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Connexin45 (GJC1) loss-of-function mutation contributes to familial atrial fibrillation and conduction disease

  • Author Footnotes
    1 These authors contributed equally to this work.
    Ruo-Gu Li
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Ying-Jia Xu
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Cardiology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Willy G. Ye
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada
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  • Yan-Jie Li
    Affiliations
    Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
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  • Honghong Chen
    Affiliations
    Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada
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  • Xing-Biao Qiu
    Affiliations
    Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
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  • Yi-Qing Yang
    Correspondence
    Address reprint requests and correspondence: Dr Yi-Qing Yang, Cardiovascular Research Laboratory, Shanghai Fifth People’s Hospital, Fudan University, 801 Heqing Rd, Shanghai 200240, China.
    Affiliations
    Department of Cardiology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China

    Cardiovascular Research Laboratory, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China

    Center Laboratory, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China
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  • Donglin Bai
    Correspondence
    Dr. Donglin Bai, Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, 1151 Richmond St, London, Ontario N6A 5C1, Canada.
    Affiliations
    Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada
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  • Author Footnotes
    1 These authors contributed equally to this work.
Published:January 08, 2021DOI:https://doi.org/10.1016/j.hrthm.2020.12.033

      Background

      Atrial fibrillation (AF) represents the most common clinical cardiac arrhythmia and substantially increases the risk of cerebral stroke, heart failure, and death. Although causative genes for AF have been identified, the genetic determinants for AF remain largely unclear.

      Objective

      This study aimed to investigate the molecular basis of AF in a Chinese kindred.

      Methods

      A 4-generation family with autosomal-dominant AF and other arrhythmias (atrioventricular block, sinus bradycardia, and premature ventricular contractions) was recruited. Genome-wide scan with microsatellite markers and linkage analysis as well as whole-exome sequencing analysis were performed. Electrophysiological characteristics and subcellular localization of the AF-linked mutant were analyzed using dual whole-cell patch clamps and confocal microscopy, respectively.

      Results

      A novel genetic locus for AF was mapped to chromosome 17q21.3, a 3.23-cM interval between markers D17S951 and D17S931, with a maximum 2-point logarithm of odds score of 4.2144 at marker D17S1868. Sequencing analysis revealed a heterozygous mutation in the mapping region, NM_005497.4:c.703A>T;p.(M235L), in the GJC1 gene encoding connexin45 (Cx45). The mutation cosegregated with AF in the family and was absent in 632 control individuals. The mutation decreased the coupling conductance in cell pairs (M235L/M235L, M235L/Cx45, M235L/Cx43, and M235L/Cx40), likely because of impaired subcellular localization.

      Conclusion

      This study defines a novel genetic locus for AF on chromosome 17q21.3 and reveals a loss-of-function mutation in GJC1 (Cx45) contributing to AF and other cardiac arrhythmias.

      Keywords

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