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Na_V1.5 is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. Na_V1.5 is found primarily in cardiac muscle, where it mediates the fast influx of Na⁺-ions (I_Na) across the cell membrane, resulting in the fast depolarization phase of the cardiac action potential. As such, it plays a major role in impulse propagation through the heart. A vast number of cardiac diseases is associated with mutations in Na_V1.5 (see paragraph genetics). SCN5A is the gene that encodes the cardiac sodium channel Na_V1.5.

Gene structure

SCN5A is a highly conserved gene^[2] located on human chromosome 3, where it spans more than 100 kb. The gene consists of 28 exons, of which exon 1 and in part exon 2 form the 5’ untranslated region (5’UTR) and exon 28 the 3’ untranslated region (3’UTR) of the RNA. SCN5A is part of a family of 10 genes that encode different types of sodium channels, i.e. brain-type (Na_V1.1, Na_V1.2, Na_V1.3, Na_V1.6), neuronal channels (Na_V1.7, Na_V1.8 and Na_V1.9), skeletal muscle channels (Na_V1.4) and the cardiac sodium channel Na_V1.5.

Expression pattern

SCN5A is mainly expressed in the heart, where expression is abundant in working myocardium and conduction tissue. In contrast, expression is low in the sinoatrial node and atrioventricular node.^[3] Within the heart, a transmural expression gradient from subendocardium to subsendocardium is present, with higher expression of SCN5A in the endocardium as compared to the epicardium^[3]

Splice variants

More than 10 different splice isoforms have been described for SCN5A, of which several harbour different functional properties. In the heart, two isoforms are mainly expressed (ratio 1:2), of which the least predominant one contains an extra glutamine at position 1077 (1077Q). Moreover, different isoforms are expressed during fetal life and adult, differing in the inclusion of an alternative exon 6.^[4]

Protein structure and function

Na_V1.5 is a large transmembrane protein with 4 repetitive transmembrane domains (DI-DIV), containing 6 transmembrane spanning sections each (S1-S6). The pore region of the channels, through which Na+-ions flow, are formed by the segments S5 and S6 of the 4 domains. Voltage sensing is mediated by the remaining segments, of which the positively charged S4 segments plays a fundamental role.^[2]^[5]

Na_V1.5 channels predominantly mediate the sodium current (I_Na) in cardiac cells. I_Na is responsible for the fast upstroke of the action potential, and as such plays a crucial role in impulse propagation through the heart. The conformational state of the channel, which is both voltage and time-dependent, determines whether the channel is opened or closed. At the resting membrane potential (around -85 mV), Na_V1.5 channels are closed. Upon a stimulus (through conduction by a neighboring cell), the membrane depolarizes and Na_V1.5 channels open through the outward movement of the S4 segments, leading to the initiation of the action potential. Simultaneously, a process called ‘fast inactivation’ results in closure of the channels within 1 ms. In physiological conditions, when inactivated, channels remain in closed state until the cell membrane repolarizes, where a recovery from inactivation is necessary before they become available for activation again. During the action potential, a very small fraction of sodium current persists and does not inactivate completely. This current is called ‘sustained current’, ‘late current’ or ‘I_Na,L’.^[6]^[7] Also, some channels may reactivate during the repolarizing phase of the action potential at a range of potentials where inactivation is not complete and shows overlap with activation, generating the so-called “window current”.^[8]

Sub-units and protein interaction partners

Trafficking, function and structure of Na_V1.5 can be affected by the many protein interaction partners that have been identified to date (for an extensive review, see Abriel et al 2010).^[9] Of these, the 4 sodium channel beta-subunits, encoded by the genes SCN1B, SCN2B, SCN3B and SCN4B, form an important category. In general, beta-subunits increase function of Na_V1.5, either by change in intrinsic properties or by affecting the process of trafficking to the cell surface.

Apart from the beta-subunits, other proteins, such as calmodulin, calmodulin kinase II δc, ankyrin-G and plakophilin-2, are known to interact and modulate function of Na_V1.5.^[9] Some of these have also been linked to genetic and acquired cardiac diseases.^[10]^[11]

Genetics

Mutations in SCN5A, which could result in a loss and/or a gain-of-function of the channel, are associated with a spectrum of cardiac diseases. Pathogenic mutations generally exhibit a autosomal dominant inheritance pattern, although recessive forms of SCN5A mutations are also described. Also, mutations may act as a disease modifier, especially in families where lack of direct causality is reflected by complex inheritance patterns. It is important to note that a significant amount of individuals (2-7%) in the general population carry a rare (population frequency <1%),^[12] protein-altering variant in the gene, highlighting the complexity of linking mutations directly with observed phenotypes. Interestingly, mutations that result in the same biophysical effect can give rise to different diseases.

