Ji-Fang Ma1, Fan Yang2, Saagar N Mahida3, Ling Zhao2, Xiaomin Chen4, Michael L Zhang3, Zhijun Sun5, Yan Yao6, Yi-Xin Zhang2, Gu-Yan Zheng2, Jie Dong2, Ming-Jun Feng4, Rui Zhang1, Jian Sun1, Shuo Li1, Qun-Shan Wang1, Huiqing Cao2, Emelia J Benjamin7, Patrick T Ellinor8, Yi-Gang Li9, Xiao-Li Tian10. 1. Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China. 2. 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. 3. Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA. 4. Key Laboratory of Ningbo First Hospital and Cardiovascular Center of Ningbo First Hospital, Ningbo University, 59 Liuting St., Ningbo 315010, China. 5. Cardiovascular Department, PLA General Hospital, 28 Fuxing Rd, Beijing 100853, China. 6. Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China. 7. 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. 8. Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA. 9. Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China tianxiaoli@pku.edu.cn drliyigang@outlook.com. 10. 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.
Abstract
AIMS: Atrial fibrillation (AF) is a common arrhythmia with an important heritable aspect. The genetic factors underlying AF have not been fully elucidated. METHODS AND 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Atrial fibrillation (AF) is a common arrhythmia with an important heritable aspect. The genetic factors underlying AF have not been fully elucidated. METHODS AND 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
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