torsades de pointes, ventricular arrhythmia and sudden death. We have described a point mutation (S140G) that causes persistent atrial fibrillation (AF) in a large Chinese family. Functional analysis revealed a gain-of-function effect, increasing channel density and abolishing the voltage dependency of the gating. Thus, the S140G mutation is likely to initiate and maintain AF by reducing action potential duration and effective refractory period in atrial myocytes. Recently, a case of atrial fibrillation was reported that was associated with the KCNQ1 V141M mutation, adjacent to Ser 140 found in the Chinese family. The biophysical effects of V141M were very similar to those of the S140G mutation. In vitro co-expression experiments have shown that all 5 KCNE subunits can co-assemble with KCNQ1 to produce K⁺ current with specific gating and trafficking properties. Long QT- or AF- causing KCNQ1 mutations were used to better analyze these interactions. All KCNQ1 and KCNE transcripts are present in human heart (KCNQ1>>KCNE4 KCNE1>KCNE3>KCNE2>>KCNE5). We identified a mutation in KCNE2 (R27C) that was associated with AF in two distinct families. Again, the mutant KCNE2 subunit caused a gain-of-function when co-expressed with KCNQ1.