title: TBX5 mutations contribute to early-onset atrial fibrillation in Chinese and Caucasians.
abstract: OBJECTIVE
  Atrial fibrillation (AF) is a common arrhythmia with an important heritable aspect. The genetic factors underlying AF have not been fully elucidated.
  
  
  RESULTS
  We screened six candidate genes (CAV1, KCNJ2, KCNQ1, NKX2.5, PITX2, and TBX5) for novel mutations in 139 patients of Chinese descent with early-onset AF and 576 controls. Four missense TBX5 mutations, p.R355C, p.Q376R, p.A428S, and p.S372L, were identified in evolutionarily conserved regions. We did not find any mutations in CAV1, KCNJ2, KCNQ1, NKX2.5, and PITX2. These mutations increased the expression of atrial natriuretic peptide (ANP) and connexin-40 (CX40) in the primarily cultured rat atrial myocytes but did not alter the expression of cardiac structural genes, atrial myosin heavy chain-α (MHC-α) and myosin light chain-2α (MLC-2α). Overexpression of p.R355C developed an atrial arrhythmia suggestive of paroxysmal AF in the zebrafish model. To replicate our findings, we screened TBX5 in 527 early-onset AF cases from the Massachusetts General Hospital AF study. A novel TBX5 deletion (ΔAsp118, p.D118del) was identified, while no TBX5 mutations were identified in 1176 control subjects.
  
  
  CONCLUSIONS
  Our results provide both genetic and functional evidence to support the contribution of TBX5 gene in the pathogenesis of AF. The potential mechanism of arrhythmia may be due in part to the disturbed expression of ANP and CX40.
authors.affiliation: Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
authors.forename: Ji-Fang
authors.initials: JF
authors.lastname: Ma
authors.affiliation: Department of Human Population Genetics and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine (IMM), Peking University, 5 Yiheyuan Rd., Beijing 100871, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Saagar N
authors.initials: SN
authors.lastname: Mahida
authors.affiliation: Department of Human Population Genetics and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine (IMM), Peking University, 5 Yiheyuan Rd., Beijing 100871, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Ningbo First Hospital and Cardiovascular Center of Ningbo First Hospital, Ningbo University, 59 Liuting St., Ningbo 315010, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Zhang
authors.affiliation: Cardiovascular Department, PLA General Hospital, 28 Fuxing Rd, Beijing 100853, China.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Human Population Genetics and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine (IMM), Peking University, 5 Yiheyuan Rd., Beijing 100871, China.
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zhang
authors.affiliation: Department of Human Population Genetics and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine (IMM), Peking University, 5 Yiheyuan Rd., Beijing 100871, China.
authors.forename: Gu-Yan
authors.initials: GY
authors.lastname: Zheng
authors.affiliation: Department of Human Population Genetics and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine (IMM), Peking University, 5 Yiheyuan Rd., Beijing 100871, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Dong
authors.affiliation: Key Laboratory of Ningbo First Hospital and Cardiovascular Center of Ningbo First Hospital, Ningbo University, 59 Liuting St., Ningbo 315010, China.
authors.forename: Ming-Jun
authors.initials: MJ
authors.lastname: Feng
authors.affiliation: Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
authors.forename: Qun-Shan
authors.initials: QS
authors.lastname: Wang
authors.affiliation: Department of Human Population Genetics and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine (IMM), Peking University, 5 Yiheyuan Rd., Beijing 100871, China.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Cao
authors.affiliation: Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA Preventive Medicine Section, Department of Medicine, Boston University School of Medicine, Boston, MA, USA Cardiology Section, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Emelia J
authors.initials: EJ
authors.lastname: Benjamin
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Ellinor
authors.affiliation: Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China tianxiaoli@pku.edu.cn drliyigang@outlook.com.
authors.forename: Yi-Gang
authors.initials: YG
authors.lastname: Li
authors.affiliation: Department of Human Population Genetics and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine (IMM), Peking University, 5 Yiheyuan Rd., Beijing 100871, China tianxiaoli@pku.edu.cn drliyigang@outlook.com.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Tian
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D044466:Asian People; D001281:Atrial Fibrillation / Q000235:genetics* / Q000378:metabolism; D017630:Connexins / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D011247:Pregnancy; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D044465:White People; D000097003:Gap Junction alpha-5 Protein
chemical_list: D017630:Connexins; D018398:Homeodomain Proteins; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D000097003:Gap Junction alpha-5 Protein; C103172:T-box transcription factor 5
keywords: ANP; Atrial fibrillation; Connexin; Mutation; TBX5