<i>SCN5A</i> Mutation Associated with Cardiac Conduction Defect and Atrial Arrhythmias

Laitinen-Forsblom, Päivi J.; Mäkynen, Pekka J.; Mäkynen, Heikki; Yli‐Mäyry, Sinikka; Virtanen, Vesa; Kontula, Kimmo; Aalto‐Setälä, Katriina

doi:10.1111/j.1540-8167.2006.00411.x

Cited by 82 publications

(65 citation statements)

References 31 publications

(71 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since then, many mutations in all domains of SCN5A have been associated with LQTS [Ackerman et al, 2004;Hofman-Bang et al, 2006;Napolitano et al, 2005], some in CCD [Bezzina et al, 2003;Laitinen-Forsblom et al, 2006;Petitprez et al, 2008;Probst et al, 2006], AF [Darbar et al, 2008;Makiyama et al, 2008b], and DCM [Olson et al, 2005]. In the clinical sudden infant and adult death syndromes (SIDS and SADS), mutations are also found in SCN5A Behr et al, 2008;Wang et al, 2007].…”

Section: Brs1-mutations In Scn5amentioning

confidence: 99%

The genetic basis of Brugada syndrome: A mutation update

et al. 2009

View full text Add to dashboard Cite

Brugada syndrome (BrS) is a condition characterized by a distinct ST-segment elevation in the right precordial leads of the electrocardiogram and, clinically, by an increased risk of cardiac arrhythmia and sudden death. The condition predominantly exhibits an autosomal dominant pattern of inheritance with an average prevalence of 5:10,000 worldwide. Currently, more than 100 mutations in seven genes have been associated with BrS. Loss-of-function mutations in SCN5A, which encodes the a-subunit of the Na v 1.5 sodium ion channel conducting the depolarizing I Na current, causes 15-20% of BrS cases. A few mutations have been described in GPD1L, which encodes glycerol-3-phosphate dehydrogenase-1 like protein; CACNA1C, which encodes the a-subunit of the Ca v 1.2 ion channel conducting the depolarizing I L,Ca current; CACNB2, which encodes the stimulating b2-subunit of the Ca v 1.2 ion channel; SCN1B and SCN3B, which, in the heart, encodes b-subunits of the Na v 1.5 sodium ion channel, and KCNE3, which encodes the ancillary inhibitory b-subunit of several potassium channels including the Kv4.3 ion channel conducting the repolarizing potassium I to current. BrS exhibits variable expressivity, reduced penetrance, and ''mixed phenotypes,'' where families contain members with BrS as well as long QT syndrome, atrial fibrillation, short QT syndrome, conduction disease, or structural heart disease, have also been described.

show abstract

Section: Brs1-mutations In Scn5amentioning

confidence: 99%

The genetic basis of Brugada syndrome: A mutation update

et al. 2009

View full text Add to dashboard Cite

show abstract

“…Subsequently, D1275N mutation was reported in a family affected by DCM, sinus node dysfunction, atrial and ventricular tachyarrhythmias and conduction disorders (McNair et al, 2004;Olson et al, 2005;Ge et al, 2008). More recently, it was also reported in a family with atrial tachyarrhythmias, conduction disease, and ventricular enlargement, but without impaired contractility, as opposed to the previous family (Laitinen-Forsblom et al, 2006). Finally, this mutation was also identified in a patient with atrial flutter, atrial standstill, conduction disease, and sinus node dysfunction (Watanabe et al, 2011).…”

Section: A Model For Scn5a-related Dilated Cardiomyopathy: the Scn5a-mentioning

confidence: 94%

“…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).…”

mentioning

confidence: 99%

Mouse models of SCN5A-related cardiac arrhythmias

Charpentier

Bourgé

Mérot

2008

Progress in Biophysics and Molecular Biology

View full text Add to dashboard Cite

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.

show abstract

“…Although SCN5A does not play a prominent role in sinus node activity, loss of function mutations may lead to bradycardia [43][44][45][46][47][48][49] by reducing excitability and impairing conduction of impulses generated in the sinus node into the atria. Recent studies using Tetrodotoxin (TTX) a selective Na+ current inhibitor have demonstrated that TTX can abolish the action potential upstroke in the periphery of the SA node but not in the center of the SA node.…”

Section: Scn5amentioning

confidence: 99%

Genetics and Sinus Node Dysfunction

Antzelevitch¹,

Nof²,

Glikson³

2009

J.A.F.I.B

View full text Add to dashboard Cite

Sinus node dysfunction (SND) is commonly encountered in the clinic. The clinical phenotype ranges from asymptomatic sinus bradycardia to complete atrail standstill. In some cases, sinus bradycardia is associated with other myocardial conditions such as congential abnormalities, myocarditis, dystrophies, cardiomyopathies as well as fibrosis or other structural remodeling of the SA Node. Although there are many etiologies for symptomatic slow heart rates, the only effective treatment available today is the implementation of a pacemaker. The predominant ion channel currents contributing to the pacemaker activity in the sinoatrail node (SAN) include currents flowing through hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, L- type Ca, T- type Ca, delayed rectifier K, and acetylcholine (ACh)-activated channels

show abstract

SCN5A Mutation Associated with Cardiac Conduction Defect and Atrial Arrhythmias

Abstract: Cardiac conduction defect and atrial arrhythmias in a large Finnish family appear to result from the SCN5A D1275N mutation. Although no sudden cardiac death was recorded in the family, at least three affected members had encountered brain infarction at the age of 30 or younger.

Cited by 82 publications

References 31 publications

The genetic basis of Brugada syndrome: A mutation update

The genetic basis of Brugada syndrome: A mutation update

Mouse models of SCN5A-related cardiac arrhythmias

Genetics and Sinus Node Dysfunction

Contact Info

Product

Resources

About