Functional dominant-negative mutation of sodium channel subunit gene SCN3B associated with atrial fibrillation in a Chinese GeneID population.
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.
Wang
Pengyun
P
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.
Yang
Qinbo
Q
Wu
Xiaofen
X
Yang
Yanzong
Y
Shi
Lisong
L
Wang
Chuchu
C
Wu
Gang
G
Xia
Yunlong
Y
Yang
Bo
B
Zhang
Rongfeng
R
Xu
Chengqi
C
Cheng
Xiang
X
Li
Sisi
S
Zhao
Yuanyuan
Y
Fu
Fenfen
F
Liao
Yuhua
Y
Fang
Fang
F
Chen
Qiuyun
Q
Tu
Xin
X
Wang
Qing K
QK
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
C493324:SCN3B protein, human; D015222:Sodium Channels; D062549:Voltage-Gated Sodium Channel beta-3 Subunit