CC BY
20
ФУНДАМЕНТАЛЬНЫЕ ИССЛЕДОВАНИЯ И МЕЖДИСЦИПЛИНАРНЫЕ ТЕХНОЛОГИИ ■
КАНАЛОПАТИИ: МАЛЫЕ ДЕФЕКТЫ В ИОННЫХ КАНАЛАХ С ЛЕТАЛЬНЫМ ИСХОДОМ
Мохамед Ясин Амарух1, Хьюго Абриль2
1 Лаборатория окружающей среды и природных веществ, Университет Sidi Mohamed Ben AbdeLLah-Fes, междисциплинарный факультет Таза, Таза, Марокко
2 Отделение клинических исследований, Университет Берна, Берн, Швейцария
Статья подготовлена по докладу, представленному на 4-м Российско-швейцарском научном форуме (сентябрь 2014 г., Москва, Россия)
Ионные каналы представляют собой трансмембранные белки, которые обеспечивают прохождение ионов в соответствии с направлением их электрохимических градиентов. Отклонения в работе ионных каналов сердца связываются с аритмиями и внезапной сердечной смертью. У пациентов с унаследованными формами аритмии были описаны мутации в генах, кодирующих субъединицы сердечных ионных каналов. Примеры врожденных сердечных каналопатий включают синдром удлиненного интервала й-Т, синдром Бругада и полиморфную желудочковую тахикардию, вызванную физической нагрузкой. Ген БСИБЛ, кодирующий порообразующую субъединицу потенциалзависимого натриевого канала N8^.5, - интересный пример ионного канала, дисфункция которого может вызвать различные врожденные нарушения сердечного ритма. Этот небольшой обзор описывает, как замена одного остатка в натриевом канале N8^,5 может повлиять на его структуру и функции. Особое внимание уделено последним исследованиям, описывающим миссенс-мутацию, связанную с наследственной формой полиморфной желудочковой тахикардией, вызванной физической нагрузкой.
Клин. и эксперимент. хир. Журн. им. акад. Б.В. Петровского. - 2014. - № 4. - С. 5-11.
Ключевые слова:
ионные каналы, каналопатии
Channelopathies: small defects in ion channels with fatal consequences
Mohamed-Yassine Amarouch1, Hugues Abriel2
1 Environment & Natural Substances Laboratory, University of Sidi Mohamed Ben Abdellah-Fes, Multidisciplinar^ Faculty of Taza, Taza, Morocco
2 Department of Clinical Research, University of Bern, Bern, Switzerland
Ion channels are transmembrane proteins that allow the passage of ions according to the direction of their electrochemical gradients. Abnormalities in cardiac ion channel function have been linked to arrhythmias and sudden cardiac death. Mutations in the genes coding for cardiac ion channel subunits have been described in patients with inherited forms of arrhythmic disorders. Examples of genetic cardiac channelopathies include congenital long QT syndrome, Brugada syndrome, and exercise-induced polymorphic ventricular tachycardia.
Clin. Experiment. Surg. Petrovsky J. - 2014. - N 4. - P. 5-11.
The SCN5A gene, a gene coding for the pore-forming subunit of the cardiac voltage-gated sodium channel Nav1,5, is an interesting example of a ion channel whose malfunction can induce a variety of inherited cardiac arrhythmias. This short review describes how the substitution of one residue of Na 1,5 can affect its
v
structure and function. Particular interest will be given to recent studies describing a missense mutation associated with an inherited form of exercise-induced polymorphic ventricular arrhythmia.
CORRESPONDENCE
Dr. Mohamed Yassine Amarouch, PhD Environment & Natural Substances Laboratory, University of Sidi Mohamed Ben Abdellah-Fes, Multidisciplinary Faculty of Taza, Taza, Morocco
E-mail: [email protected]
Keywords:
ion channels, channelopathies
Introduction
Ion channel dysfunction is the principal pathophysiological mechanism underlying various inherited forms of arrhythmic disorders [2]. In cardiac cells, the upstroke of the action potential is the result of the passage of a large and rapid influx of sodium ions through the cardiac voltage-gated sodium channel (Nav1,5). Mutations in the SCN5A gene, which codes for the Na 1,5 channel, have been associated
v
with aberrant cardiac excitability phenotypes including congenital long QT syndrome type 3 (LQT3), cardiac conduction disease, Brugada syndrome (BrS), sudden infant death syndrome and dilated cardiomyopathy [3]. Several recent studies have reported additional SCN5A-dependent clinical phenotypes [4-9], such as Multifocal Ectopic Purkinje-related Premature Contractions (MEPPC) and exercise-induced polymorphic ventricular arrhythmia, which have been linked to the presence of the p.R222Q and p.I141V mutations of Nav1,5 [5, 6, 9]. These mutations affect the biophysical properties of Nav1,5 by shifting its voltage dependence of steady-state of inactivation and/or activation towards more negative potentials and hastening its activation and inactivation kinetics. In addition, the sodium currents that are generated by these mutant channels have larger sodium window current peaks which are shifted towards more negative potentials [5-7, 9].
