Article
Author: Miura, Katsuyuki ; Komuro, Issei ; Fujita, Masashi ; Yamada, Noriaki ; Inanobe, Atsushi ; Kitakaze, Masafumi ; Asanuma, Hiroshi ; Ebana, Yusuke ; Naiki, Nobu ; Ishino, Saki ; Shimizu, Akio ; Yamazaki, Satoru ; Shinomiya, Haruki ; Kurachi, Yoshihisa ; Kobayashi, Hatasu ; Ueshima, Hirotsugu ; Asakura, Masanori ; Minamino, Tetsuo ; Nishida, Yuya ; Matsuura, Norio ; Yamashita, Toru ; Yamagishi, Masakazu ; Hashimoto, Norio ; Kioka, Hidetaka ; Zankov, Dimitar P. ; Makiyama, Takeru ; Koizumi, Akio ; Kato, Hisakazu ; Miyashita, Yohei ; Ogita, Hisakazu ; Horie, Minoru ; Ohno, Seiko ; Asano, Yoshihiro ; Hayashi, Kenshi ; Takuwa, Ayako ; Kawakami, Koichi ; Tsukamoto, Osamu ; Furukawa, Tetsushi ; Takashima, Seiji ; Sakata, Yasushi
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 (
IKACh
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
IKACh
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
IKACh
channel blocker NIP-151 repressed the increased current and improved bradyarrhythmia phenotypes in the mutant zebrafish.
Conclusions::
The
IKACh
channel is associated with the pathophysiology of bradyarrhythmia and atrial fibrillation, and the mutant
IKACh
channel (
KCNJ3
p.N83H) can be effectively inhibited by NIP-151, a selective
IKACh
channel blocker. Thus, the
IKACh
channel might be considered to be a suitable pharmacological target for patients who have bradyarrhythmia with a gain-of-function mutation in the
IKACh
channel.