Abstract 2922: KCNQ1 Gain-of-function Mutation Associated With Familial Atrial Fibrillation

Abstract

Background : Family history is a risk factor for atrial fibrillation (AF). We report here a 3-generation Caucasian family with familial AF and a highly dysfunctional mutation in KCNQ1 . Methods and Results: In the proband, there was a 9-bp duplication resulting in insertion of the amino acids IAP (IAP54 –56) in the N-terminus of the protein. The kindred included 4 other family members with AF or palpitations. Each affected family member presented with early onset paroxysmal lone AF and no QT prolongation. This variant has previously been reported in presumed healthy African-American individuals (minor allele frequency 1.3%), but has not been studied in vitro . In transfected CHO cells, coexpression of IAP54 –56 with KCNE1 generated currents that were much larger and activated much earlier that wild-type I Ks ( Figure ); e.g. at +20 mV, peak current was 75±8 [IAP54 –56] vs 25±5 [wt] pA/pF after 5-sec pulses (n=7 each, P<0.001). Computational simulations of human atrial action potential (AP) that incorporated Markov models of wt or IAP54 –56-I Ks were performed. At a cycle length of 400ms, accelerated activation of IAP54 –56-I Ks resulted in open state accumulation and increased maximum I Ks amplitude ~40-fold (351 vs 9 pA/pF), resulting in ~6-fold AP duration shortening (44 vs 259 ms). Conclusions: We have identified a KCNQ1 indel in a moderate sized Caucasian kindred with familial AF and normal QT intervals. This variant results in an I Ks gain-of-function and the resulting shortening of atrial action potentials may predispose to AF. This variant has been reported in 1.3% of African-Americans, suggesting it may be a common risk allele in some populations.