Identification of transmembrane protein 168 mutation in familial Brugada syndrome

FASEB J. 2020 May;34(5):6399-6417. doi: 10.1096/fj.201902991R.

Akio Shimizu ¹, Dimitar P Zankov ¹ ², Akira Sato ¹, Masahiro Komeno ¹, Futoshi Toyoda ³, Satoru Yamazaki ⁴, Toshinori Makita ⁵, Taichi Noda ⁶, Masahito Ikawa ⁶, Yoshihiro Asano ⁷, Yohei Miyashita ⁸, Seiji Takashima ⁹, Hiroshi Morita ¹⁰, Taisuke Ishikawa ¹¹, Naomasa Makita ¹¹, Masahito Hitosugi ¹², Hiroshi Matsuura ³, Seiko Ohno ² ¹³, Minoru Horie ¹³, Hisakazu Ogita ¹

Affiliations

1 Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science, Otsu, Japan.
2 Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Suita, Japan.
3 Division of Cell Physiology, Department of Physiology, Shiga University of Medical Science, Otsu, Japan.
4 Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center, Suita, Japan.
5 Division of Cardiac Electrophysiology, Department of Cardiovascular Center, Osaka Red Cross Hospital, Osaka, Japan.
6 Animal Resource Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.
7 Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
8 Department of Legal Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
9 Department of Medical Biochemistry, Osaka University Graduate School of Medicine, Suita, Japan.
10 Department of Cardiovascular Therapeutics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
11 Omics Research Center, National Cerebral and Cardiovascular Center, Suita, Japan.
12 Department of Legal Medicine, Shiga University of Medical Science, Otsu, Japan.
13 Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan.

PMID: 32175648 DOI: 10.1096/fj.201902991R

Abstract

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 Na_v 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 Na_v 1.5 expression was also impaired. This impairment was dependent on increased Nedd4-2 binding to Na_v 1.5 and subsequent ubiquitination. Collectively, our results show an association between the TMEM168 1616G>A mutation and arrhythmogenesis in a family with BrS.

Keywords

fatal ventricular arrhythmia; sodium channel; ubiquitination.

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