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
 · 
120 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major source of the substantially increased morbidity and mortality. Growing studies demonstrate that genetic defects play pivotal roles in a subgroup of AF. However, AF is a genetically heterogeneous disorder and the molecular basis of AF in a majority of cases remains unknown. The whole coding region of the GATA4 gene, which encodes a zinc-finger transcription factor essential for cardiogenesis, was analyzed in 130 unrelated probands with AF in contrast to 200 unrelated ethnically matched healthy individuals used as controls. The available family members of the probands harboring the identified mutations were genotyped. The functional effect of the mutant GATA4 was characterized using a luciferase reporter assay system. Two novel heterozygous GATA4 mutations, p.S70T and p.S160T, were identified in 2 unrelated families with AF inherited as an autosomal dominant trait, respectively, which co-segregated with AF in each family with complete penetrance. Functional analysis showed that the mutations of GATA4 were associated with a significantly decreased transcriptional activity. The findings provide new insight into the molecular mechanism involved in the pathogenesis of AF, suggesting the potential implications in the genetic diagnosis and gene-specific therapy of this common arrhythmia.
    Clinica chimica acta; international journal of clinical chemistry 06/2011; 412(19-20):1825-30. · 2.54 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cardiac sodium channel β-subunit mutations have been associated with several inherited cardiac arrhythmia syndromes. To identify and characterize variations in SCN1Bb associated with Brugada syndrome (BrS) and sudden infant death syndrome (SIDS). All known exons and intron borders of the BrS-susceptibility genes were amplified and sequenced in both directions. Wild type (WT) and mutant genes were expressed in TSA201 cells and studied using co-immunoprecipitation and whole-cell patch-clamp techniques. Patient 1 was a 44-year-old man with an ajmaline-induced type 1 ST-segment elevation in V1 and V2 supporting the diagnosis of BrS. Patient 2 was a 62-year-old woman displaying a coved-type BrS electrocardiogram who developed cardiac arrest during fever. Patient 3 was a 4-month-old female SIDS case. A R214Q variant was detected in exon 3A of SCN1Bb (Na(v)1B) in all three probands, but not in any other gene previously associated with BrS or SIDS. R214Q was identified in 4 of 807 ethnically-matched healthy controls (0.50%). Co-expression of SCN5A/WT + SCN1Bb/R214Q resulted in peak sodium channel current (I(Na)) 56.5% smaller compared to SCN5A/WT + SCN1Bb/WT (n = 11-12, P<0.05). Co-expression of KCND3/WT + SCN1Bb/R214Q induced a Kv4.3 current (transient outward potassium current, I(to)) 70.6% greater compared with KCND3/WT + SCN1Bb/WT (n = 10-11, P<0.01). Co-immunoprecipitation indicated structural association between Na(v)β1B and Na(v)1.5 and K(v)4.3. Our results suggest that R214Q variation in SCN1Bb is a functional polymorphism that may serve as a modifier of the substrate responsible for BrS or SIDS phenotypes via a combined loss of function of sodium channel current and gain of function of transient outward potassium current.
    Heart rhythm: the official journal of the Heart Rhythm Society 12/2011; 9(5):760-9. · 4.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Atrial fibrillation (AF) is the most-common sustained arrhythmia observed in clinical practice, but response to therapy is highly variable between patients. Current drug therapies to suppress AF are incompletely and unpredictably effective and carry substantial risk of proarrhythmia and noncardiac toxicities. The limited success of therapy for AF is partially the result of heterogeneity of the underlying substrate, interindividual differences in disease mechanisms, and our inability to predict response to therapies in individual patients. In this Review, we discuss the evidence that variability in response to drug therapy is also conditioned by the underlying genetic substrate for AF. Increased susceptibility to AF is mediated through diverse genetic mechanisms, including modulation of the atrial action-potential duration, conduction slowing, and impaired cell-to-cell communication, as well as novel mechanisms, such as regulation of signalling proteins important in the pathogenesis of AF. However, the translation of genetic data to the care of the patients with AF has been limited because of poor understanding of the underlying mechanisms associated with common AF-susceptibility loci, a dearth of prospective, adequately powered studies, and the challenges associated with determining efficacy of antiarrhythmic drugs. What is apparent, however, is the need for appropriately designed, genotype-directed clinical trials.
    Nature Reviews Cardiology 04/2013; · 10.40 Impact Factor

Full-text (2 Sources)

View
10 Downloads
Available from
May 26, 2014