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Molecular genetics of Brugada syndrome |
| Tie KE1,Xin TU1,Shuoyan ZHANG2,Yuhua LIAO3,Qing K. WANG4, |
| 1.Key Laboratory of Molecular
Biophysics of the Ministry of Education, College of Life Science and
Technology and Center for Human Genome Research, Huazhong University
of Science and Technology, Wuhan 430074, China；Cardio-X Institute, Huazhong
University of Science and Technology, Wuhan 430074, China; 2.Institute of Cardiology,
Union Hospital, Tongji Medical College, Huazhong University of Science
and Technology, Wuhan 430074, China; 3.Cardio-X Institute, Huazhong
University of Science and Technology, Wuhan 430074, China；Institute of Cardiology,
Union Hospital, Tongji Medical College, Huazhong University of Science
and Technology, Wuhan 430074, China; 4.Key Laboratory of Molecular
Biophysics of the Ministry of Education, College of Life Science and
Technology and Center for Human Genome Research, Huazhong University
of Science and Technology, Wuhan 430074, China；Cardio-X Institute, Huazhong
University of Science and Technology, Wuhan 430074, China；Center for Cardiovascular
Genetics, Cleveland Clinic, Cleveland, OH 44195, USA; |
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Abstract Brugada syndrome (BrS) is a life-threatening cardiac rhythm disorder characterized by persistent ST-segment elevation in leads V1―V3 and right bundle branch block on electrocardiograms (ECG), and by syncope and sudden death from ventricular tachycardia (VT) and ventricular fibrillation (VF). BrS is responsible for nearly 4% of sudden cardiac deaths and considered to be the most common cause of natural death in males younger than 50 years in some Asian countries. Since the first disease-causing gene for BrS (the cardiac sodium channel gene SCN5A) was identified in 1998, extensive investigations on both clinical and basic aspects of BrS have occurred rapidly. SCN5A mutations remain the most common cause of BrS; nearly 300 SCN5A mutations have been identified and are responsible for 20%―30% of BrS cases. Commercial genetic testing is available for SCN5A. Recently, seven other disease-causing genes for BrS have been identified and include GPD1L (BrS2), CACNA1C (Cav1.2, BrS3), CACNB2 (Cavβ2, BrS4), SCN1B (Navβ1, BrS5), KCNE3 (MiRP2, BrS6), SCN3B (Navβ3, BrS7), and HCN4 (BrS8). This article will briefly review the progress made over the past decade in our understanding of the clinical, genetic and molecular aspects of BrS.
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| Keywords
Brugada syndrome
molecular genetics
arrhythmia
sudden death
SCN5A
ion channel
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Issue Date: 01 August 2010
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Abbott G W, Goldstein S A(2001). Potassiumchannel subunits encoded by the KCNE gene family: physiology and pathophysiologyof the MinK-related peptides (MiRPs). MolInterv, 1(2): 95―107
|
|
Antzelevitch C(2001). The Brugada syndrome: ionic basis and arrhythmia mechanisms. J Cardiovasc Electrophysiol, 12(2): 268―272
|
|
Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, LeMarec H, Nademanee K, Perez Riera A R, Shimizu W, Schulze-Bahr E, Tan H, Wilde A(2005). Brugada syndrome:report of the second consensus conference: endorsed by the Heart RhythmSociety and the European Heart Rhythm Association. Circulation, 111(5): 659―670
|
|
Antzelevitch C, Brugada R(2002). Feverand Brugada syndrome. Pacing Clin Electrophysiol, 25(11): 1537―1539
|
|
Antzelevitch C, Nof E(2008). Brugadasyndrome: recent advances and controversies. Curr Cardiol Rep, 10(5): 376―383
|
|
Antzelevitch C, Pollevick G D, Cordeiro J M, Casis O, Sanguinetti M C, Aizawa Y, Guerchicoff A, Pfeiffer R, Oliva A, Wollnik B, Gelber P, Bonaros E P Jr, Burashnikov E, Wu Y, Sargent J D, Schickel S, Oberheiden R, Bhatia A, Hsu L F, Ha?ssaguerre M, Schimpf R, Borggrefe M, Wolpert C(2007). Loss-of-functionmutations in the cardiac calcium channel underlie a new clinical entitycharacterized by ST-segment elevation, short QT intervals, and suddencardiac death. Circulation, 115(4): 442―449
|
|
Bai R, Napolitano C, Bloise R, Monteforte N, Priori S G(2009). Yieldof genetic screening in inherited cardiac channelopathies: how toprioritize access to genetic testing. CircArrhythm Electrophysiol, 2(1): 6―15
|
|
Barajas-Martinez H, Haufe V, Chamberland C, Roy M J, Fecteau M H, Cordeiro J M, Dumaine R(2009). Largerdispersion of INa in female dog ventricle as a mechanism for gender-specificincidence of cardiac arrhythmias. CardiovascRes, 81(1): 82―89
|
|
Benito B, Brugada J, Brugada R, Brugada P(2009). Brugada syndrome. Rev EspCardiol, 62(11): 1297―1315
|
|
Bezzina C, Veldkamp M W, van Den Berg M P, Postma A V, Rook M B, Viersma J W, van Langen I M, Tan-Sindhunata G, Bink-Boelkens M T, van DerHout A H, Mannens M M, Wilde A A(1999). A singleNa(+) channel mutation causing both long-QT and Brugada syndromes. Circ Res, 85(12): 1206―1213
|
|
Bezzina C R, Shimizu W, Yang P, Koopmann T T, Tanck M W, Miyamoto Y, Kamakura S, Roden D M, Wilde A A(2006). Common sodium channel promoter haplotypein Asian subjects underlies variability in cardiac conduction. Circulation, 113(3): 338―344
|
|
Bodi I, Mikala G, Koch S E, Akhter S A, Schwartz A(2005). The L-typecalcium channel in the heart: the beat goes on. J Clin Invest, 115(12): 3306―3317
|
|
Brugada P, Brugada J(1992). Rightbundle branch block, persistent ST segment elevation and sudden cardiacdeath: a distinct clinical and electrocardiographic syndrome. A multicenterreport. J Am Coll Cardiol, 20(6): 1391―1396
|
|
Chen Q, Kirsch G E, Zhang D, Brugada R, Brugada J, Brugada P, Potenza D, Moya A, Borggrefe M, Breithardt G, Ortiz-Lopez R, Wang Z, Antzelevitch C, O’Brien R E, Schulze-Bahr E, Keating M T, Towbin J A, Wang Q(1998). Genetic basis and molecular mechanismfor idiopathic ventricular fibrillation. Nature, 392(6673): 293―296
|
|
Cordeiro J M, Barajas-Martinez H, Hong K, Burashnikov E, Pfeiffer R, Orsino A M, Wu Y S, Hu D, Brugada J, Brugada P, Antzelevitch C, Dumaine R, Brugada R(2006). Compoundheterozygous mutations P336L and I1660V in the human cardiac sodiumchannel associated with the Brugada syndrome. Circulation, 114(19): 2026―2033
|
|
Cordeiro J M, Marieb M, Pfeiffer R, Calloe K, Burashnikov E, Antzelevitch C(2009). Accelerated inactivation of the L-typecalcium current due to a mutation in CACNB2b underlies Brugada syndrome. J Mol Cell Cardiol, 46(5): 695―703
