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Heterozygous carriers of the A414G mutation in the HCN4 gene, which encodes the HCN4 protein, show moderate to severe sinus bradycardia. Tetramers of HCN4 subunits constitute the ion channels that conduct the cardiac hyperpolarization-activated &#x2018;funny current&#x2019; (I f ), which plays an important modulating role in the pacemaker activity of sinus node cells.We assessed the mechanism by which the A414G mutation in HCN4 causes sinus bradycardia. We carried out voltage clamp experiments on HCN4 channels expressed in Chinese hamster ovary (CHO) cells and incorporated the experimentally observed mutation-induced changes in I f  into the Fabbri-Severi model of a single human sinus node cell.In the Fabbri-Severi model, the experimentally observed effects on I f  increased the cycle length from 813 to 1004 ms, corresponding with a 19% decrease in beating rate from 74 to 60 beats/min. These mutation effects became more prominent at 10 nM ACh (vagal tone) and in the presence of a hyperpolarizing atrial load.We conclude that the experimentally identified mutation-induced changes in I f  can explain the clinically observed sinus bradycardia in carriers of the A414G mutation in the HCN4 gene.

Mechanism of Sinus Bradycardia in Carriers of the A414G Mutation in the HCN4 Gene