Biochemical and Biophysical Research Communications
Gain-of-function mutation of Nav1.5 in atrial fibrillation enhances cellular excitability and lowers the threshold for action potential firing
Section snippets
Methods
Molecular screening. Genomic DNA was extracted from whole blood from probands with “idiopathic” AF. Genetic analysis was performed by direct DNA sequencing of the coding region of the GJA5, KCNQ1, KCNA5, and SCN5A genes. Affected and control patients in this study were of Western European descent. All study participants provided written informed consent and the research protocol was approved by the Ethics Board of the University of Ottawa Heart Institute.
Expression of Nav1.5 in tsA201 cells and
Mutation detection and clinical phenotype
DNA sequencing identified a novel, heterozygous mutation in exon 26 of the SCN5A gene in a single proband and his affected mother. This mutation leads to an amino acid substitution of lysine for arginine (K1493R) in the DIII–IV linker of the Nav1.5 channel (Fig. 1A). K1493 is a highly conserved amino acid across species and is six amino acids downstream from the fast inactivation IFM (isoleucine–phenylalanine–methionine) motif of sodium channels (Fig. 1B) [8]. This genetic variant was absent
Discussion
We describe the association of a novel genetic mutation in the voltage-gated cardiac sodium channel gene with lone atrial fibrillation. This missense K1493R mutation was present in a mother and son with early onset atrial fibrillation and no structural heart disease. The highly conserved, charged K1493 residue is located within the cytoplasmic loop domain which joins domains III and IV, and is six amino acids C-terminal to the fast inactivation IFM (isoleucine–phenylalanine–methionine) motif of
Acknowledgments
This work was supported in part by grants from the Heart and Stroke Foundations of Ontario (M.H.G.) and Quebec (M.C.), and from the Early Researcher Award program from the Government of Ontario (M.H.G.).
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