Novel pore mutation in SCN5A manifests as a spectrum of phenotypes ranging from atrial flutter, conduction disease, and Brugada syndrome to sudden cardiac death

Rossenbacker, Tom; Carroll, Sheila J.; Liu, Huajun; Kuipéri, Cuno; Ravel, Thomy de; Devriendt, Koen; Carmeliet, Peter; Kass, Robert S.; Heidbüchel, Hein

doi:10.1016/j.hrthm.2004.07.001

Cited by 70 publications

(44 citation statements)

References 18 publications

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“…Мутация R367H подавляет ток INav1.5 из-за потери одного функционального аллеля [10]. Близлежащая к новой замене L1217R изученная мутация S1218I вызывает нарушение транспорта натриевых каналов, а не активационные или инактивационные кинетические дефекты, при-водя к 50%-му снижению пиковой плотности тока натрия в гетерозиготном состоянии и появ-лению признаков синдрома Бругада [32].…”

Section: Discussionunclassified

“…Генотипи-рование выявило известную мутацию R367H, локализованную в первом поровом сегменте на-триевого канала между DI-S5 и DI-S6. Для мута-ции R367H показана связь с синдромом Бругада и дефектами сердечной проводимости [10,22,23]. Больному имплантирован КД, показавший при последующих проверках мотивированные срабатывания.…”

Section: результатыunclassified

“…Замена глицина на арги-нин (G1406R в оригинальной публикации, G1408R в настоящей нумерации) в регионе DIII-S5/S6 вызывает синдром Бругада и нару-шения проводимости [9], а замена глутамино-вой кислоты лизином (E161K) в области DI-S2 к этим двум нарушениям добавляет СССУ [4]. Отмечено сочетание признаков синдрома Бру-гада с СССУ и фибрилляцией предсердий (ФП) [10]. Клинические признаки LQTS3 и наруше-ния проводимости описаны у пациентов с мута-цией delKPQ1505-1507, расположенной рядом с делецией delK1500 [11].…”

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Brugada syndrome and cardiac sodium channelopathy overlap syndromes: different faces of SCN5A mutations

Bockeriа¹,

Pronicheva²,

Serguladze³

et al. 2018

Ann aritmol

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Section: Discussionunclassified

Section: результатыunclassified

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Brugada syndrome and cardiac sodium channelopathy overlap syndromes: different faces of SCN5A mutations

Bockeriа¹,

Pronicheva²,

Serguladze³

et al. 2018

Ann aritmol

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“…8,9 Accordingly, several rare variants in genes encoding cardiac sodium and potassium channels have been found both in patients with AF and in patients with BrS. This is the case for the variants in SCN5A (c. 647C4T (p.(Ser216Leu)), rs201002736, 10,11 c. 1127G4A (p.(Arg376His)), rs199473101, 10,12 c. 3157G4A (p.(Glu1053Lys)), rs137854617, 10,13 and c. 6010T4C (p.(Phe2004Leu)), rs41311117 14,15 ), SCN1Bb (c. 641G4A (p.(Arg214Gln)), rs66876876 16,17 ), SCN3B (c. 29T4C (p.(Leu10Pro)), rs121918282 18,19 ), MOG1 (c. 181G4T…”

