Circ Genom Precis Med 2021 04 25;14(2):e003144. Epub 2021 Feb 25.
Victor Chang Cardiac Research Institute, Darlinghurst (V.N.-K., C.L., A.-K.A., C.D.C., A.J., I.G.H., M.S., M.O., G.T., R.J., R.P.H., A.P.H., D.F.).
Background: encodes the α-subunit of the large-conductance Ca-activated K channel, K1.1, and lies within a linkage interval for atrial fibrillation (AF). Insights into the cardiac functions of K1.1 are limited, and has not been investigated as an AF candidate gene.
Methods: The gene was sequenced in 118 patients with familial AF. The role of K1.1 in normal cardiac structure and function was evaluated in humans, mice, zebrafish, and fly. A novel variant was functionally characterized.
Results: A complex variant was identified in 1 kindred with AF. To evaluate potential disease mechanisms, we first evaluated the distribution of K1.1 in normal hearts using immunostaining and immunogold electron microscopy. K1.1 was seen throughout the atria and ventricles in humans and mice, with strong expression in the sinus node. In an ex vivo murine sinoatrial node preparation, addition of the K1.1 antagonist, paxilline, blunted the increase in beating rate induced by adrenergic receptor stimulation. Knockdown of the K1.1 ortholog, , in zebrafish embryos resulted in sinus bradycardia with dilatation and reduced contraction of the atrium and ventricle. Genetic inactivation of the K1.1 ortholog, , systemically or in adult stages, also slowed the heartbeat and produced fibrillatory cardiac contractions. Electrophysiological characterization of -deficient flies revealed bursts of action potentials, reflecting increased events of fibrillatory arrhythmias. Flies with cardiac-specific overexpression of the human mutant also showed increased heart period and bursts of action potentials, similar to the K1.1 loss-of-function models.
Conclusions: Our data point to a highly conserved role of K1.1 in sinus node function in humans, mice, zebrafish, and fly and suggest that K1.1 loss of function may predispose to AF.