|
|
Delpón E, Cordeiro J M, Nú?ez L, Thomsen P E, Guerchicoff A, Pollevick G D, Wu Y, Kanters J K, Larsen C T, Hofman-Bang J, Burashnikov E, Christiansen M, Antzelevitch C(2008). Functionaleffects of KCNE3 mutation and its role in the development of Brugadasyndrome. Circ Arrhythm Electrophysiol, 1(3): 209―218
|
|
Di Diego J M, Cordeiro J M, Goodrow R J, Fish J M, Zygmunt A C, Pérez G J, Scornik F S, Antzelevitch C(2002). Ionic and cellular basis for thepredominance of the Brugada syndrome phenotype in males. Circulation, 106(15): 2004―2011
|
|
Donohue D, Tehrani F, Jamehdor R, Lam C, Movahed M R(2008). The prevalence ofBrugada ECG in adult patients in a large university hospital in thewestern United States. Am Heart Hosp J, 6(1): 48―50
|
|
Eleftheriadis D, Panagiotis V, Eleftheriadis N(2004). Recurrent syncopic episodes as aconsequence of combined Brugada syndrome and paroxysmal atrial fibrillation.Which is the therapy of choice? Int J Cardiol, 94(2―3): 319―320
|
|
Fowler S J, Napolitano C, Priori S G(2010). When is genetic testing useful inpatients suspected to have inherited cardiac arrhythmias? Curr Opin Cardiol, 25(1): 37―45
|
|
Frustaci A, Priori S G, Pieroni M, Chimenti C, Napolitano C, Rivolta I, Sanna T, Bellocci F, Russo M A(2005). Cardiac histological substrate in patients with clinicalphenotype of Brugada syndrome. Circulation, 112(24): 3680―3687
|
|
Ginsburg G S, Willard H F(2009). Genomicand personalized medicine: foundations and applications. Transl Res, 154(6): 277―287
|
|
Hedley P L, J?rgensen P, Schlamowitz S, Moolman-Smook J, Kanters J K, Corfield V A, Christiansen M(2009). The genetic basis of Brugada syndrome:a mutation update. Hum Mutat, 30(9): 1256―1266
|
|
Hermida J S, Lemoine J L, Aoun F B, Jarry G, Rey J L, Quiret J C(2000). Prevalence of the brugada syndrome in an apparentlyhealthy population. Am J Cardiol, 86(1): 91―94
|
|
Hu D, Barajas-Martinez H, Burashnikov E, Springer M, Wu Y, Varro A, Pfeiffer R, Koopmann T T, Cordeiro J M, Guerchicoff A, Pollevick G D, Antzelevitch C(2009). A mutation in the beta 3 subunitof the cardiac sodium channel associated with Brugada ECG phenotype. Circ Cardiovasc Genet, 2(3): 270―278
|
|
|
|
London B, Michalec M, Mehdi H, Zhu X, Kerchner L, Sanyal S, Viswanathan P C, Pfahnl A E, Shang L L, Madhusudanan M, Baty C J, Lagana S, Aleong R, Gutmann R, Ackerman M J, McNamara D M, Weiss R, Dudley S C Jr(2007). Mutation in glycerol-3-phosphate dehydrogenase1 like gene (GPD1-L) decreases cardiac Na+ current and causes inheritedarrhythmias. Circulation, 116(20): 2260―2268
|
|
Makielski J C, Farley A L(2006). Na(+)current in human ventricle: implications for sodium loading and homeostasis. J Cardiovasc Electrophysiol, 17(Suppl 1): S15―S20
|
|
Makiyama T, Akao M, Haruna Y, Tsuji K, Doi T, Ohno S, Nishio Y, Kita T, Horie M(2008). Mutation analysis of the glycerol-3 phosphate dehydrogenase-1 like(GPD1L) gene in Japanese patients with Brugada syndrome. Circ J, 72(10): 1705―1706
|
|
Matsuo K, Kurita T, Inagaki M, Kakishita M, Aihara N, Shimizu W, Taguchi A, Suyama K, Kamakura S, Shimomura K(1999). The circadian pattern of the development of ventricularfibrillation in patients with Brugada syndrome. Eur Heart J, 20(6): 465―470
