Abstract 18901: Direct Evidence that a KCNQ1 Mutation is Linked to Familial Early-onset Atrial Fibrillation

Abstract

KCNQ1 encodes the voltage-gated α-subunit of the I Ks channel complex (Kv7.1), and KCNQ1 mutations are associated with multiple arrhythmia syndromes. Over the past 12 years, hundreds of different KCNQ1 mutations have been linked to congenital long QT syndrome but only three KCNQ1 variants, each identified in only one family, are linked to familial early-onset AF (<50 years of age). The scant genetic linkage between KCNQ1 and early-onset AF raises the question as to whether these KCNQ1 variants actually cause familial early-onset AF or simply unmask a latent genetic predisposition. We now report that a single KCNQ1 variant, pArg231His or R231H, is identified in five unrelated families with a high penetrance of familial early-onset AF. Whole-cell patch clamp of cells heterologously expressing the obligatory I Ks β-subunit KCNE1 with wild-type KCNQ1 (WT) or WT and R231H (to mimic the patients’ genotypes) showed that cells co-expressing R231H increased current at negative and resting membrane potentials. Additionally, currents recorded from cells using a human atrial action potential (AP) waveform at physiological temperature showed that WT is minimally activated during the atrial AP and co-expression of R231H increases current measured during the atrial AP waveform by greater than 20-fold (WT, n = 10; WT & R231H, n = 12, p<0.0001). Simulations using a computational model of a human atrial AP also predicted that I Ks is normally minimally activated in the atria and R231H would dramatically increase I Ks and shorten the atrial AP. We conclude that KCNQ1 mutations are capable of causing familial early-onset AF by increasing I Ks during the atrial AP and shortening atrial refractoriness.