5dbr

Structural highlights

Disease

[SCN5A_HUMAN] Defects in SCN5A are a cause of progressive familial heart block type 1A (PFHB1A) [MIM:113900]; also known as Lenegre-Lev disease or progressive cardiac conduction defect (PCCD). PFHB1A is an autosomal dominant cardiac bundle branch disorder that may progress to complete heart block. PFHB1A is characterized by progressive alteration of cardiac conduction through the His-Purkinje system with right or left bundle branch block and widening of QRS complexes, leading to complete atrioventricular block and causing syncope and sudden death.^{[1] [2] [3] [4] [5] [6]} Defects in SCN5A are the cause of long QT syndrome type 3 (LQT3) [MIM:603830]. Long QT syndromes are heart disorders characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress. LQT3 inheritance is an autosomal dominant.^{[7] [8] [9] [10] [11] [12] [13] [14]} [:]^{[15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34]} Defects in SCN5A are the cause of Brugada syndrome type 1 (BRGDA1) [MIM:601144]. An autosomal dominant tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs (called ventricular fibrillation), the individual will faint and may die in a few minutes if the heart is not reset.^{[35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60]} Defects in SCN5A are the cause of sick sinus syndrome type 1 (SSS1) [MIM:608567]. The term 'sick sinus syndrome' encompasses a variety of conditions caused by sinus node dysfunction. The most common clinical manifestations are syncope, presyncope, dizziness, and fatigue. Electrocardiogram typically shows sinus bradycardia, sinus arrest, and/or sinoatrial block. Episodes of atrial tachycardias coexisting with sinus bradycardia ('tachycardia-bradycardia syndrome') are also common in this disorder. SSS occurs most often in the elderly associated with underlying heart disease or previous cardiac surgery, but can also occur in the fetus, infant, or child without heart disease or other contributing factors, in which case it is considered to be a congenital disorder.^{[61] [62] [63] [64]} Defects in SCN5A are the cause of familial paroxysmal ventricular fibrillation type 1 (VF1) [MIM:603829]. A cardiac arrhythmia marked by fibrillary contractions of the ventricular muscle due to rapid repetitive excitation of myocardial fibers without coordinated contraction of the ventricle and by absence of atrial activity.^{[65] [66]} Defects in SCN5A may be a cause of sudden infant death syndrome (SIDS) [MIM:272120]. SIDS is the sudden death of an infant younger than 1 year that remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of clinical history. Pathophysiologic mechanisms for SIDS may include respiratory dysfunction, cardiac dysrhythmias, cardiorespiratory instability, and inborn errors of metabolism, but definitive pathogenic mechanisms precipitating an infant sudden death remain elusive. Long QT syndromes-associated mutations can be responsible for some of SIDS cases.^{[67] [68] [69]} Defects in SCN5A may be a cause of familial atrial standstill (FAS) [MIM:108770]. Atrial standstill is an extremely rare arrhythmia, characterized by the absence of electrical and mechanical activity in the atria. Electrocardiographically, it is characterized by bradycardia, the absence of P waves, and a junctional narrow complex escape rhythm.