To date, loss-of-function mutations have been associated with Brugada syndrome (BrS),^[13]^[14]^[15] progressive cardiac conduction disease (Lev-Lenègre disease),^[16]^[17] dilated cardiomyopathy (DCM),^[18]^[19] sick sinus syndrome,^[20] and atrial fibrillation.^[21]

Mutations resulting in a gain-of-function are causal for Long QT syndrome type 3^[15]^[22] and are also more recently implicated in multifocal ectopic Purkinje-related premature contractions (MEPPC)^[19]^[23] Some gain-of-function mutations are also associated with AF and DCM.^[24] Gain-of-function of Na_V1.5 is generally reflected by an increase in I_Na,L, a slowed rate of inactivation or a shift in voltage dependence of activation or inactivation (resulting in an increased window-current).

SCN5A variations in the general population

Genetic variations in SCN5A, i.e. single nucleotide polymorphisms (SNPs) have been described in both coding and non-coding regions of the gene. These variations are typically present at relatively high frequencies within the general population. Genome Wide Association Studies (GWAS) have used this type of common genetic variation to identify genetic loci associated with variability in phenotypic traits. In the cardiovascular field this powerful technique has been used to detect loci involved in variation in electrocardiographic parameters (i.e. PR-, QRS- and QTc-interval duration) in the general population.^[12] The rationale behind this technique is that common genetic variation present in the general population can influence cardiac conduction in non-diseased individuals. Interestingly, these studies consistently identified the SCN5A-SCN10A genomic region on chromosome 3 to be associated with variation in QTc-interval, QRS duration and PR-interval.^[12] These results indicate that genetic variation at the SCN5A locus is not only involved in disease #genetics but also plays a role in the variation in cardiac function between individuals in the general population.

Na_V1.5 as a pharmacological target

The cardiac sodium channel Na_V1.5 has since long been a common target in the pharmacologic treatment of arrhythmic events. Classically, sodium channel blockers that block the peak sodium current are classified as Class I anti-arrhythmic agents and further subdivided in class IA, IB and IC, depending on their ability to change the length of the cardiac action potential.^[25]^[26] Use of such sodium channel blockers is among others indicated in patients with ventricular reentrant tachyarrhythmia in the setting of cardiac ischemia and in patients with atrial fibrillation in absence of structural heart disease.^[26]

