title: Functional dominant-negative mutation of sodium channel subunit gene SCN3B associated with atrial fibrillation in a Chinese GeneID population.
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.
authors.affiliation: 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.
authors.forename: Pengyun
authors.initials: P
authors.lastname: Wang
authors.forename: Qinbo
authors.initials: Q
authors.lastname: Yang
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Wu
authors.forename: Yanzong
authors.initials: Y
authors.lastname: Yang
authors.forename: Lisong
authors.initials: L
authors.lastname: Shi
authors.forename: Chuchu
authors.initials: C
authors.lastname: Wang
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Xia
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.forename: Rongfeng
authors.initials: R
authors.lastname: Zhang
authors.forename: Chengqi
authors.initials: C
authors.lastname: Xu
authors.forename: Xiang
authors.initials: X
authors.lastname: Cheng
authors.forename: Sisi
authors.initials: S
authors.lastname: Li
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Fenfen
authors.initials: F
authors.lastname: Fu
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Liao
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.forename: Qiuyun
authors.initials: Q
authors.lastname: Chen
authors.forename: Xin
authors.initials: X
authors.lastname: Tu
authors.forename: Qing K
authors.initials: QK
authors.lastname: Wang
mesh_terms: D000368:Aged; D044466:Asian People / Q000235:genetics*; D001281:Atrial Fibrillation / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015222:Sodium Channels / Q000235:genetics*; D062549:Voltage-Gated Sodium Channel beta-3 Subunit
chemical_list: C493324:SCN3B protein, human; D015222:Sodium Channels; D062549:Voltage-Gated Sodium Channel beta-3 Subunit