^{[70] [71]} Defects in SCN5A are the cause of cardiomyopathy dilated type 1E (CMD1E) [MIM:601154]; also known as dilated cardiomyopathy with conduction disorder and arrhythmia or dilated cardiomyopathy with conduction defect 2. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.^{[72] [73]} Defects in SCN5A are the cause of familial atrial fibrillation type 10 (ATFB10) [MIM:614022]. ATFB10 is a familial form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure.^{[74] [75] [76]}

Function

[SCN5A_HUMAN] This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-resistant Na(+) channel isoform. This channel is responsible for the initial upstroke of the action potential. Channel inactivation is regulated by intracellular calcium levels.^[77]

References

1. ↑ Schott JJ, Alshinawi C, Kyndt F, Probst V, Hoorntje TM, Hulsbeek M, Wilde AA, Escande D, Mannens MM, Le Marec H. Cardiac conduction defects associate with mutations in SCN5A. Nat Genet. 1999 Sep;23(1):20-1. PMID:10471492 doi:10.1038/12618
2. ↑ Tan HL, Bink-Boelkens MT, Bezzina CR, Viswanathan PC, Beaufort-Krol GC, van Tintelen PJ, van den Berg MP, Wilde AA, Balser JR. A sodium-channel mutation causes isolated cardiac conduction disease. Nature. 2001 Feb 22;409(6823):1043-7. PMID:11234013 doi:10.1038/35059090
3. ↑ Wang DW, Viswanathan PC, Balser JR, George AL Jr, Benson DW. Clinical, genetic, and biophysical characterization of SCN5A mutations associated with atrioventricular conduction block. Circulation. 2002 Jan 22;105(3):341-6. PMID:11804990
4. ↑ Bezzina CR, Rook MB, Groenewegen WA, Herfst LJ, van der Wal AC, Lam J, Jongsma HJ, Wilde AA, Mannens MM. Compound heterozygosity for mutations (W156X and R225W) in SCN5A associated with severe cardiac conduction disturbances and degenerative changes in the conduction system. Circ Res. 2003 Feb 7;92(2):159-68. PMID:12574143
5. ↑ Viswanathan PC, Benson DW, Balser JR. A common SCN5A polymorphism modulates the biophysical effects of an SCN5A mutation. J Clin Invest. 2003 Feb;111(3):341-6. PMID:12569159 doi:10.1172/JCI16879
6. ↑ Meregalli PG, Tan HL, Probst V, Koopmann TT, Tanck MW, Bhuiyan ZA, Sacher F, Kyndt F, Schott JJ, Albuisson J, Mabo P, Bezzina CR, Le Marec H, Wilde AA. Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies. Heart Rhythm. 2009 Mar;6(3):341-8. Epub 2008 Nov 11. PMID:19251209 doi:S1547-5271(08)01092-8
7. ↑ Schott JJ, Alshinawi C, Kyndt F, Probst V, Hoorntje TM, Hulsbeek M, Wilde AA, Escande D, Mannens MM, Le Marec H. Cardiac conduction defects associate with mutations in SCN5A. Nat Genet. 1999 Sep;23(1):20-1. PMID:10471492 doi:10.1038/12618
8. ↑ Ye B, Valdivia CR, Ackerman MJ, Makielski JC. A common human SCN5A polymorphism modifies expression of an arrhythmia causing mutation. Physiol Genomics. 2003 Feb 6;12(3):187-93. PMID:12454206 doi:10.1152/physiolgenomics.00117.2002
9. ↑ Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, Moss AJ, Towbin JA, Keating MT. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell. 1995 Mar 10;80(5):805-11. PMID:7889574