References

^ PDB: 1byy; Rohl CA, Boeckman FA, Baker C, Scheuer T, Catterall WA, Klevit RE (January 1999). "Solution structure of the sodium channel inactivation gate". Biochemistry 38 (3): 855–61. doi:10.1021/bi9823380. PMID 9893979.
^ ^a ^b Catterall WA (2014). "Sodium channels, inherited epilepsy, and antiepileptic drugs". Annual Review of Pharmacology and Toxicology 54: 317–38. doi:10.1146/annurev-pharmtox-011112-140232. PMID 24392695.
^ ^a ^b Remme CA, Verkerk AO, Hoogaars WM, Aanhaanen WT, Scicluna BP, Annink C, van den Hoff MJ, Wilde AA, van Veen TA, Veldkamp MW, de Bakker JM, Christoffels VM, Bezzina CR (Sep 2009). "The cardiac sodium channel displays differential distribution in the conduction system and transmural heterogeneity in the murine ventricular myocardium". Basic Research in Cardiology 104 (5): 511–22. doi:10.1007/s00395-009-0012-8. PMID 19255801.
^ Schroeter A, Walzik S, Blechschmidt S, Haufe V, Benndorf K, Zimmer T (Jul 2010). "Structure and function of splice variants of the cardiac voltage-gated sodium channel Na(v)1.5". Journal of Molecular and Cellular Cardiology 49 (1): 16–24. doi:10.1016/j.yjmcc.2010.04.004. PMID 20398673.
^ Chen-Izu Y, Shaw RM, Pitt GS, Yarov-Yarovoy V, Sack JT, Abriel H, Aldrich RW, Belardinelli L, Cannell MB, Catterall WA, Chazin WJ, Chiamvimonvat N, Deschenes I, Grandi E, Hund TJ, Izu LT, Maier LS, Maltsev VA, Marionneau C, Mohler PJ, Rajamani S, Rasmusson RL, Sobie EA, Clancy CE, Bers DM (Mar 2015). "Na+ channel function, regulation, structure, trafficking and sequestration". The Journal of Physiology 593 (6): 1347–60. doi:10.1113/jphysiol.2014.281428. PMID 25772290.
^ Maltsev VA, Sabbah HN, Higgins RS, Silverman N, Lesch M, Undrovinas AI (Dec 1998). "Novel, ultraslow inactivating sodium current in human ventricular cardiomyocytes". Circulation 98 (23): 2545–52. PMID 9843461.
^ Sakmann BF, Spindler AJ, Bryant SM, Linz KW, Noble D (Nov 2000). "Distribution of a persistent sodium current across the ventricular wall in guinea pigs". Circulation Research 87 (10): 910–4. PMID 11073887.
^ Attwell D, Cohen I, Eisner D, Ohba M, Ojeda C (Mar 1979). "The steady state TTX-sensitive ("window") sodium current in cardiac Purkinje fibres". Pflügers Archiv 379 (2): 137–42. PMID 571107.
^ ^a ^b Abriel H (Jan 2010). "Cardiac sodium channel Na(v)1.5 and interacting proteins: Physiology and pathophysiology". Journal of Molecular and Cellular Cardiology 48 (1): 2–11. doi:10.1016/j.yjmcc.2009.08.025. PMID 19744495.
^ Herren AW, Bers DM, Grandi E (Aug 2013). "Post-translational modifications of the cardiac Na channel: contribution of CaMKII-dependent phosphorylation to acquired arrhythmias". American Journal of Physiology. Heart and Circulatory Physiology 305 (4): H431–45. doi:10.1152/ajpheart.00306.2013. PMID 23771687.
^ Cerrone M, Lin X, Zhang M, Agullo-Pascual E, Pfenniger A, Chkourko Gusky H, Novelli V, Kim C, Tirasawadichai T, Judge DP, Rothenberg E, Chen HS, Napolitano C, Priori SG, Delmar M (Mar 2014). "Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype". Circulation 129 (10): 1092–103. doi:10.1161/CIRCULATIONAHA.113.003077. PMID 24352520.
^ ^a ^b ^c Lodder EM, Bezzina CR (Jan 2014). "Genomics of cardiac electrical function". Briefings in Functional Genomics 13 (1): 39–50. doi:10.1093/bfgp/elt029. PMID 23956259.
^ 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 (Mar 1998). "Genetic basis and molecular mechanism for idiopathic ventricular fibrillation". Nature 392 (6673): 293–6. doi:10.1038/32675. PMID 9521325.
^ 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 (Dec 1999). "A single Na(+) channel mutation causing both long-QT and Brugada syndromes". Circulation Research 85 (12): 1206–13. PMID 10590249.
^ ^a ^b Remme CA, Verkerk AO, Nuyens D, van Ginneken AC, van Brunschot S, Belterman CN, Wilders R, van Roon MA, Tan HL, Wilde AA, Carmeliet P, de Bakker JM, Veldkamp MW, Bezzina CR (Dec 2006). "Overlap syndrome of cardiac sodium channel disease in mice carrying the equivalent mutation of human SCN5A-1795insD". Circulation 114 (24): 2584–94. doi:10.1161/CIRCULATIONAHA.106.653949. PMID 17145985.
^ Schott JJ, Alshinawi C, Kyndt F, Probst V, Hoorntje TM, Hulsbeek M, Wilde AA, Escande D, Mannens MM, Le Marec H (Sep 1999). "Cardiac conduction defects associate with mutations in SCN5A". Nature Genetics 23 (1): 20–1. doi:10.1038/12618. PMID 10471492.
^ Tan HL, Bink-Boelkens MT, Bezzina CR, Viswanathan PC, Beaufort-Krol GC, van Tintelen PJ, van den Berg MP, Wilde AA, Balser JR (Feb 2001). "A sodium-channel mutation causes isolated cardiac conduction disease". Nature 409 (6823): 1043–7. doi:10.1038/35059090. PMID 11234013.
^ McNair WP, Ku L, Taylor MR, Fain PR, Dao D, Wolfel E, Mestroni L (Oct 2004). "SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia". Circulation 110 (15): 2163–7. doi:10.1161/01.CIR.0000144458.58660.BB. PMID 15466643.
^ ^a ^b Laurent G, Saal S, Amarouch MY, Béziau DM, Marsman RF, Faivre L, Barc J, Dina C, Bertaux G, Barthez O, Thauvin-Robinet C, Charron P, Fressart V, Maltret A, Villain E, Baron E, Mérot J, Turpault R, Coudière Y, Charpentier F, Schott JJ, Loussouarn G, Wilde AA, Wolf JE, Baró I, Kyndt F, Probst V (Jul 2012). "Multifocal ectopic Purkinje-related premature contractions: a new SCN5A-related cardiac channelopathy". Journal of the American College of Cardiology 60 (2): 144–56. doi:10.1016/j.jacc.2012.02.052. PMID 22766342.
^ Benson DW, Wang DW, Dyment M, Knilans TK, Fish FA, Strieper MJ, Rhodes TH, George AL (Oct 2003). "Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A)". The Journal of Clinical Investigation 112 (7): 1019–28. doi:10.1172/JCI18062. PMID 14523039.
^ Makiyama T, Akao M, Shizuta S, Doi T, Nishiyama K, Oka Y, Ohno S, Nishio Y, Tsuji K, Itoh H, Kimura T, Kita T, Horie M (Oct 2008). "A novel SCN5A gain-of-function mutation M1875T associated with familial atrial fibrillation". Journal of the American College of Cardiology 52 (16): 1326–34. doi:10.1016/j.jacc.2008.07.013. PMID 18929244.
^ Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, Moss AJ, Towbin JA, Keating MT (Mar 1995). "SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome". Cell 80 (5): 805–11. PMID 7889574.
^ Mann SA, Castro ML, Ohanian M, Guo G, Zodgekar P, Sheu A, Stockhammer K, Thompson T, Playford D, Subbiah R, Kuchar D, Aggarwal A, Vandenberg JI, Fatkin D (Oct 2012). "R222Q SCN5A mutation is associated with reversible ventricular ectopy and dilated cardiomyopathy". Journal of the American College of Cardiology 60 (16): 1566–73. doi:10.1016/j.jacc.2012.05.050. PMID 22999724.
^ Olson TM, Michels VV, Ballew JD, Reyna SP, Karst ML, Herron KJ, Horton SC, Rodeheffer RJ, Anderson JL (Jan 2005). "Sodium channel mutations and susceptibility to heart failure and atrial fibrillation". Jama 293 (4): 447–54. doi:10.1001/jama.293.4.447. PMID 15671429.
^ Milne JR, Hellestrand KJ, Bexton RS, Burnett PJ, Debbas NM, Camm AJ (Feb 1984). "Class 1 antiarrhythmic drugs--characteristic electrocardiographic differences when assessed by atrial and ventricular pacing". European Heart Journal 5 (2): 99–107. PMID 6723689.
^ ^a ^b Balser JR (Apr 2001). "The cardiac sodium channel: gating function and molecular pharmacology". Journal of Molecular and Cellular Cardiology 33 (4): 599–613. doi:10.1006/jmcc.2000.1346. PMID 11273715.

