Mutation in the S3 segment of KCNQ1 results in familial lone atrial fibrillation

BACKGROUND Mutations in several ion channel genes have been reported to cause rare cases of familial atrial fibrillation (AF). OBJECTIVE The purpose of this study was to determine the genetic basis for AF in a family with autosomal dominant AF. METHODS Family members were evaluated by 12-lead ECG, echocardiogram, signal-averaged P-wave analysis, and laboratory studies. Fourteen family members in AF-324 were studied. Six individuals had AF, with a mean age at onset of 32 years (range 16-59 years). RESULTS Compared with unaffected family members, those with AF had a Longer mean QRS duration (100 vs 86 ms, P = .015) but no difference in the corrected QT interval (423 +/- 15 ms vs 421 +/- 21 ms). The known loci for AF and other cardiovascular diseases were evaluated. Evidence of Linkage was obtained with marker D11S4088 located within KCNQ1, and a highly conserved serine in the third transmembrane region was found to be mutated to a proline (S209P). Compared to the wild-type channel, the S209P mutant activates more rapidly, deactivates more slowly, and has a hyperpolarizing shift in the voltage activation curve. A fraction of the mutant channels are constitutively open at all voltages, resulting in a net increase in I-Ks current. CONCLUSION We identified a family with Lone AF due to a mutation in the highly conserved S3 domain of KCNQ1, a region of the channel not previously implicated in the pathogenesis of AF.