The present review gives a general overview of the molecular mechanisms associated with cardiac arrhythmias related to SCN5A mutations. Particular interest will be given to recent studies that highlight
the structural and functional effects of the p.I141V mutation on the Na 1,5 channel, as well as the effects
v
on cardiac cell excitability.
The cardiac voltage-gated channel Na 1,5
v '
The SCN5A gene, located on chromosome 3p21, encodes the a-subunit of the cardiac voltage-gated sodium channel [10]. The a-subunit, Nav1,5, is composed of intracellular N and C terminal tails, as well as four homologous domains (DI-DIV), each consisting of six transmembrane segments (Fig. 1). The first four segments (S1-S4) comprise the voltage-sensing domain, and the last two segments (S5 and S6) form the pore of the channel when assembled in a tetrameric configuration. The four homologous domains are linked by intracellular loops DI-II, DII-III, and DIII-IV (Fig. 1). Nav1,5 activation is initiated by the outward movement of the positively charged S4 segments of the four domains of the channel protein. The increase in sodium permeability induces rapid membrane depolarization that characterizes the initial phase of the cardiac action potential, followed by rapid inactivation, mainly mediated by the movement of the intracellular DIII-DIV loop [11].
Similar to many membrane proteins, the cardiac sodium channel Na 1,5 has been found to interact
v
with partner proteins that regulate the channel's biology and function [12]. Some of these interacting proteins, which are localized in specific regions
Fig. 1. Topology of Nav1,5 and its interacting proteins. The pore-forming alpha subunit of Nav1,5 consists of four homologous domains (DI-DIV), linked by intracellular loops. Many of the regulatory proteins are shown to interact at the intracellular loops or at the C-terminus of Nav1,5. For some of these proteins that have been shown to associate with Nav1,5, the sites of interaction on the Nav1,5 channel are still unknown (with permission from Shy et al., 2014 [1])
NH2
DI
DII
DIII
DIV
OOOH
( CaMKIIS
NH2
( ankyrin-G
( a-actinin-2
( calmodulin ( ned d4-like
( syntrophin OOOH
dystrophin )
utrophin )
( plasmoglein-2 ( desmoglein-2 ^^
( caveolin 3 ?
( telethonin ?
( gpd-l ?
( ZASP ?
of the cardiomyocyte, have been shown to interact with the same regulatory domain of Nav1,5 [1, 12]. Shy and colleagues [13] demonstrated that the Nav1,5 channels are expressed as at least two distinct functional pools that are localized at the intercalated discs and the lateral membranes of the cardiomyocyte [13].
While the Na 1,5 subunit is the main isoform al-
v
lowing for the passage of the sodium ion current in the heart, other Nav a-subunits have been shown to contribute to the cardiac sodium current [14]. Even though these isoforms are fewer in number than Nav1,5 [15], they are proposed to be an important components of the macromolecular complex of the cardiac sodium channel. The Antzelevitch group recently published interesting results consistent with this hypothesis. The Nav1,8 sodium channel was shown to interact with Nav1,5 in HEK cells [16]. Mutations in the SCN10A gene, which encodes the Nav1,8 subunit, were linked to the occurrence of BrS via it effect on the main cardiac isoform of the voltage gated sodium channel, Na 1.5 [16].
Examples of genetic cardiac sodium channelopathies
Long QTsyndrome type 3
Congenital Long QT syndrome (LQTS) is an inherited disorder characterized by prolongation of the QT interval on electrocardiograms (ECG) and a propensity for ventricular tachyarrhythmias, notably torsades de pointes which may lead to cardiac sudden death. Prolonged QT interval reflects delayed repolarization of the ventricular cardiomyocyte. Several mutations in genes encoding for ion channels or their regulatory proteins have been associated with different subtypes of LQTS [17]. The most common ones are type 1, type 2 and type 3 [18].
