Abstract 14126: Novel KCNQ1 Missense Mutation Associated with Juvenile-Onset Atrial Fibrillation
Introduction; Atrial fibrillation (AF) is the most common cardiac arrhythmia occurring in the general population. Recently, several gene mutations associated with ion channels were reported to cause AF. We also reported two AF patients who carried mutations, SCN5A-M1875T or KCNJ2-M301K.
Hypotheses; We assessed the hypotheses that juvenile-onset of AF would be related to the mutations in ion channel genes and that the mutant channel would change the channel function and thereby cause AF.
Methods and Results Our study cohort consisted of 21 AF patients (18 males) whose onsets of AF were < 50 years old. The mean age of the patients was 30 ± 12 y.o. We performed mutation screening in reported causative genes and identified three mutations including novel KCNQ1-G229D. The patient with KCNQ1-G229D was a 16-year-old boy who first suffered paroxysmal AF. Several antiarrhythmic drugs were ineffective and finally he received a pulmonary vein isolation procedure using a radiofrequency catheter ablation. In order to assess the functional outcome induced by the KCNQ1-G229D mutation, we performed a whole-cell patch-clamp analysis using Chinese hamster ovary (CHO) cells. We first expressed KCNQ1-G229D with KCNE1. The peak current depolarized to +30mV was 253.4 ±32.9 pA/pF and the tail current at -120 mV was -86.7±18.9 pA/pF (n=5). However, we could not analyze the channel properties because of the enormously slow deactivation, the tail current did not back to zero 15 seconds after the first stimuli and the next stimuli produced prompt opening of the channel. Therefore we next analyzed the channel with KCNQ1-G229D and WT in co-expression with KCNE1, the half-activation potential of peak and tail current revealed a pronounced negative shift from +7.2 ±2.3 mV to -2.1±2.5 mV and from +1.9±2.2 mV to -16.2 ±8.5 mV, respectively (n=7).
Conclusion We identified a novel KCNQ1-G229D mutation in a juvenile-onset AF patient, and the mutant channel displayed ‘gain of function’, which would be the cause of AF.
- © 2012 by American Heart Association, Inc.