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A novel NKX2.5 loss-of-function mutation responsible for familial atrial fibrillation

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Atrial fibrillation (AF) represents the most common form of sustained cardiac arrhythmia and accounts for substantial morbidity and mortality. Increasing evidence demonstrates that abnormal cardiovascular development is involved in the pathogenesis of AF. In this study, the coding exons and splice sites of the NKX2.5 gene, which encodes a homeodomain-containing transcription factor pivotal for normal cardiovascular morphogenesis, were sequenced in 110 unrelated index patients with familial AF. The available relatives of the mutation carrier and 200 unrelated ethnically-matched healthy individuals serving as controls were subsequently genotyped. The disease-causing potential of the identified NKX2.5 variation was predicted by MutationTaster. The functional characteristics of the mutant NKX2.5 protein were analyzed using a dual-luciferase reporter assay system. As a result, a novel heterozygous NKX2.5 mutation, p.F145S, was identified in a family with AF transmitted as an autosomal dominant trait, which co-segregated with AF in the family with complete penetrance. The detected substitution, which altered the amino acid completely conserved evolutionarily across species, was absent in 400 control chromosomes and was automatically predicted to be causative. Functional analysis demonstrated that the NKX2.5 mutant was associated with significantly decreased transcriptional activity compared with its wild-type counterpart. To the best of our knowledge, this is the first report on the association of the NKX2.5 loss-of-function mutation with increased susceptibility to familial AF. The findings of the present study provide novel insights into the molecular mechanism underlying AF, suggesting the potential implications for the early prophylaxis and allele-specific therapy of AF.
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Document Type: Research Article

Affiliations: 1: Department of Cardiothoracic Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P.R. China 2: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200030, P.R. China 3: Department of Cardiovascular Research, Shanghai Chest Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200030, P.R. China

Publication date: January 1, 2013

More about this publication?
  • The International Journal of Molecular Medicine is a monthly, peer-reviewed journal devoted to the publication of high quality studies related to the molecular mechanisms of human disease. The journal welcomes research on all aspects of molecular and clinical research, ranging from biochemistry to immunology, pathology, genetics, human genomics, microbiology, molecular pathogenesis, molecular cardiology, molecular surgery and molecular psychology.

    The International Journal of Molecular Medicine aims to provide an insight for researchers within the community in regard to developing molecular tools and identifying molecular targets for the diagnosis and treatment of a diverse number of human diseases.
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