Using a candidate gene approach, the causative gene of LQT3 was identified as SCN5A. A deletion of three amino acids, Lys, Pro, Gln (KPQ) at positions 1505-1507 was found in several families [19, 20]. The functional characterization of this deletion revealed an alteration of the rapid inactivation process of Nav1,5 [21]. Since then, a growing number of SCN5A mutations have been identified in patients with LQT3. The majority of these mutations were also found to affect the rapid inactivation of Nav1,5 [21, 22]. The Nav1,5-Y1795C (YC) is an example of one of these mutations. In addition to a slower onset of fast inactivation, the YC mutant was shown to increase the expression of sustained (or persistent) sodium channel activity compared to wild type channels [22]. LQT3 may also result from the modification of other biophysical parameters of Nav1,5. Mutations that induce a larger sodium current density, an in-
creased window current, or a faster recovery from inactivation have been also associated with the LQT3 phenotype [22-25].
As a consequence, SCN5A mutations that are linked to the LQT3 syndrome could modify the delicate balance between outward and inward currents that are involved in the plateau phase of the action potential. Under such pathological conditions, the balance would be in favor of the inward currents, resulting in prolongation of the ventricular action potential and QT interval.
Brugada syndrome
Brugada syndrome is an inherited cardiac arrhythmia characterized by ST-segment elevation in the right precordial leads on ECG. It is associated with an increased risk of sudden cardiac death [26]. In some cases, the ECG pattern of BrS is only visible under a drug challenge test. The two sodium channel blockers and anti-arrhythmic drugs ajmaline and flecainide are most often used to unmask the ECG pathological changes [27].
Among all of the susceptibility genes that are described for BrS, 15-30% of the identified mutations are located in SCN5A [28, 29]. More than 300 mutations have been found in this gene, many of which have been shown to be a loss of function mutations (see the online database Inherited Arrhythmias Database at http://www.fsm. it/cardmoc/). The mechanisms underlying this loss of function include: alterations in channel expression, defects in Nav1,5 trafficking to the plasma membrane, or alterations of the biophysical properties reflected by either a total loss of function (non-functional channels) or a reduced current density affecting activation and inactivation [22, 30, 31].
The exact link between SCN5A loss of function mutations and BrS is poorly understood. To date, two mechanisms have been proposed: the depolarization and repolarization hypotheses.
The depolarization hypothesis is based on the right ventricular conduction slowing and the involvement of structural abnormalities such as fibrosis [32, 33]. The heterogeneity of conduction velocities in the right ventricular epicardium would be more pronounced in the presence of a Nav1,5 loss of function mutation, and may trigger epicardial reentrant excitation waves [34].
The repolarization hypothesis is based on the transmural dispersion of repolarization between the right ventricular endocardium and epicardium [35]. The outward potassium current Ito, is larger in the right ventricular epicardium as compared to the endocardium. The action potential durations are, therefore, shorter in the epicardium. Nav1,5 loss of function would further shorten epicardial
action potential duration, and may hence facilitate reentrant excitation waves between the depolarized endocardium and prematurely repolarized epicardium [34].
Regardless of the mechanisms proposed by these two hypotheses, several findings challenge the monogenic origin of BrS, especially, the causative role of Na 1,5 loss of function in the occurrence of BrS.
v
Lack of segregation was found in large BrS-affected families that had SCN5A-positive and SCN5A-negative family members [29]. Furthermore, recent findings suggest that common genetic variants might have a strong impact on the manifestation of genetic diseases such as BrS [36].
Exercise-induced polymorphic ventricular arrhythmias
Premature ventricular complexes (PVCs) induced by a sympathetic stimulus, i.e. physical exercise, can increase the risk of sudden cardiac death. The occurrence of exercise-induced PVCs, bigeminy and ventricular tachycardias in structurally normal hearts (characteristics of catechol-aminergic polymorphic ventricular tachycardia) are associated with increased mortality [37-39]. Mutations in the SCN5A gene were recently linked to familial forms of exercise-induced polymorphic ventricular arrhythmia [9]. The first segment of domain I of the Na 1,5 channel contains amino
v
acids that are highly conserved between Nav iso-forms. One of these amino acids is isoleucine 141. Its substitution to valine in Na 1,5 channels has
v
been linked to the occurrence of inherited exercise-induced polymorphic ventricular arrhythmias [9]. A large multigenerational family, presenting with exercise-induced polymorphic ventricular arrhythmia, was clinically characterized and followed for 10 years by Swan and colleagues. Exome-sequenc-ing identified a mutation in the SCN5A gene that resulted in a p.I141V substitution. The functional characterization of this mutation in HEK293 cells showed that the presence of the p.I141V substitution shifted the voltage dependence of steady state activation towards more negative potentials. No significant differences were observed in regards to the voltage dependence of steady-state inactivation [9]. When compared to the WT window current, the p.I141V window current exhibited a larger peak that was shifted towards more negative potentials. In silico investigation of the molecular effects of the p.I141V mutation suggested a reduced excitation threshold for the action potential generation in the presence of this mutation as compared to the WT condition [9]. Interestingly, the biophysical changes seen with a p.I141V substitution in Na 1.5 were similar to those seen
v
with a p.I141V substitution in the Na 1.4 channel,
as well as to those seen with a p.I136V substitution in Na 1.7. The latter mutations were associated with
v
the occurrence of myotonia and erythromelalgia, respectively [40-42].