10. ↑ Wang Q, Shen J, Li Z, Timothy K, Vincent GM, Priori SG, Schwartz PJ, Keating MT. Cardiac sodium channel mutations in patients with long QT syndrome, an inherited cardiac arrhythmia. Hum Mol Genet. 1995 Sep;4(9):1603-7. PMID:8541846
11. ↑ Bennett PB, Yazawa K, Makita N, George AL Jr. Molecular mechanism for an inherited cardiac arrhythmia. Nature. 1995 Aug 24;376(6542):683-5. PMID:7651517 doi:http://dx.doi.org/10.1038/376683a0
12. ↑ An RH, Wang XL, Kerem B, Benhorin J, Medina A, Goldmit M, Kass RS. Novel LQT-3 mutation affects Na+ channel activity through interactions between alpha- and beta1-subunits. Circ Res. 1998 Jul 27;83(2):141-6. PMID:9686753
13. ↑ Makita N, Shirai N, Nagashima M, Matsuoka R, Yamada Y, Tohse N, Kitabatake A. A de novo missense mutation of human cardiac Na+ channel exhibiting novel molecular mechanisms of long QT syndrome. FEBS Lett. 1998 Feb 13;423(1):5-9. PMID:9506831
14. ↑ Benhorin J, Goldmit M, MacCluer JW, Blangero J, Goffen R, Leibovitch A, Rahat A, Wang Q, Medina A, Towbin J, Kerem B. Identification of a new SCN5A mutation, D1840G, associated with the long QT syndrome. Mutations in brief no. 153. Online. Hum Mutat. 1998;12(1):72. PMID:10627139 doi:<72::AID-HUMU17>3.0.CO;2-Z 10.1002/(SICI)1098-1004(1998)12:1<72::AID-HUMU17>3.0.CO;2-Z
15. ↑ Wattanasirichaigoon D, Vesely MR, Duggal P, Levine JC, Blume ED, Wolff GS, Edwards SB, Beggs AH. Sodium channel abnormalities are infrequent in patients with long QT syndrome: identification of two novel SCN5A mutations. Am J Med Genet. 1999 Oct 29;86(5):470-6. PMID:10508990
16. ↑ Wei J, Wang DW, Alings M, Fish F, Wathen M, Roden DM, George AL Jr. Congenital long-QT syndrome caused by a novel mutation in a conserved acidic domain of the cardiac Na+ channel. Circulation. 1999 Jun 22;99(24):3165-71. PMID:10377081
17. ↑ Bezzina C, Veldkamp MW, van Den Berg MP, Postma AV, Rook MB, Viersma JW, van Langen IM, Tan-Sindhunata G, Bink-Boelkens MT, van Der Hout AH, Mannens MM, Wilde AA. A single Na(+) channel mutation causing both long-QT and Brugada syndromes. Circ Res. 1999 Dec 3-17;85(12):1206-13. PMID:10590249
18. ↑ Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, Moss AJ, Schwartz PJ, Towbin JA, Vincent GM, Keating MT. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation. 2000 Sep 5;102(10):1178-85. PMID:10973849
19. ↑ Schwartz PJ, Priori SG, Dumaine R, Napolitano C, Antzelevitch C, Stramba-Badiale M, Richard TA, Berti MR, Bloise R. A molecular link between the sudden infant death syndrome and the long-QT syndrome. N Engl J Med. 2000 Jul 27;343(4):262-7. PMID:10911008 doi:10.1056/NEJM200007273430405
20. ↑ Abriel H, Cabo C, Wehrens XH, Rivolta I, Motoike HK, Memmi M, Napolitano C, Priori SG, Kass RS. Novel arrhythmogenic mechanism revealed by a long-QT syndrome mutation in the cardiac Na(+) channel. Circ Res. 2001 Apr 13;88(7):740-5. PMID:11304498
21. ↑ Rivolta I, Abriel H, Tateyama M, Liu H, Memmi M, Vardas P, Napolitano C, Priori SG, Kass RS. Inherited Brugada and long QT-3 syndrome mutations of a single residue of the cardiac sodium channel confer distinct channel and clinical phenotypes. J Biol Chem. 2001 Aug 17;276(33):30623-30. Epub 2001 Jun 15. PMID:11410597 doi:10.1074/jbc.M104471200
