Nagasaki U Link
Nagasaki University Graduate School of Biomedical Sciences 長崎大学学院医歯薬学総合研究科

Genetic basis of lethal arrhythmias

Inherited arrhythmias (Japanese only)


We are analyzing genomic DNAs of patients and their families who are at high risk for sudden cardiac death or inherited arrhythmias including Brugada syndrome, long QT syndrome and progressive cardiac conduction defect. The total number of samples exceeds 1,400 as of March 2016. Rather than a conventional target gene approach using Sanger method, we are currently using new high throughput approaches including whole-exome sequencing and genome-wide association study to discover responsible genetic variations that may not have been previously recognized predisposing to sudden death. For defining the pathophysiological mechanisms underlying these life-threatening arrhythmias, we perform in vivo/in vitro functional analysis including patch clamp strategy and genetically modified animals. As a large international project of genome-wide association studies on Brugada syndrome (Bezzina et al. Nature Genet 2013), we identified 3 loci susceptible to BrS-type ECG. We continue working on identifying novella genetic substrates that determine the individual risks of sudden cardiac death in Brugada syndrome and long QT syndrome. This is a translational research in collaboration with many domestic and oversea institutions under the support of the AMED grant (2015-2017). As for the functional aspects of of lethal arrhythmias, we have successfully demonstrated the underlying mechanism of lethal ventricular arrhythmia associated with a novel short QT mutation using a computer simulation (Harrell et al Int J Cardiol 2015) under the support of HD Physiology grant (2009-2014). We also showed the novel pathophysiology in Brugada syndrome (Nademanee et al. J Am Coll Cardiol. 2015) and cardiac conduction defect (Daumy et al.  Int J Cardiol 2016) through extensive international collaborations.


Electrophysiological abnormality of TRPM4 mutation identified in patients with progressive cardiac conduction defect (Daumy et al. Int J Cardiol. 2016)

HD Physiology computer simulation:
Arrhythmogenicity of a novel short QT mutation.

Fibrosis and gap junction dysfunction play pivotal role in the pathogenesis of Brugada syndrome (Nademanee et al. J Am Coll Cardiol. 2015


Manhattan plot showing the association of SNPs with Brugada syndrome in a GWAS (Bezzina et al, Nat. Genet.  2013 )


E1784K Current traces

SCN5A-E1784K Current traces (Makita et al, J Clin Invest  2008)



Koichiro Yoshiura
Nagasaki University, Atomic Bomb Institute, Human Genetics
Toshihiro Tanaka
Tokyo Medical and Dental University
Minoru Horie
Shiga University of Medical Science, Cardiovascular and Respiratory Medicine
Wataru Shimizu
Nihon Medical School, Cardiology
Akihiko Nogami
Tsukuba University, Cardiology
Koji Maemura
Nagasaki University, Cardiovascular Medicine
Naoki Mochizuki
National Cerebral and Cardiovascular Center, Cell Biology
Takeru Aiba
National Cerebral and Cardiovascular Center, Cardiovascular Medicine
Takeru Makiyama
Kyoto University, Cardiovascular Medicine
Hiroshi Watanabe
Niigata University, Cardiovascular Medicine
Jean-Jacques Schott
INSERM, Nantes, France
Alfred L. George Jr.
Northwestern University, Chicago, IL, USA
Can Hasdemir
Ege University School of Medicine, Izmir, Turkey
Dan M. Roden
Vanderbilt University, Nashville, Tennessee, USA
Connie R. Bezzina
Academic Medical Center, Amsterdam, The Netherlands
Glenn I. Fishman
New York University, New York City, USA



  1. Daumy X,  Makita N, Schott J et al. “Targeted resequencing identifies TRPM4 as a major gene predisposing to progressive familial heart block type I”.Int J Cardiol. 2016; 207:349-358 (pdf) (PubMed:26820365)
  2. Nademanee K,  Makita N et al. “Fibrosis, Connexin43 and Conduction Abnormalities in the Brugada Syndrome”. J Am Coll Cardiol. 2015; 66(18):1976-1986. (pdf) (PubMed: 26516000)
  3. Koizumi A, Ishikawa T et al Eur Heart J. 2015 (in press)(PubMed:26429810)
  4. Hayashi K, Makita N et al., “Functional Characterization of Rare Variants Implicated in Susceptibility to Lone Atrial Fibrillation”.  Circ Arrhythm Electrophysiol.2015; 8: 1095-1104.(pdf) (Supplement)(PubMed: 26129877)
  5. Harrell DT, Ashihara T, Ishikawa T, Maemura K, Makita N et al. “Genotype-dependent difference in age of manifestation and arrhythmia complication in short QT syndrome”. Int J Cardiol. 2015;190:393-402. (pdf) (Supplement) (PubMed: 25974115)
  6. Ishikawa T, Harrell DT, Tsuji Y, Makita N et al. “A novel mutation in the α-myosin heavy chain gene is associated with sick sinus syndrome”. Circ Arrhythm Electrophysiol.2015; 8: 400-408. (pdf) (PubMed: 25717017)
  7. Makita N, Ishikawa T, Tsuji Y, George AL, Jr. et al. “Novel Calmodulin (CALM2) Mutations Associated with Congenital Arrhythmia Susceptibility”Circ Cardiovasc Genet 2014;7:466-474. (pdf) (PubMed: 24917665)
  8. Abe K, Harrell DT, Ishikawa T, Tsuji Y, Makita N et al. “Sodium Channelopathy Underlying Familial Sick Sinus Syndrome with Early Onset and Predominantly Male Characteristics”Circ Arrhythm Electrophysiol.2014;7:511-517. (pdf) (PubMed: 24762805)
  9. Nakano Y, Makita N et al. A nonsynonymous polymorphism in semaphorin 3A as a risk factor for human unexplained cardiac arrest with documented ventricular fibrillation. PLoS Genet. 2013;9:e1003364. (pdf) (PubMed: 23593010)
  10. Bezzina CR, Makita N et al. “Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death”.  Nat. Genet. 45, 1044-1049, 2013  (pdf)(PubMed: 23872634)
  11. Ishikawa T, Makita N et al. “A novel disease gene for Brugada syndrome: sarcolemmal membrane-associated protein gene mutations impair intracellular trafficking of hNav1.5”Circ Arrhythm Electrophysiol. 5:1098-1107,2012 (pdf) (PubMed: 23064965)
  12. Makita N, Schott JJ, et al. “A connexin40 mutation associated with a malignant variant of progressive familial heart block type I”. Circ Arrhythm Electrophysiol, 5:163-172, 2012  (pdf)(PubMed: 22247482)
  13. Makita N, George AL Jr, Roden DM et al. “The E1784K mutation in SCN5A is associated with mixed phenotype of type 3 long QT syndrome”J Clin Invest 118, 2219-2229, 2008. (pdf)(PubMed: 18451998)
  14. Makita N et al. “Drug-induced long-QT syndrome associated with a subclinical SCN5A mutation”Circulation 106, 1269-1274, 2002  (pdf)
  15. Makita N, George AL Jr. et al. “Cardiac Na+ channel dysfunction in the Brugada syndrome is aggravated by b1 subunit”. Circulation 101, 54-60, 2000 (pdf)
  16. Bennett PB, Yazawa K, Makita N, George Al. “Molecular mechanism for an inherited cardiac arrhythmia”Nature 376, 683-685,1995 (pdf)(PubMed: 7651517)
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