As aforementioned, the presence of the p.I141V mutation affects the activation process of the Nav1,5 channel. Similar biophysical modifications were observed with other SCN5A mutants, such as p.R222Q [5-7]. The functional study of this mutationin COS-7 cells showed that the presence of this mutation shifted the voltage-dependence of steady-state activation towards more negative potentials, as well as increased and shifted the sodium window current as compared to the WT condition [5, 6].
The similarities in the biophysical modifications that were induced by the p.I141V mutation (located in the S1-DI) and the p.R222Q mutation (located in the S4-DI) of Nav1,5 channels, as well as their association with similar clinical manifestations (cardiac hy-perexcitability phenotypes), supports the hypothesis that there are intra-segment interactions inside the voltage-sensing domain (VSD). These interactions may stabilize the activated state of the channels that carry the p.I141V or p.R222Q mutations. To test this hypothesis, the structural bases of the p.I141V biophysical alterations were investigated by performing molecular dynamic (MD) simulations using an atomistic model of Nav1,4. In the presence of the p.I141V mutation, the MD simulations predicted the proximity of the Y168 residue in the S2-DI segment with the R225 residue in S4-DI [43] (Fig. 2). This spatial proximity was predicted to allow for the formation of a hydrogen bond between the Y168 hydroxyl group and the R225 backbone [43]. Based on this model, the newly-formed hydrogen bond may stabilize the activated state of the p.I141V mutant.
The MD simulation predictions were partially confirmed by the functional analyses of the single (p.Y168F) and double mutants (p.I141V-Y168F) of Na 1,5, where the Y168 residue was substituted with
v
phenylalanine in order to prevent formation of the putative hydrogen bond between Y168 and R225 [43]. The biophysical characterization of the p.I141V-Y168F double mutant showed abolition of the p.I141V effect on the Nav1,5 channels [43]. Destabilization of the activated state of this channel was observed for the single mutant, suggesting a compensatory role of the Y168 and R225 residues on the stability of the voltage-sensing domain rather than hydrogen formation [43].
In conclusion, there has been tremendous progress made in the field of cardiac channelopathies over the past two decades. In most cases, it is possible to propose plausible models describing how single mutations in the genes coding for ion channels may lead to severe arrhythmias that increase the risk for
R219
Fig. 2. Voltage sensing domain configurations of the WT (a) and the p.I141V mutants (b) of Nav1,4 channel. In the presence of the p.I141V mutation, MD simulation predicted the formation of a hydrogen bond (green arrow) between the S2-Y168 and S4-R225 residues, thus stabilizing the open confirmation ofthe channel (From Amarouch et al., 2014)[43]
A
sudden cardiac death. New powerful computational approaches [44] will hopefully enhance our understanding of the molecular, cellular, and organismic details of these pathologies. Such technologies may also help us to define new preventive and therapeutic strategies for these disorders.
Acknowledgments
The group of H.A. is supported by a grant of the Swiss National Science Foundation 310030-14060 and from the European Community's Seventh Framework Programme FP7/2007-2013 under grant agreement no. HEALTH-F2-2009-241526, EUTrigTreat.
Reference
1. Shy D., Gillet L., Abriel H. Cardiac sodium channel NaV1.5 distribution in myocytes via interacting proteins: the multiple pool model // Biochim. Biophys. Acta. -2013. - Vol. 1833. - P. 886-894.
2. Abriel H., Zaklyazminskaya E.V. Cardiac channelopathies: genetic and molecular mechanisms // Gene. -
2013. - Vol. 517. - P. 1-11.
3. Wilde A.A., Brugada R. Phenotypical manifestations of mutations in the genes encoding subunits of the cardiac sodium channel // Circ. Res. - 2011. - Vol. 108. -P. 884-897.