22. ↑ Ackerman MJ, Siu BL, Sturner WQ, Tester DJ, Valdivia CR, Makielski JC, Towbin JA. Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. JAMA. 2001 Nov 14;286(18):2264-9. PMID:11710892
23. ↑ Clancy CE, Rudy Y. Na(+) channel mutation that causes both Brugada and long-QT syndrome phenotypes: a simulation study of mechanism. Circulation. 2002 Mar 12;105(10):1208-13. PMID:11889015
24. ↑ Yang P, Kanki H, Drolet B, Yang T, Wei J, Viswanathan PC, Hohnloser SH, Shimizu W, Schwartz PJ, Stanton M, Murray KT, Norris K, George AL Jr, Roden DM. Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes. Circulation. 2002 Apr 23;105(16):1943-8. PMID:11997281
25. ↑ Rivolta I, Clancy CE, Tateyama M, Liu H, Priori SG, Kass RS. A novel SCN5A mutation associated with long QT-3: altered inactivation kinetics and channel dysfunction. Physiol Genomics. 2002 Sep 3;10(3):191-7. PMID:12209021 doi:10.1152/physiolgenomics.00039.2002
26. ↑ Wehrens XH, Rossenbacker T, Jongbloed RJ, Gewillig M, Heidbuchel H, Doevendans PA, Vos MA, Wellens HJ, Kass RS. A novel mutation L619F in the cardiac Na+ channel SCN5A associated with long-QT syndrome (LQT3): a role for the I-II linker in inactivation gating. Hum Mutat. 2003 May;21(5):552. PMID:12673799 doi:10.1002/humu.9136
27. ↑ Tester DJ, Will ML, Haglund CM, Ackerman MJ. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005 May;2(5):507-17. PMID:15840476 doi:10.1016/j.hrthm.2005.01.020
28. ↑ Millat G, Chevalier P, Restier-Miron L, Da Costa A, Bouvagnet P, Kugener B, Fayol L, Gonzalez Armengod C, Oddou B, Chanavat V, Froidefond E, Perraudin R, Rousson R, Rodriguez-Lafrasse C. Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome. Clin Genet. 2006 Sep;70(3):214-27. PMID:16922724 doi:10.1111/j.1399-0004.2006.00671.x
29. ↑ Bankston JR, Sampson KJ, Kateriya S, Glaaser IW, Malito DL, Chung WK, Kass RS. A novel LQT-3 mutation disrupts an inactivation gate complex with distinct rate-dependent phenotypic consequences. Channels (Austin). 2007 Jul-Aug;1(4):273-80. Epub 2007 Aug 31. PMID:18708744
30. ↑ Bankston JR, Yue M, Chung W, Spyres M, Pass RH, Silver E, Sampson KJ, Kass RS. A novel and lethal de novo LQT-3 mutation in a newborn with distinct molecular pharmacology and therapeutic response. PLoS One. 2007 Dec 5;2(12):e1258. PMID:18060054 doi:10.1371/journal.pone.0001258
31. ↑ Benito B, Brugada R, Perich RM, Lizotte E, Cinca J, Mont L, Berruezo A, Tolosana JM, Freixa X, Brugada P, Brugada J. A mutation in the sodium channel is responsible for the association of long QT syndrome and familial atrial fibrillation. Heart Rhythm. 2008 Oct;5(10):1434-40. doi: 10.1016/j.hrthm.2008.07.013. Epub 2008, Jul 19. PMID:18929331 doi:10.1016/j.hrthm.2008.07.013
32. ↑ Lin MT, Wu MH, Chang CC, Chiu SN, Theriault O, Huang H, Christe G, Ficker E, Chahine M. In utero onset of long QT syndrome with atrioventricular block and spontaneous or lidocaine-induced ventricular tachycardia: compound effects of hERG pore region mutation and SCN5A N-terminus variant. Heart Rhythm. 2008 Nov;5(11):1567-74. Epub 2008 Aug 17. PMID:18848812 doi:S1547-5271(08)00775-3