External links

GeneReviews/NIH/NCBI/UW entry on Brugada syndrome
GeneReviews/NIH/NCBI/UW entry on Romano-Ward Syndrome
SCN5A protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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1. 小児におけるてんかん症候群 epilepsy syndromes in children
2. 先天性および後天性ＱＴ延長症候群の遺伝学 genetics of congenital and acquired long qt syndrome
3. ブルガダ症候群および突然の心停止 brugada syndrome
4. 腎集合管ナトリウムチャンネルの遺伝的障害：リドル症候群および偽性低アルドステロン症1型 genetic disorders of the collecting tubule sodium channel liddles syndrome and pseudohypoaldosteronism type 1
5. 洞不全症候群の症状および原因 manifestations and causes of the sick sinus syndrome

English Journal

Cardiac sodium channel NaV1.5 distribution in myocytes via interacting proteins: The multiple pool model.

Shy D, Gillet L, Abriel H.SourceDepartment of Clinical Research, University of Bern, Bern, Switzerland.
Biochimica et biophysica acta.Biochim Biophys Acta.2013 Apr;1833(4):886-94. doi: 10.1016/j.bbamcr.2012.10.026. Epub 2012 Oct 31.
The cardiac sodium current (I) is responsible for the rapid depolarization of cardiac cells, thus allowing for their contraction. It is also involved in regulating the duration of the cardiac action potential (AP) and propagation of the impulse throughout the myocardium. Cardiac I is generated by th
PMID 23123192

Identification of a novel KCNQ1 mutation in a large Saudi family with long QT syndrome: clinical consequences and preventive implications.

