The KCNJ3 p.N83H mutation causes hereditary bradyarrhythmias via gain of IKACh channel function, which was effectively inhibited by the selective blocker NIP-151 in a transgenic zebrafish model.
The KCNJ3 p.N83H gain-of-function mutation causes hereditary bradyarrhythmias, and its effects can be reversed by the selective I KACh channel blocker NIP-151 in a zebrafish model, suggesting a novel therapeutic target.
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>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 by KCNJ5 ) 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 in KCNJ3 and KCNJ5 , suggesting the relevance of both genes to these arrhythmias. Cellular electrophysiological studies revealed that the KCNJ3 p.N83H mutation caused a gain of I KACh channel function by increasing the basal current, even in the absence of m 2 muscarinic receptor stimulation. We generated transgenic zebrafish expressing mutant human KCNJ3 in the atrium specifically. It is interesting to note that the selective I KACh channel blocker NIP-151 repressed the increased current and improved bradyarrhythmia phenotypes in the mutant zebrafish. Conclusions: The I KACh channel is associated with the pathophysiology of bradyarrhythmia and atrial fibrillation, and the mutant I KACh channel ( KCNJ3 p.N83H) can be effectively inhibited by NIP-151, a selective I KACh channel blocker. Thus, the I KACh channel might be considered to be a suitable pharmacological target for patients who have bradyarrhythmia with a gain-of-function mutation in the I KACh channel.
Yamada et al. (Fri,) conducted a other in Bradyarrhythmias and Atrial Fibrillation (n=2,192). KCNJ3 p.N83H mutation was evaluated on Identification of causative mutation and channel function. The KCNJ3 p.N83H mutation causes hereditary bradyarrhythmias via gain of IKACh channel function, which was effectively inhibited by the selective blocker NIP-151 in a transgenic zebrafish model.
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