Cardiac channelopathies: Genetic and molecular mechanisms

Abriel, Hugues; Zaklyazminskaya, E. V.

doi:10.1016/j.gene.2012.12.061

Cited by 103 publications

(92 citation statements)

References 145 publications

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“…A missense variant was located in the dachsous cadherin-related 1 gene (DCHS1; NM_003737.2: c.3415C>T: p.Arg1139Cys) with disease-causing protein function predictions and an allele frequency of 3.7e-05 in the general population (ExAC). The second variant was a one nucleotide, frame-shifting deletion in the transforming growth factor beta 2 gene (TGFβ2; NM_001135599.2: c.440delC: p.Pro.147fs*27) leading to a truncated protein, 9 not previously described in respective databases or in the scientific literature. The ancestral alleles of both variants were highly conserved during evolution.…”

Section: Case Imentioning

confidence: 99%

“…Channelopathies primarily affect the heart rhythm and cardiac electrical conduction including cardiac diseases such as long QT syndrome (LQTS), short QT syndrome (SQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), Brugada syndrome (BrS), and idiopathic ventricular fibrillation [9]. Cardiomyopathies on the other hand refer to myocardial disorders characterized by a structural and functional abnormal heart muscle [10].…”

Section: Introductionmentioning

confidence: 99%

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Post-mortem whole-exome sequencing (WES) with a focus on cardiac disease-associated genes in five young sudden unexplained death (SUD) cases

et al. 2016

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Sudden death of healthy young adults in the absence of any medical reason is generally categorised as autopsy-negative sudden unexplained death (SUD). Approximately 30 % of all SUD cases can be explained by lethal sequence variants in cardiac genes causing disturbed ion channel functions (channelopathies) or minimal structural heart abnormalities (cardiomyopathies). The aim of this study was to perform whole-exome sequencing (WES) in five young SUD cases in order to identify potentially diseasecausing mutations with a focus on 184 genes associated with cardiac diseases or sudden death. WES analysis enabled the identification of damaging-predicted cardiac sequence alterations in three out of five SUD cases. Two SUD victims carried disease-causing variants in long QT syndrome (LQTS)-associated genes (KCNH2, SCN5A). In a third case, WES identified variants in two genes involved in mitral valve prolapse and thoracic aortic aneurism (DCHS1, TGF2). The genome of a fourth case carried several minor variants involved in arrhythmia pointing to a multigene influence that might have contributed to sudden death. Our results confirm that post-mortem genetic testing in SUD cases in addition to the conventional autopsy can help to identify familial cardiac diseases and can contribute to the identification of genetic risk factors for sudden death.

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Section: Case Imentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Post-mortem whole-exome sequencing (WES) with a focus on cardiac disease-associated genes in five young sudden unexplained death (SUD) cases

et al. 2016

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“…В этом отноше-нии в целях диагностики рекомендованы: эхокардиография (ЭхоКГ), ЭКГ по специальным протоколам для выявления арит-могенной дисплазии правого желудочка, синдрома Бругада; ЭКГ высокого разрешения [8,14,[32][33][34]. При подозрении на первич-ные каналопатии показаны медико-генетическое консультиро-вание и при необходимости выборочное или расширенное моле-кулярно-генетическое исследование [35,36].…”

Section: терапевтический архив 5 2015unclassified

Algorithm for the management of patients with ventricular arrhythmias

Ev¹,

Tv²,

Тулинцева³

et al. 2015

Ter. arkh.

