Abstract
Since 2003, several loss-of-function mutations in the HCN4 gene, which encodes the HCN4 protein, have been associated with sinus node dysfunction. In human sinoatrial node (SAN), HCN4 is the most abundant of the four isoforms of the HCN family. Tetramers of HCN subunits constitute the ion channels that conduct the hyperpolarization-activated “funny” current (If), which plays an important modulating role in SAN pacemaker activity. Voltage-clamp experiments on HCN4 channels expressed in COS-7, CHO and HEK-293 cells, as well as in Xenopus oocytes have revealed changes in the expression and kinetics of mutant channels, but the extent to which especially the kinetic changes would affect If flowing during a human SAN action potential often remains unresolved. In our contribution to the Topical Collection on Human Single Nucleotide Polymorphisms and Disease Diagnostics, we provide an updated review of the mutation-induced changes in the expression and kinetics of HCN4 channels and provide an overview of their effects on If during the time course of a human SAN action potential, as assessed in simulated action potential clamp experiments. Future research may solve apparent inconsistencies between data from clinical studies and data from in vitro and in silico experiments.
Highlights
Since 2003, several loss-of-function mutations in the HCN4 gene, which encodes the HCN4 protein, have been associated with sinus node dysfunction
Voltage-clamp experiments on wild-type and mutant human HCN4 channels expressed in COS-7, CHO and HEK-293 cells, as well as in Xenopus oocytes have revealed changes in the expression and/or kinetics of mutant HCN4 channels, but the extent to which especially the kinetic changes would affect If flowing during a human sinoatrial node (SAN) action potential often remains unresolved
We provided an overview of the HCN4 and KCNE2 mutations associated with sinus node dysfunction [30]
Summary
The “sick sinus syndrome” has been defined as the “intrinsic inadequacy of the sinoatrial node (SAN) to perform its pacemaking function due to a disorder of automaticity and/or inability to transmit its impulse to the rest of the atrium” [1]. HCN transcript in the human SAN is HCN4 [11] It is, not surprising that the HCN4 locus has been identified as a modulator of heart rate in a genome-wide association study (GWAS) [12] and that reduced HCN4 expression due to endurance exercise is associated with a lower resting heart rate [13]. We provided an overview of the HCN4 and KCNE2 mutations associated with sinus node dysfunction [30]. This overview was limited to the seven HCN4 mutations and a single. We point to apparent inconsistencies between data from clinical studies and data from in vitro and in silico experiments
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