33. ↑ Makita N, Behr E, Shimizu W, Horie M, Sunami A, Crotti L, Schulze-Bahr E, Fukuhara S, Mochizuki N, Makiyama T, Itoh H, Christiansen M, McKeown P, Miyamoto K, Kamakura S, Tsutsui H, Schwartz PJ, George AL Jr, Roden DM. The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome. J Clin Invest. 2008 Jun;118(6):2219-29. doi: 10.1172/JCI34057. PMID:18451998 doi:10.1172/JCI34057
34. ↑ Shinlapawittayatorn K, Du XX, Liu H, Ficker E, Kaufman ES, Deschenes I. A common SCN5A polymorphism modulates the biophysical defects of SCN5A mutations. Heart Rhythm. 2011 Mar;8(3):455-62. doi: 10.1016/j.hrthm.2010.11.034. Epub 2010, Nov 23. PMID:21109022 doi:10.1016/j.hrthm.2010.11.034
35. ↑ Schott JJ, Alshinawi C, Kyndt F, Probst V, Hoorntje TM, Hulsbeek M, Wilde AA, Escande D, Mannens MM, Le Marec H. Cardiac conduction defects associate with mutations in SCN5A. Nat Genet. 1999 Sep;23(1):20-1. PMID:10471492 doi:10.1038/12618
36. ↑ Meregalli PG, Tan HL, Probst V, Koopmann TT, Tanck MW, Bhuiyan ZA, Sacher F, Kyndt F, Schott JJ, Albuisson J, Mabo P, Bezzina CR, Le Marec H, Wilde AA. Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies. Heart Rhythm. 2009 Mar;6(3):341-8. Epub 2008 Nov 11. PMID:19251209 doi:S1547-5271(08)01092-8
37. ↑ Rivolta I, Abriel H, Tateyama M, Liu H, Memmi M, Vardas P, Napolitano C, Priori SG, Kass RS. Inherited Brugada and long QT-3 syndrome mutations of a single residue of the cardiac sodium channel confer distinct channel and clinical phenotypes. J Biol Chem. 2001 Aug 17;276(33):30623-30. Epub 2001 Jun 15. PMID:11410597 doi:10.1074/jbc.M104471200
38. ↑ Chen Q, Kirsch GE, 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 RE, Schulze-Bahr E, Keating MT, Towbin JA, Wang Q. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature. 1998 Mar 19;392(6673):293-6. PMID:9521325 doi:10.1038/32675
39. ↑ Rook MB, Bezzina Alshinawi C, Groenewegen WA, van Gelder IC, van Ginneken AC, Jongsma HJ, Mannens MM, Wilde AA. Human SCN5A gene mutations alter cardiac sodium channel kinetics and are associated with the Brugada syndrome. Cardiovasc Res. 1999 Dec;44(3):507-17. PMID:10690282
40. ↑ Dumaine R, Towbin JA, Brugada P, Vatta M, Nesterenko DV, Nesterenko VV, Brugada J, Brugada R, Antzelevitch C. Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. Circ Res. 1999 Oct 29;85(9):803-9. PMID:10532948
41. ↑ Makita N, Shirai N, Wang DW, Sasaki K, George AL Jr, Kanno M, Kitabatake A. Cardiac Na(+) channel dysfunction in Brugada syndrome is aggravated by beta(1)-subunit. Circulation. 2000 Jan 4-11;101(1):54-60. PMID:10618304
42. ↑ Smits JP, Eckardt L, Probst V, Bezzina CR, Schott JJ, Remme CA, Haverkamp W, Breithardt G, Escande D, Schulze-Bahr E, LeMarec H, Wilde AA. Genotype-phenotype relationship in Brugada syndrome: electrocardiographic features differentiate SCN5A-related patients from non-SCN5A-related patients. J Am Coll Cardiol. 2002 Jul 17;40(2):350-6. PMID:12106943
43. ↑ Priori SG, Napolitano C, Gasparini M, Pappone C, Della Bella P, Giordano U, Bloise R, Giustetto C, De Nardis R, Grillo M, Ronchetti E, Faggiano G, Nastoli J. Natural history of Brugada syndrome: insights for risk stratification and management. Circulation. 2002 Mar 19;105(11):1342-7. PMID:11901046
