title: Genetic defects in a His-Purkinje system transcription factor, IRX3, cause lethal cardiac arrhythmias.
abstract: Ventricular fibrillation (VF), the main cause of sudden cardiac death (SCD), occurs most frequently in the acute phase of myocardial infarction: a certain fraction of VF, however, develops in an apparently healthy heart, referred as idiopathic VF. The contribution of perturbation in the fast conduction system in the ventricle, the His-Purkinje system, for idiopathic VF has been implicated, but the underlying mechanism remains unknown. Irx3/IRX3 encodes a transcription factor specifically expressed in the His-Purkinje system in the heart. Genetic deletion of Irx3 provides a mouse model of ventricular fast conduction disturbance without anatomical or contraction abnormalities. The aim of this study was to examine the link between perturbed His-Purkinje system and idiopathic VF in Irx3-null mice, and to search for IRX3 genetic defects in idiopathic VF patients in human.
  
  
  
  Telemetry electrocardiogram recording showed that Irx3-deleted mice developed frequent ventricular tachyarrhythmias mostly at night. Ventricular tachyarrhythmias were enhanced by exercise and sympathetic nerve activation. In human, the sequence analysis of IRX3 exons in 130 probands of idiopathic VF without SCN5A mutations revealed two novel IRX3 mutations, 1262G>C (R421P) and 1453C>A (P485T). Ventricular fibrillation associated with physical activities in both probands with IRX3 mutations. In HL-1 cells and neonatal mouse ventricular myocytes, IRX3 transfection up-regulated SCN5A and connexin-40 mRNA, which was attenuated by IRX3 mutations.
  
  
  
  IRX3 genetic defects and resultant functional perturbation in the His-Purkinje system are novel genetic risk factors of idiopathic VF, and would improve risk stratification and preventive therapy for SCD in otherwise healthy hearts.
authors.affiliation: Department of Bio-Informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Koizumi
authors.affiliation: Department of Biofunctional Informatics, Tokyo Medical and Dental University, Tokyo, Japan t_furukawa.bip@mri.tmd.ac.jp sasano.bi@tmd.ac.jp.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Sasano
authors.affiliation: Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Kimura
authors.affiliation: Department of Preventive Cardiology, National Cerebral and Cardiovascular Center, Suita, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: Department of Preventive Cardiology, National Cerebral and Cardiovascular Center, Suita, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Aiba
authors.affiliation: Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: Division of Cardiology, Yokohama Rosai Hospital, Yokohama, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Nogami
authors.affiliation: Department of Cardiology, Tokyo Metropolitan Hiroo Hospital, Tokyo, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Fukamizu
authors.affiliation: Department of Cardiology, Tokyo Metropolitan Hiroo Hospital, Tokyo, Japan.
authors.forename: Harumizu
authors.initials: H
authors.lastname: Sakurada
authors.affiliation: Cardiovascular Center, Yokosuka Kyosai Hospital, Yokohama, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Division of Cardiology, Hiratsuka Kyosai Hospital, Hiratsuka, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Department of Genetics Groups, RIKEN Center for Allergy and Immunology, Yokohama, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ishikura
authors.affiliation: Department of Genetics Groups, RIKEN Center for Allergy and Immunology, Yokohama, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.affiliation: Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Arimura
authors.affiliation: Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Kimura
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan Heart Rhythm Center, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Hirao
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Isobe
authors.affiliation: Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Shimizu
authors.affiliation: Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Miura
authors.affiliation: Department of Bio-Informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan t_furukawa.bip@mri.tmd.ac.jp sasano.bi@tmd.ac.jp.
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Furukawa
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac; D016757:Death, Sudden, Cardiac; D006329:Heart Conduction System; D018398:Homeodomain Proteins; D006801:Humans; D051379:Mice; D014157:Transcription Factors; D014693:Ventricular Fibrillation
chemical_list: D018398:Homeodomain Proteins; C501598:IRX3 protein, human; C501599:Irx3 protein, mouse; D014157:Transcription Factors
keywords: Cardiac conduction system; Sudden cardiac death; Ventricular fibrillation