Shinwari Z, Al-Hazzani A, Dzimiri N, Tulbah S, Mallawi Y, Al-Fayyadh M, Al-Hassnan Z.SourceCardiovascular Genetics Program, King Faisal Specialist Hospital & Research Center (KFSH&RC), Riyadh, Saudi Arabia; College of Science, King Saud University, Riyadh, Saudi Arabia.
Clinical genetics.Clin Genet.2013 Apr;83(4):370-4. doi: 10.1111/j.1399-0004.2012.01914.x. Epub 2012 Jul 10.
Congenital long QT syndrome (LQTS) is an inherited potentially fatal arrhythmogenic disorder that is characterized by prolonged corrected QT (QTc) interval. Mutations in three genes (KCNQ1, KCNH2, and SCN5A) account for the majority of the cases. However, 10 other genes are now known to be implicate
PMID 22708720

Japanese Journal

Identification of Six Novel SCN5A Mutations in Japanese Patients With Brugada Syndrome

Nakajima Tadashi,Kaneko Yoshiaki,Saito Akihiro,Irie Tadanobu,Tange Shoichi,Iso Tatsuya,Kurabayashi Masahiko
International Heart Journal 52(1), 27-31, 2011
… Mutations in SCN5A are linked to Brugada syndrome in approximately 20% of all cases (BrS1). … Several dozen distinct SCN5A mutations in BrS1 have been associated with the increased risk of cardiac arrhythmias. … The current study analyzed the SCN5A gene to elucidate the potential variability of clinical features in Japanese BrS1 subjects. … We identified 8 different SCN5A mutations, including 6 novel mutations (CPA group: 1/7, Sy group: 3/10, Asy group: 4/13). …
NAID 130000410636

S20-6 フレカイニドのTDMにおけるCYP2D6とSCN5A遺伝子多型解析(シンポジウムS20 病院薬剤師による薬物治療個別化への遺伝子情報の活用,臨床から学び臨床へと還元する医療薬学)

本間真人,土岐浩介,青沼和隆,幸田幸直
日本医療薬学会年会講演要旨集 20, 245, 2010-10-25
NAID 110008108189

Related Pictures

Cardiac Sodium Channel ( SCN5A ) Variants Topology of SCN5A Encoded Protein Masonic Medical Research Laboratory Mutations in the SCN5A gene account for Role of Transmembrane Proteins (SCN5A SCN5A Polymorphism Restores Trafficking of Open in new tab Mutación del gen MinK (LQT5) enel

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リンク元	「ブルガダ症候群」
関連記事	「SCN」

「ブルガダ症候群」

Sodium channel, voltage gated, type V alpha subunit
	Solution structure of the Nav1.5 inactivation gate.
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	2KBI, 2L53, 4DCK, 4DJC, 4JQ0, 4OVN
Identifiers
Symbols	SCN5A ; CDCD2; CMD1E; CMPD2; HB1; HB2; HBBD; HH1; ICCD; IVF; LQT3; Nav1.5; PFHB1; SSS1; VF1
External IDs	OMIM: 600163 MGI: 98251 HomoloGene: 22738 IUPHAR: 582 ChEMBL: 1980 GeneCards: SCN5A Gene
Gene ontology
Molecular function	• voltage-gated sodium channel activity; • protein binding; • calmodulin binding; • fibroblast growth factor binding; • enzyme binding; • protein kinase binding; • protein domain specific binding; • ankyrin binding; • ubiquitin protein ligase binding; • ion channel binding; • nitric-oxide synthase binding; • voltage-gated sodium channel activity involved in cardiac muscle cell action potential; • voltage-gated sodium channel activity involved in AV node cell action potential; • voltage-gated sodium channel activity involved in bundle of His cell action potential; • voltage-gated sodium channel activity involved in Purkinje myocyte action potential; • voltage-gated sodium channel activity involved in SA node cell action potential; • scaffold protein binding;
Cellular component	• voltage-gated sodium channel complex; • intracellular; • endoplasmic reticulum; • plasma membrane; • caveola; • cell surface; • intercalated disc; • integral component of membrane; • lateral plasma membrane; • Z disc; • T-tubule; • sarcolemma;
Biological process	• regulation of heart rate; • cardiac ventricle development; • brainstem development; • sodium ion transport; • axon guidance; • positive regulation of sodium ion transport; • response to denervation involved in regulation of muscle adaptation; • neuronal action potential; • telencephalon development; • cerebellum development; • sodium ion transmembrane transport; • odontogenesis of dentin-containing tooth; • positive regulation of action potential; • positive regulation of epithelial cell proliferation; • membrane depolarization; • cardiac muscle contraction; • regulation of ventricular cardiac muscle cell membrane repolarization; • regulation of atrial cardiac muscle cell membrane depolarization; • regulation of atrial cardiac muscle cell membrane repolarization; • regulation of ventricular cardiac muscle cell membrane depolarization; • cellular response to calcium ion; • cardiac muscle cell action potential involved in contraction; • regulation of cardiac muscle cell contraction; • ventricular cardiac muscle cell action potential; • membrane depolarization during action potential; • membrane depolarization during cardiac muscle cell action potential; • SA node cell action potential; • AV node cell action potential; • bundle of His cell action potential; • membrane depolarization during AV node cell action potential; • membrane depolarization during SA node cell action potential; • membrane depolarization during Purkinje myocyte cell action potential; • membrane depolarization during bundle of His cell action potential; • AV node cell to bundle of His cell communication; • regulation of heart rate by cardiac conduction; • regulation of sodium ion transmembrane transport;
	Sources: Amigo / QuickGO
Orthologs
	v; t; e;