|
|
Miyasaka Y, Tsuji H, Yamada K, Tokunaga S, Saito D, Imuro Y, Matsumoto N, Iwasaka T(2001). Prevalenceand mortality of the Brugada-type electrocardiogram in one city inJapan. J Am Coll Cardiol, 38(3): 771―774
|
|
Morita H, Kusano-Fukushima K, Nagase S, Fujimoto Y, Hisamatsu K, Fujio H, Haraoka K, Kobayashi M, Morita S T, Nakamura K, Emori T, Matsubara H, Hina K, Kita T, Fukatani M, Ohe T(2002). Atrialfibrillation and atrial vulnerability in patients with Brugada syndrome. J Am Coll Cardiol, 40(8): 1437―1444
|
|
Ogawa R, Kishi R, Takagi A, Sakaue I, Takahashi H, Matsumoto N, Masuhara K, Nakazawa K, Kobayashi S, Miyake F, Echizen H(2010). A novelmicrosatellite polymorphism of sodium channel beta1-subunit gene (SCN1B)may underlie abnormal cardiac excitation manifested by coved-typeST-elevation compatible with Brugada syndrome in Japanese. Int J Clin Pharmacol Ther, 48(2): 109―119
|
|
Papavassiliu T, Wolpert C, Flüchter S, Schimpf R, Neff W, Haase K K, Düber C, Borggrefe M(2004). Magneticresonance imaging findings in patients with Brugada syndrome. J Cardiovasc Electrophysiol, 15(10): 1133―1138
|
|
Pereira N L, Weinshilboum R M(2009). Cardiovascularpharmacogenomics and individualized drug therapy. Nat Rev Cardiol, 6(10): 632―638
|
|
Poelzing S, Forleo C, Samodell M, Dudash L, Sorrentino S, Anaclerio M, Troccoli R, Iacoviello M, Romito R, Guida P, Chahine M, Pitzalis M, Deschênes I(2006). SCN5Apolymorphism restores trafficking of a Brugada syndrome mutation ona separate gene. Circulation, 114(5): 368―376
|
|
Robin N H, Tabereaux P B, Benza R, Korf B R(2007). Genetic testing in cardiovascular disease. J Am Coll Cardiol, 50(8): 727―737
|
|
Rossenbacker T, Carroll S J, Liu H, Kuipéri C, de Ravel T J, Devriendt K, Carmeliet P, Kass R S, Heidbüchel H(2004). Novel pore mutationin SCN5A manifests as a spectrum of phenotypes ranging from atrialflutter, conduction disease, and Brugada syndrome to sudden cardiacdeath. Heart Rhythm, 1(5): 610―615
|
|
Rossenbacker T, Priori S G(2007). The Brugadasyndrome. Curr Opin Cardiol, 22(3): 163―170
|
|
Ruan Y, Liu N, Napolitano C, Priori S G(2008). Therapeutic strategies for long-QT syndrome: does themolecular substrate matter? Circ ArrhythmElectrophysiol, 1(4): 290―297
|
|
|
|
Schimpf R, Borggrefe M, Wolpert C(2008). Clinical and molecular genetics ofthe short QT syndrome. Curr Opin Cardiol, 23(3): 192―198
|
|
Schulze-Bahr E, Eckardt L, Breithardt G, Seidl K, Wichter T, Wolpert C, Borggrefe M, Haverkamp W(2003). Sodium channel gene (SCN5A) mutationsin 44 index patients with Brugada syndrome: different incidences infamilial and sporadic disease. Hum Mutat, 21(6): 651―652
|
|
Scragg J L, Jones R D, Channer K S, Jones T H, Peers C(2004). Testosterone is apotent inhibitor of L-type Ca(2+) channels. Biochem Biophys Res Commun, 318(2): 503―506
|
|
Shirai N, Makita N, Sasaki K, Yokoi H, Sakuma I, Sakurada H, Akai J, Kimura A, Hiraoka M, Kitabatake A(2002). A mutantcardiac sodium channel with multiple biophysical defects associatedwith overlapping clinical features of Brugada syndrome and cardiacconduction disease. Cardiovasc Res, 53(2): 348―354
