Referenced in: none

Automatically associated channels: Kir2.1 , Kv11.1 , Kv7.1 , Nav1.5 , Slo1

Title: A Novel KCNQ1 Missense Mutation Identified in a Patient with Juvenile-Onset Atrial Fibrillation Causes Constitutively Open IKs Channels.

Authors: Kanae Hasegawa, Seiko Ohno, Takashi Ashihara, Hideki Itoh, Wei-Guang Ding, Futoshi Toyoda, Takeru Makiyama, Hisaaki Aoki, Yoshihide Nakamura, Brian P Delisle, Hiroshi Matsuura, Minoru Horie

Journal, date & volume: Heart Rhythm, 2013 Oct 1 , ,

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/24096004

Abstract
Atrial fibrillation (AF) is one of the most common cardiac arrhythmias. In some patients, the disease is inheritable; however, hereditary aspects of AF remain not fully elucidated.The purpose of this study was to identify genetic backgrounds that contribute to juvenile-onset AF and to define the mechanism.In 30 consecutive juvenile-onset AF patients (onset age <50 years), we screened AF-related genes (KCNQ1, KCNH2, KCNE1-3, KCNE5, KCNJ2, SCN5A). We analyzed the function of mutant channels using whole-cell patch-clamp techniques and computer simulations.Among the juvenile-onset AF patients, we identified three mutations (10%): SCN5A-M1875T, KCNJ2-M301K, and KCNQ1-G229D. Because KCNQ1 variant (G229D) identified in a 16-year-old boy was novel, we focused on the proband. The G229D-IKs was found to induce a large instantaneous activating component without deactivation after repolarization to -50 mV. In addition, wild-type (WT)/G229D-IKs (WT and mutant coexpression) displayed both instantaneous and time-dependent activating currents. Compared to WT-IKs, the tail current densities in WT/G229D-IKs were larger at test potentials between -130 and -40 mV but smaller at test potentials between 20 and 50 mV. Moreover, WT/G229D-IKs resulted in a negative voltage shift for current activation (-35.2 mV) and slower deactivation. WT/G229D-IKs conducted a large outward current induced by an atrial action potential waveform, and computer simulation incorporating the WT/G229D-IKs results revealed that the mutation shortened atrial but not ventricular action potential.A novel KCNQ1-G229D mutation identified in a juvenile-onset AF patient altered the IKs activity and kinetics, thereby increasing the arrhythmogenicity to AF.