　　[★]

英: Brugada syndrome
同: Brugada症候群
関

概念

特発性心室細動をもたらす症候群の一つ。
基礎疾患を有さない若年者～中年の失神発作が特徴的
非発作時には無症状であるが、発作時には突然死を来す可能性がある。
反復する多型性心室頻拍、心室細動を来たし、放置すれば突然死に至。

歴史

1992年、Brugadaらは洞調律時に右脚ブロック様QRS波形、V1-V3においてST上昇を示し、心室細動を来した、器質疾患を有さない8例を報告。

病因

SCN5A geneの突然変異　→　Naの流入が緩徐＠RV流出路心外膜領域　→　活動電位の短縮(action potential shortening　→　正常な心外膜とrapidly depolarized RV outflow epicardiumの間の電位差によりV1-V3でのST上昇を起こす　→　局所的リエントリ誘発　→　致死性心室不整脈 (HIM.1442)

心筋Naチャネル遺伝子SCN5Aの以上がが原因の20%を占めるが、その他CACNA1C,CACNB2,GPD1-L,SCN1B,KCNE3,SCNE3Bなど多くの遺伝子異常と関係があるとされる。

疫学

30-50歳代の男性に多い
若年から中年の男性に多く、20-30%は突然死の家族歴を有する。
日本や東南アジアに多く、日本では成人の1%にBrugada型心電図を認める。

症状

前駆症状を伴わない失神発作が初発症状。
反復する多型性心室頻拍、心室細動。
放置により突然死する可能性が大きい

uptodate

突然死(sudden cardiac arest)は初発症状の1/3を占める。
不整脈は22-65歳で見られ、副交感神経が活発となる日中より夜間、起床中よりも就寝中にみられる。
突然死と運動とは無関係とされている。

検査

心電図

特徴は以下の２つである。

1)完全あるいは不完全右脚ブロック様QRS波形(つまり、V1-V3でJ波が見られる)

V1,V2のrSの後ろにJ波が出現している。右脚ブロックのV1誘導の心電図ではrSr'が認められるが、さきのJ波があたかもr'の様に見え、右脚ブロック様QRS波形と称している

2)右側胸部誘導(V1-V2(V3))のST上昇(coved型あるいはsaddle back型)

ST上昇はcoved型(右下がり。陰性T波)、saddle back型(J波とT波が高く、その間が低くなって鞍状のSTを呈する)のパターンを示す。J波の高さが2mm以上でcoved型ST上昇と陰性T波を示す所見が最も診断価値が高い。

[show details]

薬物誘発検査？(HIM.1442)

Naチャネルブロッカー(フレカイニド、プロカインアミド)でBrugada symdromeが増悪するかどうかを見る？(HIM.1442)。

薬物負荷試験

ピルシカイニドでcoved型ST上昇を誘発できるとされる。心室頻拍や心室細動を誘発することがある。

診断

心電図

失神　＋　右脚ブロック様QRS波形

治療

植え込み型除細動器(ICD)が第一選択

予後

植え込み型除細動器を埋め込んだ後の予後は良好

ガイドライン

QT延長症候群（先天性・二次性）とBrugada症候群の診療に関するガイドライン

http://www.j-circ.or.jp/guideline/pdf/JCS2007_ohe_h.pdf

国試

103A020、102A058

「SCN」

　　[★] 視交叉上核、視交差上核

関: suprachiasmatic、suprachiasmatic nuclei、suprachiasmatic nucleus

[pmid9893979-1] PDB: 1byy; Rohl CA, Boeckman FA, Baker C, Scheuer T, Catterall WA, Klevit RE (January 1999). "Solution structure of the sodium channel inactivation gate". Biochemistry 38 (3): 855–61. doi:10.1021/bi9823380. PMID 9893979.

[ref_24392695-2] Catterall WA (2014). "Sodium channels, inherited epilepsy, and antiepileptic drugs". Annual Review of Pharmacology and Toxicology 54: 317–38. doi:10.1146/annurev-pharmtox-011112-140232. PMID 24392695.