|
|
Stieber J, Herrmann S, Feil S, L?ster J, Feil R, Biel M, Hofmann F, Ludwig A(2003). The hyperpolarization-activatedchannel HCN4 is required for the generation of pacemaker action potentialsin the embryonic heart. Proc Natl AcadSci U S A, 100(25): 15235―15240
|
|
Takehara N, Makita N, Kawabe J, Sato N, Kawamura Y, Kitabatake A, Kikuchi K(2004). A cardiacsodium channel mutation identified in Brugada syndrome associatedwith atrial standstill. J Intern Med, 255(1): 137―142
|
|
Tan H L, Bardai A, Shimizu W, Moss A J, Schulze-Bahr E, Noda T, Wilde A A(2006). Genotype-specific onset of arrhythmias in congenital long-QT syndrome:possible therapy implications. Circulation, 114(20): 2096―2103
|
|
Thomas K, Grant A O(2008). Ethnicityand arrhythmia susceptibility. J CardiovascElectrophysiol, 19(4): 427―429
|
|
Ueda K, Hirano Y, Higashiuesato Y, Aizawa Y, Hayashi T, Inagaki N, Tana T, Ohya Y, Takishita S, Muratani H, Hiraoka M, Kimura A(2009). Role of HCN4 channel in preventing ventricular arrhythmia. J Hum Genet, 54(2): 115―121
|
|
Valdivia C R, Ueda K, Ackerman M J, Makielski J C(2009). GPD1L links redox state to cardiac excitability by PKC-dependentphosphorylation of the sodium channel SCN5A. Am J Physiol Heart Circ Physiol, 297(4): H1446―H1452
|
|
Van Norstrand D W, Valdivia C R, Tester D J, Ueda K, London B, Makielski J C, Ackerman M J(2007). Molecularand functional characterization of novel glycerol-3-phosphate dehydrogenase1 like gene (GPD1-L) mutations in sudden infant death syndrome. Circulation, 116(20): 2253―2259
|
|
Vatta M, Dumaine R, Varghese G, Richard T A, Shimizu W, Aihara N, Nademanee K, Brugada R, Brugada J, Veerakul G, Li H, Bowles N E, Brugada P, Antzelevitch C, Towbin J A(2002). Genetic and biophysical basis ofsudden unexplained nocturnal death syndrome (SUNDS), a disease allelicto Brugada syndrome. Hum Mol Genet, 11(3): 337―345
|
|
Watanabe H, Koopmann T T, Le Scouarnec S, Yang T, Ingram C R, Schott J J, Demolombe S, Probst V, Anselme F, Escande D, Wiesfeld A C, Pfeufer A, K??b S, Wichmann H E, Hasdemir C, Aizawa Y, Wilde A A, Roden D M, Bezzina C R(2008). Sodium channel beta1subunit mutations associated with Brugada syndrome and cardiac conductiondisease in humans. J Clin Invest, 118(6): 2260―2268
|
|
Weiss R, Barmada M M, Nguyen T, Seibel J S, Cavlovich D, Kornblit C A, Angelilli A, Villanueva F, McNamara D M, London B(2002). Clinical and molecular heterogeneity in the Brugadasyndrome: a novel gene locus on chromosome 3. Circulation, 105(6): 707―713
|
|
Wilde A A, Antzelevitch C, Borggrefe M, Brugada J, Brugada R, Brugada P, Corrado D, Hauer R N, Kass R S, Nademanee K, Priori S G, Towbin J A, and the Study Group on the Molecular Basis of Arrhythmiasof the European Society of Cardiology (2002). Proposed diagnostic criteria for the Brugada syndrome. Eur Heart J, 23(21): 1648―1654
|
|
Yokokawa M, Noda T, Okamura H, Satomi K, Suyama K, Kurita T, Aihara N, Kamakura S, Shimizu W(2007). Comparison of long-term follow-upof electrocardiographic features in Brugada syndrome between the SCN5A-positiveprobands and the SCN5A-negative probands. Am J Cardiol, 100(4): 649―655
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