44. ↑ Vatta M, Dumaine R, Varghese G, Richard TA, Shimizu W, Aihara N, Nademanee K, Brugada R, Brugada J, Veerakul G, Li H, Bowles NE, Brugada P, Antzelevitch C, Towbin JA. Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome. Hum Mol Genet. 2002 Feb 1;11(3):337-45. PMID:11823453
45. ↑ Vatta M, Dumaine R, Antzelevitch C, Brugada R, Li H, Bowles NE, Nademanee K, Brugada J, Brugada P, Towbin JA. Novel mutations in domain I of SCN5A cause Brugada syndrome. Mol Genet Metab. 2002 Apr;75(4):317-24. PMID:12051963 doi:10.1016/S1096-7192(02)00006-9
46. ↑ Valdivia CR, Tester DJ, Rok BA, Porter CB, Munger TM, Jahangir A, Makielski JC, Ackerman MJ. A trafficking defective, Brugada syndrome-causing SCN5A mutation rescued by drugs. Cardiovasc Res. 2004 Apr 1;62(1):53-62. PMID:15023552 doi:10.1016/j.cardiores.2004.01.022
47. ↑ Shin DJ, Jang Y, Park HY, Lee JE, Yang K, Kim E, Bae Y, Kim J, Kim J, Kim SS, Lee MH, Chahine M, Yoon SK. Genetic analysis of the cardiac sodium channel gene SCN5A in Koreans with Brugada syndrome. J Hum Genet. 2004;49(10):573-8. Epub 2004 Aug 26. PMID:15338453 doi:10.1007/s10038-004-0182-z
48. ↑ Mohler PJ, Rivolta I, Napolitano C, LeMaillet G, Lambert S, Priori SG, Bennett V. Nav1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Nav1.5 on the surface of cardiomyocytes. Proc Natl Acad Sci U S A. 2004 Dec 14;101(50):17533-8. Epub 2004 Dec 3. PMID:15579534 doi:10.1073/pnas.0403711101
49. ↑ Amin AS, Verkerk AO, Bhuiyan ZA, Wilde AA, Tan HL. Novel Brugada syndrome-causing mutation in ion-conducting pore of cardiac Na+ channel does not affect ion selectivity properties. Acta Physiol Scand. 2005 Dec;185(4):291-301. PMID:16266370 doi:10.1111/j.1365-201X.2005.01496.x
50. ↑ Yokoi H, Makita N, Sasaki K, Takagi Y, Okumura Y, Nishino T, Makiyama T, Kitabatake A, Horie M, Watanabe I, Tsutsui H. Double SCN5A mutation underlying asymptomatic Brugada syndrome. Heart Rhythm. 2005 Mar;2(3):285-92. PMID:15851320 doi:S1547-5271(04)00804-5
51. ↑ Makiyama T, Akao M, Tsuji K, Doi T, Ohno S, Takenaka K, Kobori A, Ninomiya T, Yoshida H, Takano M, Makita N, Yanagisawa F, Higashi Y, Takeyama Y, Kita T, Horie M. High risk for bradyarrhythmic complications in patients with Brugada syndrome caused by SCN5A gene mutations. J Am Coll Cardiol. 2005 Dec 6;46(11):2100-6. Epub 2005 Nov 4. PMID:16325048 doi:S0735-1097(05)02200-X
52. ↑ Keller DI, Huang H, Zhao J, Frank R, Suarez V, Delacretaz E, Brink M, Osswald S, Schwick N, Chahine M. A novel SCN5A mutation, F1344S, identified in a patient with Brugada syndrome and fever-induced ventricular fibrillation. Cardiovasc Res. 2006 Jun 1;70(3):521-9. Epub 2006 Mar 3. PMID:16616735 doi:10.1016/j.cardiores.2006.02.030
53. ↑ Cordeiro JM, Barajas-Martinez H, Hong K, Burashnikov E, Pfeiffer R, Orsino AM, Wu YS, Hu D, Brugada J, Brugada P, Antzelevitch C, Dumaine R, Brugada R. Compound heterozygous mutations P336L and I1660V in the human cardiac sodium channel associated with the Brugada syndrome. Circulation. 2006 Nov 7;114(19):2026-33. Epub 2006 Oct 30. PMID:17075016 doi:10.1161/CIRCULATIONAHA.106.627489