4. Beckermann T.M., McLeod K., Murday V. et al. Novel SCN5A mutation in amiodarone-responsive multifocal ventricular ectopy-associated cardiomyopathy // Heart Rhythm: the official journal of the Heart Rhythm Society. -
2014. - Vol. 11. - P. 1446-1453.
5. Laurent G., Saal S., Amarouch M.Y. et al. Multifocal ectopic Purkinje-related premature contractions: a new SCN5A-related cardiac channelopathy // J. Am. Coll. Cardiol. - 2012. - Vol. 60. - P. 144-156.
6. Mann S.A., Castro M.L., Ohanian M. et al. R222Q SCN5A mutation is associated with reversible ventricular
ectopy and dilated cardiomyopathy // J. Am. Coll. Cardiol. -2012. - Vol. 60. - P. 1566-1573.
7. Nair K., Pekhletski R., Harris L. et al. Escape capture bigeminy: phenotypic marker of cardiac sodium channel voltage sensor mutation R222Q // Heart Rhythm: the official journal of the Heart Rhythm Society. - 2012. -Vol. 9. - P. e1681-1688.
8. Nguyen T.P., Wang D.W., Rhodes T.H., George A.L. Jr. Divergent biophysical defects caused by mutant sodium channels in dilated cardiomyopathy with arrhythmia // Circ. Res. - 2008. - Vol. 102. - P. 364-371.
9. Swan H., Amarouch M.Y., Leinonen J. et al. A Gain-of-Function Mutation of the SCN5A Gene Causes Exercise-Induced Polymorphic Ventricular Arrhythmias // Circ. Car-diovasc. Genet. - 2014. - Vol. 7, N 6. - P. 771-781.
10. Wang Q., Li Z., Shen J., Keating M.T. Genomic organization of the human SCN5A gene encoding the cardiac sodium channel // Genomics. - 1996. - Vol. 34. -P. 9-16.
11. Marban E., Yamagishi T., Tomaselli G.F. Structure and function of voltage-gated sodium channels // J. Physiol. -1998. - Vol. 508, pt 3. - P. 647-657.
12. Abriel H. Cardiac sodium channel Na(v)1.5 and interacting proteins: Physiology and pathophysiology // J. Mol. Cell. Cardiol. - 2010. - Vol. 48. - P. 2-11.
13. Shy D., Gillet L, Ogrodnik J. et al. PDZ domain-binding motif regulates cardiomyocyte compartment-specific NaV1.5 channel expression and function // Circulation. -2014. - Vol. 130. - P. 147-160.
14. Maier S.K., Westenbroek R.E., Schenkman K.A. et al. An unexpected role for brain-type sodium channels in coupling of cell surface depolarization to contraction in the heart // Proc. Natl Acad. Sci. USA. - 2002. - Vol. 99. -P. 4073-4078.
15. Maier S.K., Westenbroek R.E., McCormick K.A. et al. Distinct subcellular localization of different sodium channel alpha and beta subunits in single ventricular myocytes from mouse heart // Circulation. - 2004. - Vol. 109. -P. 1421-1427.
16. Hu D., Barajas-Martinez H., Pfeiffer R. et al. Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome // J. Am. Coll. Cardiol. - 2014. -Vol. 64. - P. 66-79.
17. Tester D.J., Ackerman M.J. Genetics of long QT syndrome // Methodist DeBakey Cardiovasc. J. - 2014. -Vol. 10. - P. 29-33.
18. Goldenberg I., Zareba W, Moss A.J. Long QT Syndrome // Curr. Probl. Cardiol. - 2008. - Vol. 33. - P. 629-694.
19. Jiang C., Atkinson D., Towbin J.A. et al. Two long QT syndrome loci map to chromosomes 3 and 7 with evidence for further heterogeneity // Nat. Genet. - 1994. - Vol. 8. -P. 141-147.
20. Wang Q., Shen J., Splawski I. et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome // Cell. - 1995. - Vol. 80. - P. 805-811.
21. Bennett P.B., Yazawa K., Makita N, George A.L. Jr. Molecular mechanism for an inherited cardiac arrhythmia // Nature. - 1995. - Vol. 376. - P. 683-685.
22. RivoltaI., Abriel H., Tateyama M. et al. 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. - Vol. 276. -P. 30623-30630.
23. Wang D.W., Yazawa K., George A.L. Jr., Bennett P.B. Characterization of human cardiac Na+ channel mutations in the congenital long QT syndrome // Proc. Natl Acad. Sci. USA. - 1996. - Vol. 93. - P. 13200-13205.