[Remme_2009-3] Remme CA, Verkerk AO, Hoogaars WM, Aanhaanen WT, Scicluna BP, Annink C, van den Hoff MJ, Wilde AA, van Veen TA, Veldkamp MW, de Bakker JM, Christoffels VM, Bezzina CR (Sep 2009). "The cardiac sodium channel displays differential distribution in the conduction system and transmural heterogeneity in the murine ventricular myocardium". Basic Research in Cardiology 104 (5): 511–22. doi:10.1007/s00395-009-0012-8. PMID 19255801.

[pmid_20398673-4] Schroeter A, Walzik S, Blechschmidt S, Haufe V, Benndorf K, Zimmer T (Jul 2010). "Structure and function of splice variants of the cardiac voltage-gated sodium channel Na(v)1.5". Journal of Molecular and Cellular Cardiology 49 (1): 16–24. doi:10.1016/j.yjmcc.2010.04.004. PMID 20398673.

[ref_25772290-5] Chen-Izu Y, Shaw RM, Pitt GS, Yarov-Yarovoy V, Sack JT, Abriel H, Aldrich RW, Belardinelli L, Cannell MB, Catterall WA, Chazin WJ, Chiamvimonvat N, Deschenes I, Grandi E, Hund TJ, Izu LT, Maier LS, Maltsev VA, Marionneau C, Mohler PJ, Rajamani S, Rasmusson RL, Sobie EA, Clancy CE, Bers DM (Mar 2015). "Na+ channel function, regulation, structure, trafficking and sequestration". The Journal of Physiology 593 (6): 1347–60. doi:10.1113/jphysiol.2014.281428. PMID 25772290.

[ref_9843461-6] Maltsev VA, Sabbah HN, Higgins RS, Silverman N, Lesch M, Undrovinas AI (Dec 1998). "Novel, ultraslow inactivating sodium current in human ventricular cardiomyocytes". Circulation 98 (23): 2545–52. PMID 9843461.

[ref_11073887-7] Sakmann BF, Spindler AJ, Bryant SM, Linz KW, Noble D (Nov 2000). "Distribution of a persistent sodium current across the ventricular wall in guinea pigs". Circulation Research 87 (10): 910–4. PMID 11073887.

[pmid_571107-8] Attwell D, Cohen I, Eisner D, Ohba M, Ojeda C (Mar 1979). "The steady state TTX-sensitive ("window") sodium current in cardiac Purkinje fibres". Pflügers Archiv 379 (2): 137–42. PMID 571107.

[pmid_19744495-9] Abriel H (Jan 2010). "Cardiac sodium channel Na(v)1.5 and interacting proteins: Physiology and pathophysiology". Journal of Molecular and Cellular Cardiology 48 (1): 2–11. doi:10.1016/j.yjmcc.2009.08.025. PMID 19744495.

[pmid_23771687-10] Herren AW, Bers DM, Grandi E (Aug 2013). "Post-translational modifications of the cardiac Na channel: contribution of CaMKII-dependent phosphorylation to acquired arrhythmias". American Journal of Physiology. Heart and Circulatory Physiology 305 (4): H431–45. doi:10.1152/ajpheart.00306.2013. PMID 23771687.

[pmid_24352520-11] Cerrone M, Lin X, Zhang M, Agullo-Pascual E, Pfenniger A, Chkourko Gusky H, Novelli V, Kim C, Tirasawadichai T, Judge DP, Rothenberg E, Chen HS, Napolitano C, Priori SG, Delmar M (Mar 2014). "Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype". Circulation 129 (10): 1092–103. doi:10.1161/CIRCULATIONAHA.113.003077. PMID 24352520.

[pmid_23956259-12] Lodder EM, Bezzina CR (Jan 2014). "Genomics of cardiac electrical function". Briefings in Functional Genomics 13 (1): 39–50. doi:10.1093/bfgp/elt029. PMID 23956259.

[pmid_9521325-13] 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 (Mar 1998). "Genetic basis and molecular mechanism for idiopathic ventricular fibrillation". Nature 392 (6673): 293–6. doi:10.1038/32675. PMID 9521325.

[pmid_10590249-14] 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 (Dec 1999). "A single Na(+) channel mutation causing both long-QT and Brugada syndromes". Circulation Research 85 (12): 1206–13. PMID 10590249.