54. ↑ Liang P, Liu WL, Hu DY, Li CL, Tao WH, Li L. [Novel SCN5A gene mutations associated with Brugada syndrome: V95I, A1649V and delF1617] Zhonghua Xin Xue Guan Bing Za Zhi. 2006 Jul;34(7):616-9. PMID:17081365
55. ↑ Pfahnl AE, Viswanathan PC, Weiss R, Shang LL, Sanyal S, Shusterman V, Kornblit C, London B, Dudley SC Jr. A sodium channel pore mutation causing Brugada syndrome. Heart Rhythm. 2007 Jan;4(1):46-53. Epub 2006 Sep 28. PMID:17198989 doi:S1547-5271(06)02054-6
56. ↑ Tian L, Zhu JF, Yang JG. [Gene (SCN5A) mutation analysis of a Chinese family with Brugada syndrome] Zhonghua Xin Xue Guan Bing Za Zhi. 2007 Dec;35(12):1122-5. PMID:18341814
57. ↑ Zhang Y, Wang T, Ma A, Zhou X, Gui J, Wan H, Shi R, Huang C, Grace AA, Huang CL, Trump D, Zhang H, Zimmer T, Lei M. Correlations between clinical and physiological consequences of the novel mutation R878C in a highly conserved pore residue in the cardiac Na+ channel. Acta Physiol (Oxf). 2008 Dec;194(4):311-23. Epub 2008 Jul 24. PMID:18616619 doi:APS1883
58. ↑ Bebarova M, O'Hara T, Geelen JL, Jongbloed RJ, Timmermans C, Arens YH, Rodriguez LM, Rudy Y, Volders PG. Subepicardial phase 0 block and discontinuous transmural conduction underlie right precordial ST-segment elevation by a SCN5A loss-of-function mutation. Am J Physiol Heart Circ Physiol. 2008 Jul;295(1):H48-58. Epub 2008 May 2. PMID:18456723 doi:91495.2007
59. ↑ Petitprez S, Jespersen T, Pruvot E, Keller DI, Corbaz C, Schlapfer J, Abriel H, Kucera JP. Analyses of a novel SCN5A mutation (C1850S): conduction vs. repolarization disorder hypotheses in the Brugada syndrome. Cardiovasc Res. 2008 Jun 1;78(3):494-504. Epub 2008 Feb 5. PMID:18252757 doi:cvn023
60. ↑ Hsueh CH, Chen WP, Lin JL, Tsai CT, Liu YB, Juang JM, Tsao HM, Su MJ, Lai LP. Distinct functional defect of three novel Brugada syndrome related cardiac sodium channel mutations. J Biomed Sci. 2009 Feb 20;16:23. doi: 10.1186/1423-0127-16-23. PMID:19272188 doi:10.1186/1423-0127-16-23
61. ↑ Schott JJ, Alshinawi C, Kyndt F, Probst V, Hoorntje TM, Hulsbeek M, Wilde AA, Escande D, Mannens MM, Le Marec H. Cardiac conduction defects associate with mutations in SCN5A. Nat Genet. 1999 Sep;23(1):20-1. PMID:10471492 doi:10.1038/12618
62. ↑ Kyndt F, Probst V, Potet F, Demolombe S, Chevallier JC, Baro I, Moisan JP, Boisseau P, Schott JJ, Escande D, Le Marec H. Novel SCN5A mutation leading either to isolated cardiac conduction defect or Brugada syndrome in a large French family. Circulation. 2001 Dec 18;104(25):3081-6. PMID:11748104
63. ↑ Benson DW, Wang DW, Dyment M, Knilans TK, Fish FA, Strieper MJ, Rhodes TH, George AL Jr. Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A). J Clin Invest. 2003 Oct;112(7):1019-28. PMID:14523039 doi:10.1172/JCI18062
64. ↑ Selly JB, Boumahni B, Edmar A, Jamal Bey K, Randrianaivo H, Clerici G, Millat G, Caillet D. [Cardiac sinus node dysfunction due to a new mutation of the SCN5A gene]. Arch Pediatr. 2012 Aug;19(8):837-41. doi: 10.1016/j.arcped.2012.04.017. Epub 2012, Jul 12. PMID:22795782 doi:10.1016/j.arcped.2012.04.017
65. ↑ Schott JJ, Alshinawi C, Kyndt F, Probst V, Hoorntje TM, Hulsbeek M, Wilde AA, Escande D, Mannens MM, Le Marec H. Cardiac conduction defects associate with mutations in SCN5A. Nat Genet. 1999 Sep;23(1):20-1. PMID:10471492 doi:10.1038/12618