24. Albert C.M., Nam E.G., Rimm E.B. et al. Cardiac sodium channel gene variants and sudden cardiac death in women // Circulation. - 2008. - Vol. 117. - P. 16-23.
25. Clancy C.E., Tateyama M., Liu H. et al. Non-equilibrium gating in cardiac Na+ channels: an original mechanism of arrhythmia // Circulation. - 2003. - Vol. 107. - P. 2233-2237.
26. Brugada P., Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report // J. Am. Coll. Cardiol. - 1992. -Vol. 20. - P. 1391-1396.
27. Bayes de Luna A., Brugada J., Baranchuk A. et al. Current electrocardiographic criteria for diagnosis of Brugada pattern: a consensus report // J. Electrocardiol. - 2012. - Vol. 45. - P. 433-442.
28. Kapplinger J.D., Tester D.J., Alders M. et al. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing // Heart Rhythm: the official journal of the Heart Rhythm Society. - 2010. - Vol. 7. -P. 33-46.
29. Probst V., Wilde A.A., Bare J. et al. SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome // Circ. Cardiovasc. Genet. - 2009. -Vol. 2. - P. 552-557.
30. Valdivia C.R., Tester D.J., Rok B.A. et al. A trafficking defective, Brugada syndrome-causing SCN5A mutation rescued by drugs // Cardiovasc. Res. - 2004. - Vol. 62. -P. 53-62.
31. Petitprez S., Jespersen T., Pruvot E. et al. Analyses of a novel SCN5A mutation (C1850S): conduction vs. repolarization disorder hypotheses in the Brugada syndrome // Cardiovasc. Res. - 2008. - Vol. 78. - P. 494-504.
32. Meregalli P.G., Wilde A.A., Tan H.L. Pathophysiological mechanisms of Brugada syndrome: depolarization disorder, repolarization disorder, or more? // Cardiovasc. Res. - 2005. - Vol. 67. - P. 367-378.
33. Frustaci A., Priori S.G., Pieroni M. et al. Cardiac histological substrate in patients with clinical phenotype of Brugada syndrome // Circulation. - 2005. - Vol. 112. -P. 3680-3687.
34. Wilde A.A., Postema P.G., Di Diego J.M. et al. The pathophysiological mechanism underlying Brugada syndrome: depolarization versus repolarization // J. Mol. Cell. Cardiol. - 2010. - Vol. 49. - P. 543-553.
35. Yan G.X., Antzelevitch C. Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogen-esis associated with ST-segment elevation // Circulation. -1999. - Vol. 100. - P. 1660-1666.
36. Bezzina C.R., Bare J., Mizusawa Y. 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. - 2013. - Vol. 45. -P. 1044-1049.
37. Leenhardt A., Lucet V., Denjoy I. et al. Catechol-aminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients // Circulation. - 1995. -Vol. 91. - P. 1512-1519.
38. Swan H., Piippo K., Viitasalo M. et al. Arrhythmic disorder mapped to chromosome 1q42-q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts // J. Am. Coll. Cardiol. - 1999. - Vol. 34. -P. 2035-2042.
39. Laitinen P.J., Brown K.M., Piippo K. et al. Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia // Circulation. -2001. - Vol. 103. - P. 485-490.
40. Cheng X., Dib-Hajj S.D., Tyrrell L., Waxman S.G. Mutation I136V alters electrophysiological properties of the Na(v)1.7 channel in a family with onset of erythromel.al.gia in the second decade // Mol. Pain. - 2008. - Vol. 4. - P. 1.
41. Lee M.J., Yu H.S., Hsieh S.T. et ai. Characterization of a familial case with primary erythromel.al.gia from Taiwan // J. Neurol. - 2007. - Vol. 254. - P. 210-214.
42. Petitprez S., Tiab L., Chen L. et ai. A novel dominant mutation of the Nav1.4 alpha-subunit domain I lead-
ing to sodium channel myotonia // Neurology. - 2008. -Vol. 71. - P. 1669-1675.
43. Amarouch M.-Y., Kasimova M.A., Tarek M., Abriei H. Functional interaction between S1 and S4 segments in voltage-gated sodium channels revealed by human channelopathies // Channels. - 2014. - Vol. 8. - P. 414-420.
44. Abriei H., de Lange E., Kucera J.P. et ai. Computational tools to investigate genetic cardiac channelopathies // Front. Physiol. - 2013. - Vol. 4. - P. 390.
