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Background: Bradyarrhythmia is a common clinical manifestation. Although the majority of cases are acquired, genetic analysis of families with bradyarrhythmia has identified a growing number of causative gene mutations. Because the only ultimate treatment for symptomatic bradyarrhythmia has been invasive surgical implantation of a pacemaker, the discovery of novel therapeutic molecular targets is necessary to improve prognosis and quality of life. Methods: We investigated a family containing 7 individuals with autosomal dominant bradyarrhythmias of sinus node dysfunction, atrial fibrillation with slow ventricular response, and atrioventricular block. To identify the causative mutation, we conducted the family-based whole exome sequencing and genome-wide linkage analysis. We characterized the mutation-related mechanisms based on the pathophysiology in vitro. After generating a transgenic animal model to confirm the human phenotypes of bradyarrhythmia, we also evaluated the efficacy of a newly identified molecular-targeted compound to upregulate heart rate in bradyarrhythmias by using the animal model. Results: We identified one heterozygous mutation,KCNJ3 c.247A&gt;C, p.N83H, as a novel cause of hereditary bradyarrhythmias in this family.KCNJ3 encodes the inwardly rectifying potassium channel Kir3.1, which combines with Kir3.4 (encoded byKCNJ5 ) to form the acetylcholine-activated potassium channel (I KACh channel) with specific expression in the atrium. An additional study using a genome cohort of 2185 patients with sporadic atrial fibrillation revealed another 5 rare mutations inKCNJ3 andKCNJ5 , suggesting the relevance of both genes to these arrhythmias. Cellular electrophysiological studies revealed that theKCNJ3 p.N83H mutation caused a gain ofI KACh channel function by increasing the basal current, even in the absence of m2 muscarinic receptor stimulation. We generated transgenic zebrafish expressing mutant humanKCNJ3 in the atrium specifically. It is interesting to note that the selectiveI KACh channel blocker NIP-151 repressed the increased current and improved bradyarrhythmia phenotypes in the mutant zebrafish.Conclusions: TheI KACh channel is associated with the pathophysiology of bradyarrhythmia and atrial fibrillation, and the mutantI KACh channel (KCNJ3 p.N83H) can be effectively inhibited by NIP-151, a selectiveI KACh channel blocker. Thus, theI KACh channel might be considered to be a suitable pharmacological target for patients who have bradyarrhythmia with a gain-of-function mutation in theI KACh channel.

Mutant KCNJ3 and KCNJ5 Potassium Channels as Novel Molecular Targets in Bradyarrhythmias and Atrial Fibrillation