66. ↑ Akai J, Makita N, Sakurada H, Shirai N, Ueda K, Kitabatake A, Nakazawa K, Kimura A, Hiraoka M. A novel SCN5A mutation associated with idiopathic ventricular fibrillation without typical ECG findings of Brugada syndrome. FEBS Lett. 2000 Aug 11;479(1-2):29-34. PMID:10940383
67. ↑ Schott JJ, Alshinawi C, Kyndt F, Probst V, Hoorntje TM, Hulsbeek M, Wilde AA, Escande D, Mannens MM, Le Marec H. Cardiac conduction defects associate with mutations in SCN5A. Nat Genet. 1999 Sep;23(1):20-1. PMID:10471492 doi:10.1038/12618
68. ↑ Otagiri T, Kijima K, Osawa M, Ishii K, Makita N, Matoba R, Umetsu K, Hayasaka K. Cardiac ion channel gene mutations in sudden infant death syndrome. Pediatr Res. 2008 Nov;64(5):482-7. PMID:18596570 doi:10.1203/PDR.0b013e3181841eca
69. ↑ Huang H, Millat G, Rodriguez-Lafrasse C, Rousson R, Kugener B, Chevalier P, Chahine M. Biophysical characterization of a new SCN5A mutation S1333Y in a SIDS infant linked to long QT syndrome. FEBS Lett. 2009 Mar 4;583(5):890-6. Epub 2009 Feb 10. PMID:19302788 doi:S0014-5793(09)00105-7
70. ↑ Schott JJ, Alshinawi C, Kyndt F, Probst V, Hoorntje TM, Hulsbeek M, Wilde AA, Escande D, Mannens MM, Le Marec H. Cardiac conduction defects associate with mutations in SCN5A. Nat Genet. 1999 Sep;23(1):20-1. PMID:10471492 doi:10.1038/12618
71. ↑ Groenewegen WA, Firouzi M, Bezzina CR, Vliex S, van Langen IM, Sandkuijl L, Smits JP, Hulsbeek M, Rook MB, Jongsma HJ, Wilde AA. A cardiac sodium channel mutation cosegregates with a rare connexin40 genotype in familial atrial standstill. Circ Res. 2003 Jan 10;92(1):14-22. PMID:12522116
72. ↑ Schott JJ, Alshinawi C, Kyndt F, Probst V, Hoorntje TM, Hulsbeek M, Wilde AA, Escande D, Mannens MM, Le Marec H. Cardiac conduction defects associate with mutations in SCN5A. Nat Genet. 1999 Sep;23(1):20-1. PMID:10471492 doi:10.1038/12618
73. ↑ McNair WP, Ku L, Taylor MR, Fain PR, Dao D, Wolfel E, Mestroni L. SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia. Circulation. 2004 Oct 12;110(15):2163-7. Epub 2004 Oct 4. PMID:15466643 doi:01.CIR.0000144458.58660.BB
74. ↑ Schott JJ, Alshinawi C, Kyndt F, Probst V, Hoorntje TM, Hulsbeek M, Wilde AA, Escande D, Mannens MM, Le Marec H. Cardiac conduction defects associate with mutations in SCN5A. Nat Genet. 1999 Sep;23(1):20-1. PMID:10471492 doi:10.1038/12618
75. ↑ Darbar D, Kannankeril PJ, Donahue BS, Kucera G, Stubblefield T, Haines JL, George AL Jr, Roden DM. Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation. Circulation. 2008 Apr 15;117(15):1927-35. Epub 2008 Mar 31. PMID:18378609 doi:CIRCULATIONAHA.107.757955
76. ↑ Ellinor PT, Nam EG, Shea MA, Milan DJ, Ruskin JN, MacRae CA. Cardiac sodium channel mutation in atrial fibrillation. Heart Rhythm. 2008 Jan;5(1):99-105. Epub 2007 Sep 19. PMID:18088563 doi:10.1016/j.hrthm.2007.09.015
77. ↑ Chagot B, Potet F, Balser JR, Chazin WJ. Solution NMR structure of the C-terminal EF-hand domain of human cardiac sodium channel NaV1.5. J Biol Chem. 2009 Mar 6;284(10):6436-45. Epub 2008 Dec 11. PMID:19074138 doi:10.1074/jbc.M807747200