著者
Mari Ichikawa Takeshi Aiba Seiko Ohno Daichi Shigemizu Junichi Ozawa Keiko Sonoda Megumi Fukuyama Hideki Itoh Yoshihiro Miyamoto Tatsuhiko Tsunoda Takeru Makiyama Toshihiro Tanaka Wataru Shimizu Minoru Horie
出版者
日本循環器学会
雑誌
Circulation Journal (ISSN:13469843)
巻号頁・発行日
pp.CJ-16-0486, (Released:2016-10-25)
参考文献数
33
被引用文献数
1 9

Background:Mutations inANK2have been reported to cause various arrhythmia phenotypes. The prevalence ofANK2mutation carriers in inherited primary arrhythmia syndrome (IPAS), however, remains unknown in Japanese. Using a next-generation sequencer, we aimed to identifyANK2mutations in our cohort of IPAS patients, in whom conventional Sanger sequencing failed to identify pathogenic mutations in major causative genes, and to assess the clinical characteristics ofANK2mutation carriers.Methods and Results:We screened 535 probands with IPAS and analyzed 46 genes including wholeANK2exons using a bench-top NGS (MiSeq, Illumina) or performed whole-exome-sequencing using HiSeq2000 (Illumina). As a result, 12 of 535 probands (2.2%, aged 0–61 years, 5 males) were found to carry 7 different heterozygousANK2mutations.ANK2-W1535R was identified in 5 LQTS patients and 1 symptomatic BrS and was predicted as damaging by multiple prediction software. In total, as to phenotype, there were 8 LQTS, 2 BrS, 1 IVF, and 1 SSS/AF. Surprisingly, 4/8 LQTS patients had the acquired type of LQTS (aLQTS) and suffered torsades de pointes. A total of 7 of 12 patients had documented malignant ventricular tachyarrhythmias.Conclusions:VariousANK2mutations are associated with a wide range of phenotypes, including aLQTS, especially with ventricular fibrillation, representing “ankyrin-B” syndrome.
著者
Hideki Itoh Kotaro Oyama Madoka Suzuki Shin’ichi Ishiwata
出版者
日本生物物理学会
雑誌
BIOPHYSICS (ISSN:13492942)
巻号頁・発行日
vol.10, pp.109-119, 2014 (Released:2014-12-17)
参考文献数
41
被引用文献数
5 8

Temperature-sensitive Ca2+ dynamics occur primarily through transient receptor potential channels, but also by means of Ca2+ channels and pumps on the endoplasmic reticulum membrane. As such, cytoplasmic Ca2+ concentration ([Ca2+]cyt) is re-equilibrated by changes in ambient temperature. The present study investigated the effects of heat pulses (heating duration: 2 s or 150 s) on [Ca2+]cyt in single WI-38 fibroblasts, which are considered as normal cells. We found that Ca2+ burst occurred immediately after short (2 s) heat pulse, which is similar to our previous report on HeLa cells, but with less thermosensitivity. The heat pulses originated from a focused 1455-nm infrared laser light were applied in the vicinity of cells under the optical microscope. Ca2+ bursts induced by the heat pulse were suppressed by treating cells with inhibitors for sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) or inositol trisphosphate receptor (IP3R). Long (150 s) heat pulses also induced Ca2+ bursts after the onset of heating and immediately after re-cooling. Cells were more thermosensitive at physiological (37°C) than at room (25°C) temperature; however, at 37°C, cells were responsive at a higher temperature (ambient temperature+heat pulse). These results strongly suggest that the heat pulse-induced Ca2+ burst is caused by a transient imbalance in Ca2+ flow between SERCA and IP3R, and offer a potential new method for thermally controlling Ca2+-regulated cellular functions.
著者
Tomoko Sakaguchi Hideki Itoh Wei-Guang Ding Keiko Tsuji Iori Nagaoka Yuko Oka Takashi Ashihara Makoto Ito Yoshihiro Yumoto Naoko Zenda Yukei Higashi Youichi Takeyama Hiroshi Matsuura Minoru Horie
出版者
(公社)日本薬理学会
雑誌
Journal of Pharmacological Sciences (ISSN:13478613)
巻号頁・発行日
vol.108, no.4, pp.462-471, 2008 (Released:2008-12-20)
参考文献数
26
被引用文献数
14 26

QT prolongation, a risk factor for arrhythmias, can result from genetic variants in one (or more) of the genes governing cardiac repolarization as well as intake of drugs known to affect a cardiac K+ channel encoded by human ether-a-go-go–related gene (HERG). In this paper, we will report a case of drug-induced long QT syndrome associated with an H1-receptor antagonist, hydroxyzine, in which a mutation was identified in the HERG gene. After taking 75 mg of hydroxyzine for several days, a 34-year-old female began to experience repetitive syncope. The deleterious effect of hydroxyzine was suspected because QTc interval shortened from 630 to 464 ms after cessation of the drug. Later on, the patient was found to harbor an A614V-HERG mutation. By using the patch-clamp technique in the heterologous expression system, we examined the functional outcome of the A614V mutation and confirmed a dominant-negative effect on HERG expression. Hydroxyzine concentration-dependently inhibited both wild-type (WT) and WT/A614V-HERG K+ currents. Half-maximum block concentrations of WT and WT/A614V-HERG K+ currents were 0.62 and 0.52 μM, respectively. Thus, accidental combination of genetic mutation and intake of hydroxyzine appeared to have led to a severe phenotype, probably, syncope due to torsade de pointes.