[pmid_17145985-15] Remme CA, Verkerk AO, Nuyens D, van Ginneken AC, van Brunschot S, Belterman CN, Wilders R, van Roon MA, Tan HL, Wilde AA, Carmeliet P, de Bakker JM, Veldkamp MW, Bezzina CR (Dec 2006). "Overlap syndrome of cardiac sodium channel disease in mice carrying the equivalent mutation of human SCN5A-1795insD". Circulation 114 (24): 2584–94. doi:10.1161/CIRCULATIONAHA.106.653949. PMID 17145985.

[pmid_10471492-16] Schott JJ, Alshinawi C, Kyndt F, Probst V, Hoorntje TM, Hulsbeek M, Wilde AA, Escande D, Mannens MM, Le Marec H (Sep 1999). "Cardiac conduction defects associate with mutations in SCN5A". Nature Genetics 23 (1): 20–1. doi:10.1038/12618. PMID 10471492.

[pmid_11234013-17] Tan HL, Bink-Boelkens MT, Bezzina CR, Viswanathan PC, Beaufort-Krol GC, van Tintelen PJ, van den Berg MP, Wilde AA, Balser JR (Feb 2001). "A sodium-channel mutation causes isolated cardiac conduction disease". Nature 409 (6823): 1043–7. doi:10.1038/35059090. PMID 11234013.

[pmid_15466643-18] McNair WP, Ku L, Taylor MR, Fain PR, Dao D, Wolfel E, Mestroni L (Oct 2004). "SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia". Circulation 110 (15): 2163–7. doi:10.1161/01.CIR.0000144458.58660.BB. PMID 15466643.

[pmid_22766342-19] Laurent G, Saal S, Amarouch MY, Béziau DM, Marsman RF, Faivre L, Barc J, Dina C, Bertaux G, Barthez O, Thauvin-Robinet C, Charron P, Fressart V, Maltret A, Villain E, Baron E, Mérot J, Turpault R, Coudière Y, Charpentier F, Schott JJ, Loussouarn G, Wilde AA, Wolf JE, Baró I, Kyndt F, Probst V (Jul 2012). "Multifocal ectopic Purkinje-related premature contractions: a new SCN5A-related cardiac channelopathy". Journal of the American College of Cardiology 60 (2): 144–56. doi:10.1016/j.jacc.2012.02.052. PMID 22766342.

[pmid_14523039-20] Benson DW, Wang DW, Dyment M, Knilans TK, Fish FA, Strieper MJ, Rhodes TH, George AL (Oct 2003). "Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A)". The Journal of Clinical Investigation 112 (7): 1019–28. doi:10.1172/JCI18062. PMID 14523039.

[pmid_18929244-21] Makiyama T, Akao M, Shizuta S, Doi T, Nishiyama K, Oka Y, Ohno S, Nishio Y, Tsuji K, Itoh H, Kimura T, Kita T, Horie M (Oct 2008). "A novel SCN5A gain-of-function mutation M1875T associated with familial atrial fibrillation". Journal of the American College of Cardiology 52 (16): 1326–34. doi:10.1016/j.jacc.2008.07.013. PMID 18929244.

[pmid_7889574-22] Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, Moss AJ, Towbin JA, Keating MT (Mar 1995). "SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome". Cell 80 (5): 805–11. PMID 7889574.

[pmid_22999724-23] Mann SA, Castro ML, Ohanian M, Guo G, Zodgekar P, Sheu A, Stockhammer K, Thompson T, Playford D, Subbiah R, Kuchar D, Aggarwal A, Vandenberg JI, Fatkin D (Oct 2012). "R222Q SCN5A mutation is associated with reversible ventricular ectopy and dilated cardiomyopathy". Journal of the American College of Cardiology 60 (16): 1566–73. doi:10.1016/j.jacc.2012.05.050. PMID 22999724.

[pmid_15671429-24] Olson TM, Michels VV, Ballew JD, Reyna SP, Karst ML, Herron KJ, Horton SC, Rodeheffer RJ, Anderson JL (Jan 2005). "Sodium channel mutations and susceptibility to heart failure and atrial fibrillation". Jama 293 (4): 447–54. doi:10.1001/jama.293.4.447. PMID 15671429.

[pmid_6723689-25] Milne JR, Hellestrand KJ, Bexton RS, Burnett PJ, Debbas NM, Camm AJ (Feb 1984). "Class 1 antiarrhythmic drugs--characteristic electrocardiographic differences when assessed by atrial and ventricular pacing". European Heart Journal 5 (2): 99–107. PMID 6723689.

[pmid_11273715-26] Balser JR (Apr 2001). "The cardiac sodium channel: gating function and molecular pharmacology". Journal of Molecular and Cellular Cardiology 33 (4): 599–613. doi:10.1006/jmcc.2000.1346. PMID 11273715.

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SCN5A