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Heart Rhythm. 2014 Jan;11(1):67-75. doi: 10.1016/j.hrthm.2013.09.073. Epub 2013 Oct 1.

A novel KCNQ1 missense mutation identified in a patient with juvenile-onset atrial fibrillation causes constitutively open IKs channels.

Author information

1
Department of Cardiovascular Biology and Medicine, Niigata University School of Medical and Dental Sciences, Niigata, Japan; Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
2
Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
3
Department of Physiology, Shiga University of Medical Science, Otsu, Japan.
4
Department of Cardiovascular and Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
5
Department of Pediatrics, Kinki University Faculty Medicine, Osaka, Japan.
6
Department of Physiology, University of Kentucky, Lexington, Kentucky.
7
Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan. Electronic address: horie@belle.shiga-med.ac.jp.

Abstract

BACKGROUND:

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.

OBJECTIVE:

The purpose of this study was to identify genetic backgrounds that contribute to juvenile-onset AF and to define the mechanism.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

A novel KCNQ1-G229D mutation identified in a juvenile-onset AF patient altered the IKs activity and kinetics, thereby increasing the arrhythmogenicity to AF.

KEYWORDS:

AF; AP; Atrial fibrillation; CHO; Chinese hamster ovary; ECG; I(Ks); Ion channel; Juvenile-onset atrial fibrillation; KCNQ1; QTc; WT; action potential; atrial fibrillation; corrected QT interval; electrocardiogram; wild type

PMID:
24096004
DOI:
10.1016/j.hrthm.2013.09.073
[Indexed for MEDLINE]

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