SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome

Wang, Qing Kenneth; Shen, Jinglai; Splawski, Igor; Atkinson, Donald L.; Li, Zhizhong; Robinson, Jennifer L.; Moss, Arthur J.; Towbin, Jeffrey A.; Keating, Mark T.

doi:10.1016/0092-8674(95)90359-3

Cited by 1,510 publications

(821 citation statements)

References 33 publications

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“…Two mutations have been associated with AS so far in the gene encoding the cardiac Na channel α subunit SCN5A, which is responsible for dominant disorders of inherited arrhythmias including type 3 long QT syndrome (LQT3) 2 , Brugada syndrome 3 , and cardiac conduction system disease 4 . We previously identified a missense mutation R367H in a transient AS case complicated with Brugada syndrome 5 , and the recombinant channel showed total loss of Na current when expressed heterologously.…”

Section: Introductionmentioning

confidence: 99%

Congenital atrial standstill associated with coinheritance of a novel SCN5A mutation and connexin 40 polymorphisms

Makita¹,

Sasaki²,

Groenewegen³

et al. 2005

Heart Rhythm

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Section: Introductionmentioning

confidence: 99%

Congenital atrial standstill associated with coinheritance of a novel SCN5A mutation and connexin 40 polymorphisms

Makita¹,

Sasaki²,

Groenewegen³

et al. 2005

Heart Rhythm

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“…These mutations in SCN5A lead to defective inactivation of the sodium channels causing an increase in late Na channel current (late I Na ) (Wang et al, 1995). Similarly, gain of function mutations in the CACNA1C gene, which encodes the L-type calcium channel Ca v 1.2, leads to multi-organ disease including prolongation of QT interval, immunodeficiency and autism (Splawski et al, 2004).…”

Section: Molecular Genetics Of Lqtsmentioning

confidence: 99%

Pharmacological approach to the treatment of long and short QT syndromes

Patel

Antzelevitch

2008

Pharmacology & Therapeutics

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Inherited channelopathies have received increasing attention in recent years. The past decade has witnessed impressive progress in our understanding of the molecular and cellular basis of arrhythmogenesis associated with inherited channelopathies. An imbalance in ionic forces induced by these channelopathies affects the duration of ventricular repolarization and amplifies the intrinsic electrical heterogeneity of the myocardium, creating an arrhythmogenic milieu. Today, many of the channelopathies have been linked to mutations in specific genes encoding either components of ion channels or membrane or regulatory proteins. Many of the channelopathies are genetically heterogeneous with a variable degree of expression of the disease. Defining the molecular basis of channelopathies can have a profound impact on patient management, particularly in cases in which genotype-specific pharmacotherapy is available.The long QT syndrome (LQTS) is one of the first identified and most studied channelopathies where abnormal prolongation of ventricular repolarization predisposes an individual to life threatening ventricular arrhythmia called Torsade de Pointes. On the other hand of the spectrum, molecular defects favoring premature repolarization lead to Short QT syndrome (SQTS), a recently described inherited channelopathy. Both of these channelopathies are associated with a high risk of sudden cardiac death due to malignant ventricular arrhythmia. Whereas pharmacological therapy is first line treatment for LQTS, defibrillators are considered as primary treatment for SQTS. This review provides a comprehensive review of the molecular genetics, clinical features, genotype-phenotype correlations and genotype-specific approach to pharmacotherapy of these two mirror-image channelopathies, SQTS and LQTS.

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“…Opening of the channel leads to a rapid influx of Na + (I Na ), which depolarizes the membrane potential within tenths of a millisecond [12] . Dysfunction of Na v 1.5 channels leads to various arrhythmias, such as long QT syndrome, Brugada syndrome, and cardiac conduction disease (also known as Lev-Lenegre syndrome) [13][14][15] . In light of this, there may be a relationship between the cardiac toxicity of bupivacaine and its use-dependent blockade of Na + channels.…”

Section: Introductionmentioning

confidence: 99%

Voltage-dependent blockade by bupivacaine of cardiac sodium channels expressed in Xenopus oocytes

et al. 2014

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Bupivacaine ranks as the most potent and efficient drug among class I local anesthetics, but its high potential for toxic reactions severely limits its clinical use. Although bupivacaine-induced toxicity is mainly caused by substantial blockade of voltage-gated sodium channels (VGSCs), how these hydrophobic molecules interact with the receptor sites to which they bind remains unclear. Na v 1.5 is the dominant isoform of VGSCs expressed in cardiac myocytes, and its dysfunction may be the cause of bupivacainetriggered arrhythmia. Here, we investigated the effect of bupivacaine on Na v 1.5 within the clinical concentration range. The electrophysiological measurements on Na v 1.5 expressed in Xenopus oocytes showed that bupivacaine induced a voltageand concentration-dependent blockade on the peak of I Na and the half-maximal inhibitory dose was 4.51 μmol/L. Consistent with other local anesthetics, bupivacaine also induced a use-dependent blockade on Na v 1.5 currents. The underlying mechanisms of this blockade may contribute to the fact that bupivacaine not only dose-dependently affected the gating kinetics of Na v 1.5 but also accelerated the development of its open-state slow inactivation. These results extend our knowledge of the action of bupivacaine on cardiac sodium channels, and therefore contribute to the safer and more efficient clinical use of bupivacaine.

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SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome

Cited by 1,510 publications

References 33 publications

Congenital atrial standstill associated with coinheritance of a novel SCN5A mutation and connexin 40 polymorphisms

Congenital atrial standstill associated with coinheritance of a novel SCN5A mutation and connexin 40 polymorphisms

Pharmacological approach to the treatment of long and short QT syndromes

Voltage-dependent blockade by bupivacaine of cardiac sodium channels expressed in Xenopus oocytes

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