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Решение проблем диагностики желудочковых нарушений ритма и выбора тактики ведения пациентов с желудочковыми аритмиями (ЖА) занимает особое место в современной кардио-логии и является очень непростой задачей. Начиная с 70-х годов прошлого столетия стали интенсивно внедрять новые методы диагностики аритмий -холтеровское мониторирование (ХМ), электрофизиологические исследования и др., появились новые противоаритмические препараты и немедикаментозные методы лечения. Однако и сегодня выбор оптимального диагностическо-го и лечебного «пути» остается очень ответственным и сложным.Первым клиническим проявлением аритмии, как правило, являются ощущение перебоев в работе сердца или сердцебиение, что само по себе должно быть поводом для выполнения ХМ. Мо-ниторирование также необходимо провести при случайной реги-страции нарушений ритма во время съемки электрокардиограм-мы (ЭКГ) или подозрении на них при осмотре больного. Аннотация В работе предлагается оригинальный алгоритм ведения пациентов с желудочковой аритмией -от момента ее первой регистрации до выбора лечебной тактики. Большое внимание уделяется выявлению структурных и ишемических изменений миокарда с применением современных методов исследования, а также участию вегетативной и центральной нервной системы в желудочковом аритмогенезе, поэтапно решаются диагностические задачи. Выделяется роль психологической диагностики. Многосуточное мониторирование (электрокардиограмма с телеметрией) позволяет оперативно приступить к этапу лечения пациента, проводить его в амбулаторных условиях, а в ряде случаев -и без отрыва от трудовой деятельности. Ключевой момент предложенного алгоритма -профилактика внезапной сердечной смерти. Алгоритм ведения пациентов с желудочковыми аритмиями Ключевые слова: желудочковые аритмии, холтеровское мониторирование, пробы с физической нагрузкой, психодиагно-стика, алгоритм ведения, лечебная тактика, адаптол, этацизин.The paper proposes an original algorithm for the management of patients with ventricular arrhythmia from its first registration to choice of treatment policy. Using modern diagnostic methods, much attention is paid to the identification of myocardial structural and ischemic changes and also to the involvement of the autonomic and central nervous systems in ventricular arrhythmogenesis. The diagnostic problems are solved step-by-step. The role of psychological diagnosis is accentuated. Longitudinal electrocardiogram monitoring with telemetric data transmission can promptly initiate treatment of patients in an outpatient setting and, in a number of cases, without discontinuing work. The key point of the algorithm proposed is to prevent sudden cardiac death. Key words: ventricular arrhythmias, Holter monitoring, exercise tests, psychodiagnosis, management algorithm, treatment policy, adaptol, ethacyzin.ААП -антиаритмический препарат ААТ -антиаритмическая терапия БАБ -β-адреноблокаторы ВНС -вегетативная нервная система ВСС -внезапная сердечная смерть ЖА -желудочковая аритмия ЖТ -желудочковая тахикардия ЖЭК -желудочковые эктопические комплексы...

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“…Mutations in the genes SCN1A, SCN4A and SCN5A, which encode Na V 1.1, Na V 1.4 and Na V 1.5, respectively, lead to various epilepsy syndromes, muscular disorders and inherited cardiac arrhythmias. [1][2][3] Na V channels are monomers with a tetrameric repeat of 6 transmembrane (TM) segments. The first 4 TM segments (S1-S4) comprise the voltage-sensing domain (VSD), and the last 2 TM segments (S5 and S6) form the pore of the channel when assembled in a tetrameric configuration.…”

Section: Introductionmentioning

confidence: 99%

“…myotonia, exercise-induced polymorphic ventricular arrhythmias and erythromelalgia. [1][2][3][4][5][6] The p.I141V mutation in Na V 1.4 and Na V 1.5, as well as its homologous p.I136V mutation in Na v 1.7, induce similar modifications in the biophysical properties of the voltage-gated sodium channels [3][4][5][6] by shifting the voltage-dependence of steady state activation toward more negative potentials and hastening the activation and inactivation kinetics. In addition, the I Na generated by these mutant channels have larger sodium window current peaks which are shifted toward more negative potentials.…”

Section: Introductionmentioning

confidence: 99%

Functional interaction between S1 and S4 segments in voltage-gated sodium channels revealed by human channelopathies

Amarouch

Kasimova

Tarek³

et al. 2014

Channels

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The p.I141V mutation of the voltage-gated sodium channel is associated with several clinical hyper-excitability phenotypes. To understand the structural bases of the p.I141V biophysical alterations, molecular dynamics simulations were performed. These simulations predicted that the p.I141V substitution induces the formation of a hydrogen bond between the Y168 residue of the S2 segment and the R225 residue of the S4 segment. We generated a p.I141V-Y168F double mutant for both the Na v 1.4 and Na v 1.5 channels. The double mutants demonstrated the abolition of the functional effects of the p.I141V mutation, consistent with the formation of a specific interaction between Y168-S2 and R225-S4. The single p.Y168F mutation, however, positively shifted the activation curve, suggesting a compensatory role of these residues on the stability of the voltage-sensing domain.

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Cardiac channelopathies: Genetic and molecular mechanisms

Cited by 103 publications

References 145 publications

Post-mortem whole-exome sequencing (WES) with a focus on cardiac disease-associated genes in five young sudden unexplained death (SUD) cases

Post-mortem whole-exome sequencing (WES) with a focus on cardiac disease-associated genes in five young sudden unexplained death (SUD) cases

Algorithm for the management of patients with ventricular arrhythmias

Functional interaction between S1 and S4 segments in voltage-gated sodium channels revealed by human channelopathies

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