@article{oai:shiga-med.repo.nii.ac.jp:00003521,
 author = {清水, 昭男 and 佐藤, 朗 and 米野, 雅大 and 豊田, 太 and 一杉, 正仁 and 松浦, 博 and 大野, 聖子 and 堀江, 稔 and 扇田, 久和 and SHIMIZU, Akio and ZANKOV, Dimitar Petrov and SATO, Akira and KOMENO, Masahiro and TOYODA, Futoshi and YAMAZAKI, Satoru and MAKITA, Toshinori and NODA, Taichi and IKAWA, Masahito and ASANO, Yoshihiro and MIYASHITA, Yohei and TAKASHIMA, Seiji and MORITA, Hiroshi and ISHIKAWA, Taisuke and MAKITA, Naomasa and HITOSUGI, Masahito and MATSUURA, Hiroshi and OHNO, Seiko and HORIE, Minoru and 扇田, 久和},
 journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
 month = {Mar},
 note = {Brugada syndrome (BrS) is an inherited channelopathy responsible for almost 20% of sudden cardiac deaths in patients with nonstructural cardiac diseases. Approximately 70% of BrS patients, the causative gene mutation(s) remains unknown. In this study, we used whole exome sequencing to investigate candidate mutations in a family clinically diagnosed with BrS. A heterozygous 1616G>A substitution (R539Q mutation) was identified in the transmembrane protein 168 (TMEM168) gene of symptomatic individuals. Similar to endogenous TMEM168, both TMEM168 wild-type (WT) and mutant proteins that were ectopically induced in HL-1 cells showed nuclear membrane localization. A significant decrease in Na+ current and Nav 1.5 protein expression was observed in HL-1 cardiomyocytes expressing mutant TMEM168. Ventricular tachyarrhythmias and conduction disorders were induced in the heterozygous Tmem168 1616G>A knock-in mice by pharmacological stimulation, but not in WT mice. Na+ current was reduced in ventricular cardiomyocytes isolated from the Tmem168 knock-in heart, and Nav 1.5 expression was also impaired. This impairment was dependent on increased Nedd4-2 binding to Nav 1.5 and subsequent ubiquitination. Collectively, our results show an association between the TMEM168 1616G>A mutation and arrhythmogenesis in a family with BrS., Journal Article},
 title = {Identification of transmembrane protein 168 mutation in familial Brugada syndrome.},
 year = {2020}
}