Article

Functional dominant-negative mutation of sodium channel subunit gene SCN3B associated with atrial fibrillation in a Chinese GeneID population.

Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, PR China.
Biochemical and Biophysical Research Communications (Impact Factor: 2.28). 07/2010; 398(1):98-104. DOI: 10.1016/j.bbrc.2010.06.042
Source: PubMed

ABSTRACT Atrial fibrillation (AF) is the most common cardiac arrhythmia in the clinic, and accounts for more than 15% of strokes. Mutations in cardiac sodium channel alpha, beta1 and beta2 subunit genes (SCN5A, SCN1B, and SCN2B) have been identified in AF patients. We hypothesize that mutations in the sodium channel beta3 subunit gene SCN3B are also associated with AF. To test this hypothesis, we carried out a large scale sequencing analysis of all coding exons and exon-intron boundaries of SCN3B in 477 AF patients (28.5% lone AF) from the GeneID Chinese Han population. A novel A130V mutation was identified in a 46-year-old patient with lone AF, and the mutation was absent in 500 controls. Mutation A130V dramatically decreased the cardiac sodium current density when expressed in HEK293/Na(v)1.5 stable cell line, but did not have significant effect on kinetics of activation, inactivation, and channel recovery from inactivation. When co-expressed with wild type SCN3B, the A130V mutant SCN3B negated the function of wild type SCN3B, suggesting that A130V acts by a dominant negative mechanism. Western blot analysis with biotinylated plasma membrane protein extracts revealed that A130V did not affect cell surface expression of Na(v)1.5 or SCN3B, suggesting that mutant A130V SCN3B may not inhibit sodium channel trafficking, instead may affect conduction of sodium ions due to its malfunction as an integral component of the channel complex. This study identifies the first AF-associated mutation in SCN3B, and suggests that mutations in SCN3B may be a new pathogenic cause of AF.

0 Bookmarks
 · 
131 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Atrial fibrillation (AF) is the most commonly sustained cardiac arrhythmia, and confers a substantially increased risk of morbidity and mortality. Increasing evidence has indicated that hereditary defects are implicated in AF. However, AF is genetically heterogeneous and the genetic etiology of AF in a significant portion of patients remains unclear. In this study, the entire coding sequence and splice junctions of the GATA6 gene, which encodes a zinc-finger transcription factor crucial for cardiogenesis, were sequenced in 140 unrelated patients with lone AF. The available relatives of the index patient carrying an identified mutation and 200 unrelated ethnically-matched healthy individuals used as the controls were genotyped. The functional characteristics of the mutant GATA6 were assessed in contrast to its wild-type counterpart using a luciferase reporter assay system. As a result, a novel heterozygous GATA6 mutation, p.G469V, was identified in a family with AF inherited in an autosomal dominant pattern. The mutation was absent in the 200 control individuals and the altered amino acid was completely conserved across species. Functional analysis demonstrated that the GATA6 mutation was associated with a significantly decreased transcriptional activity. The findings provide novel insight into the molecular mechanism involved in the pathogenesis of AF, as well as insight into potential therapies for the prevention and treatment of AF.
    International Journal of Molecular Medicine 07/2012; · 1.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Atrial fibrillation, the most common cardiac supraventricular arrhythmia, affects more than 5 million people worldwide. Increasing evidence has demonstrated that genetic factors play an important role in the pathogenesis of atrial fibrillation, and multiple genes responsible for atrial fibrillation have been identified. This review will focus on the recent findings in atrial fibrillation genetic studies and discuss the clinical implications of exploring the atrial fibrillation genetic basis. The advent of the candidate gene approach and genome-wide association studies has facilitated the process of investigating the complex genetic background underlying the pathogenesis of atrial fibrillation. Recent genetic investigations have offered further insights into the predisposing genes encoding ion channels, connexin, atrial natriuretic peptide, RyR2, T-box transcription factor, nucleoporins and zinc-finger transcription factor. Common single-nucleotide polymorphisms are important factors in the development of lone atrial fibrillation, recurrent atrial fibrillation or atrial fibrillation complicated with cardiac disorders. Analyses of candidate genes have revealed a growing number of atrial fibrillation-related genes. A better understanding of the genetic mechanism underlying atrial fibrillation would be expected to lead to more accurate risk stratification of atrial fibrillation and the discovery of optimal clinical treatment strategies that carry maximal efficacy and minimal risk in a manner that is consistent with the vision of pharmacogenomics.
    Current opinion in cardiology 03/2014; · 2.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Atrial fibrillation (AF) is the most common arrhythmia and is associated with increased morbidity. As the population ages and the prevalence of AF continues to rise, the socioeconomic consequences of AF will become increasingly burdensome. Although there are well-defined clinical risk factors for AF, a significant heritable component is also recognized. To identify the molecular basis for the heritability of AF, investigators have used a combination of classical Mendelian genetics, candidate gene screening, and genome-wide association studies. However, these avenues have, as yet, failed to define the majority of the heritability of AF. The goal of this review is to describe the results from both candidate gene and genome-wide studies, as well as to outline potential future avenues for creating a more complete understanding of AF genetics. Ultimately, a more comprehensive view of the genetic underpinnings for AF will lead to the identification of novel molecular pathways and improved risk prediction of this complex arrhythmia.
    Circulation Research 04/2014; 114(9):1469-82. · 11.09 Impact Factor

Full-text (2 Sources)

Download
25 Downloads
Available from
May 26, 2014