Identification Of A KCNE2 Gain-of-function Mutation In Patients With Familial Atrial Fibrillation

Background Atrial fibrillation(AF) is the most common cardiac arrhythmia. Its prevalence is 0.4% in the general population, increasing with age up to 5% to 9% in those over 60 years of age. AF causes a 2- to 6-fold increase in risk for stroke. However, the molecular defects and cellular mechanisms in most patients with AF remain to be identified. We have identified the first molecular genetic defect for familial AF in a Chinese kindred. By linkage analysis, the locus was mapped to chromosome 11p15.5. Candidate gene sequencing revealed an S-to-G mutation at position 140 of KCNQ1, an alpha subunit of potassium ion channels. Function analysis of the mutation revealed a gain-of-function effect on both KCNQ1-KCNE1 and KCNQ1-KCNE2 channel. Other loci such as chromosome 10q22-24, chromosome 6q14-16 and chromosome 5p13 were also identified as linked to familial AF in some patients. Therefore, familial AF is genetically heterogeneous. The other genes for the disorder in most patients remains to be identified.Objectives The aim of this study was to identify mutations associated with familial AF, and reveal the molecular basis of AF.Methods We evaluated 28 unrelated families with AF, and sequenced the 8 genes of potassium ion channels KCNQ1, HERG, KCNE1, KCNE2, KCNE3, KCNE4, KCNE5 and KCNJ2 after PCR amplification of genomic DNA. After identified the mutant gene, we constructed the recombinant vector which can express in the eukaryotic cells. We transfected them into the C.OS-7 cells for transient expression. Whole cell patch-clamping analysis was applied to detect the functional change of related ionic channel current. Controls were 462 unrelated healthy subjects.Results An arginine-to-cysteine mutation at position 27 (R27C) of KCNE2, was found in 2 of the 28 probands. The mutation was present in all affected members in the two kindreds and was absent in 462 healthy unrelated Chinese subjects. Similar to KCNQ1S140G, the mutation had a gain-of-function effect on the KCNQ1-KCNE2 channel; Unlike long QT syndrome-associated KCNE2 mutations, it did not alter HERG-KCNE2 current. The mutation did not also alter the functions of the HCN channel family either.Conclusions KCNE2 R27C is a molecular basis of familial AF. The mutation has a gain-of-function effect on cardiac potassium ion channels. It is possible that the mutation initiates and/or maintains, AF through shortening atrial action potential duration and the effective refractory period.