Section: Introductionmentioning

confidence: 98%

Brugada syndrome risk loci seem protective against atrial fibrillation

et al. 2014

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Several studies have shown an overlap between genes involved in the pathophysiological mechanisms of atrial fibrillation (AF) and Brugada Syndrome (BrS). We investigated whether three single-nucleotide polymorphisms (SNPs) (rs11708996; G4C located intronic to SCN5A, rs10428132; T4G located in SCN10A, and rs9388451; T4C located downstream to HEY2) at loci associated with BrS in a recent genome-wide association study (GWAS) also were associated with AF. A total of 657 patients diagnosed with AF and a control group comprising 741 individuals free of AF were included. The three SNPs were genotyped using TaqMan assays. The frequencies of risk alleles in the AF population and the control population were compared in two-by-two models. One variant, rs10428132 at SCN10A, was associated with a statistically significant decreased risk of AF (odds ratio (OR) ¼ 0.77, P ¼ 0.001). A meta-analysis was performed by enriching the control population with allele frequencies from controls in the recently published BrS GWAS (2230 alleles). In this meta-analysis, both rs10428132 at SCN10A (OR ¼ 0.73, P ¼ 5.7 Â 10 À6 ) and rs11708996 at SCN5A (OR ¼ 0.80, P ¼ 0.02) showed a statistically significant decreased risk of AF. When assessing the additive effect of the three loci, we found that the risk of AF decreased in a dose-responsive manner with increasing numbers of risk alleles (OR ¼ 0.50, P ¼ 0.001 for individuals carrying Z4 risk alleles vs r1 allele).In conclusion, the prevalence of three risk alleles previously associated with BrS was lower in AF patients than in patients free of AF, suggesting a protective role of these loci in developing AF.

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“…On the other hand, loss-of-function mutations decrease I Na and are responsible for cardiac conduction diseases (Schott et al, 1999;Tan et al, 2001;Probst et al, 2003), Brugada syndrome (Gussak et al, 1999), sick sinus syndrome (Benson et al, 2003), and atrial standstill (Groenewegen et al, 2003). To complicate matters further, some SCN5A mutations can lead to more complex diseases associating different phenotypic traits such as, for instance, bradycardia, conduction disease, LQT3, and Brugada syndrome (so-called overlap syndromes; Bezzina et al, 1999;Kyndt et al, 2001;Grant et al, 2002;Rossenbacker et al, 2004;Smits et al, 2005; for review, see Remme et al, 2008). Finally, there is also an association between SCN5A genetic defects and susceptibility to dilated cardiomyopathy (DCM; McNair et al, 2004) and atrial fibrillation (Laitinen-Forsblom et al, 2006;Ellinor et al, 2008).…”

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confidence: 99%

Mouse models of SCN5A-related cardiac arrhythmias

Charpentier

Bourgé

Mérot

2008

Progress in Biophysics and Molecular Biology

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Mutations of SCN5A gene, which encodes the α-subunit of the voltage-gated Na channel Na V 1.5, underlie hereditary cardiac arrhythmic syndromes such as the type 3 long QT syndrome, cardiac conduction diseases, the Brugada syndrome, the sick sinus syndrome, a trial standstill, and numerous overlap syndromes. Patch-clamp studies in heterologous expression systems have provided important information to understand the genotype-phenotype relationships of these diseases. However, they could not clarify how SCN5A mutations can be responsible for such a large spectrum of diseases, for the late age of onset or the progressiveness of some of these diseases and for the overlapping syndromes. Genetically modified mice rapidly appeared as promising tools for understanding the pathophysiological mechanisms of cardiac SCN5A-related arrhythmic syndromes and several mouse models have been established. This review presents the results obtained on these models that, for most of them, recapitulate the clinical phenotypes of the patients. This includes two models knocked out for Nav1.5 β1 and β3 auxiliary subunits that are also discussed. Despite their own limitations that we point out, the mouse models still appear as powerful tools to elucidate the pathophysiological mechanisms of SCN5A-related diseases and offer the opportunity to investigate the secondary cellular consequences of SCN5A mutations such as the expression remodeling of other genes. This points out the potential role of these genes in the overall human phenotype. Finally, they constitute useful tools for addressing the role of genetic and environmental modifiers on cardiac electrical activity.

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Novel pore mutation in SCN5A manifests as a spectrum of phenotypes ranging from atrial flutter, conduction disease, and Brugada syndrome to sudden cardiac death

Cited by 70 publications

References 18 publications

Brugada syndrome and cardiac sodium channelopathy overlap syndromes: different faces of SCN5A mutations

Brugada syndrome and cardiac sodium channelopathy overlap syndromes: different faces of SCN5A mutations

Brugada syndrome risk loci seem protective against atrial fibrillation

Mouse models of SCN5A-related cardiac arrhythmias

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