A Novel SCN5A Gain-of-Function Mutation M1875T Associated With Familial Atrial Fibrillation

Makiyama, Takeru; Akao, Masaharu; Shizuta, Satoshi; Doi, Takahiro; Nishiyama, Kei; Oka, Yuko; Ohno, Seiko; Nishio, Yoshihiko; Tsuji, Keiko; Itoh, Hideki; Kimura, Takeshi; Kita, Toru; Horie, Minoru

doi:10.1016/j.jacc.2008.07.013

Cited by 180 publications

(117 citation statements)

References 26 publications

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“…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

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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.

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Section: Brs1-mutations In Scn5amentioning

confidence: 99%

The genetic basis of Brugada syndrome: A mutation update

et al. 2009

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“…Specific variations in several genes associated with AF were identified and characterized. These AF-related genes are mainly as follows: KCNQ1, which encodes the a-subunit of slowly activating delayed rectifier potassium channel (IKs); 12 HERG, which encodes the a-subunit of the rapidly activating delayed rectifier potassium channel (IKr); 13 SCN5A, which encodes the a-subunit of the sodium channel; 14,15 Ankyrin-B, which encodes a member of a family of versatile membrane adapters, which is required for coordinated assembly of the Na/Ca exchanger, Na/K ATPase and inositol trisphosphate receptor at transverse tubule/sarcoplasmic reticulum sites in cardiomyocytes; 16 KCNJ2, which encodes the a-subunit of inward rectifier potassium channel (IK1); 17 KCNA5, which encodes the a-subunit of the ultrarapidly activating delayed rectifier potassium channel (Kv1.5); 18 Connexin 40, which is expressed selectively in atrial myocytes and mediates the coordinated electrical activation of the atria; 19 KCNE1, which encodes the b-subunit of IKs; 20 KCNE2 encoding b-subunit of IKr; 21 and KCNE3, 22 KCNE4 23 and KCNE5, 24 which encode the b-subunits of potassium channels interacting with KCNQ1, HERG and others. In addition, inheritable defects also confer substantial disease susceptibility on patients with secondary AF.…”

Section: Introductionmentioning

confidence: 99%

Novel KCNA5 loss-of-function mutations responsible for atrial fibrillation

et al. 2009

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Accumulating evidence reveals that genetic variants play pivotal roles in familial atrial fibrillation (AF). However, the molecular defects in most patients with AF remain to be identified. Here, we report on three novel KCNA5 mutations that were identified in 4 of 120 unrelated AF families. Among them, T527M was found in two AF families, and A576V and E610K in two other AF families, respectively. The mutations T527M and A576V were also detected in 2 and 1 of 256 patients with idiopathic AF, respectively. The same mutations were not observed in 200 secondary AF patients and 500 controls. Functional analyses revealed consistent loss-of-function effects of mutant KCNA5 proteins on the ultrarapidly activating delayed rectifier potassium currents. These findings expand the spectrum of mutations in KCNA5 linked to AF and provide new insight into the molecular mechanism involved in AF.

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“…44 the importance of sCn5a gain-of-function mutations in af pathogenesis was confirmed after investigations involving a fourgeneration Japanese family with an autosomal dominant form of af that carried a novel sCn5a Met1875thr mutation. 45 the novel variant exhibited perfect genotype-phenotype segregation within the family, consistent with its being fully penetrant, and was also absent from 210 ethnically matched controls. the proband was noted to have increased right atrial excitability during radiofrequency catheter ablation for af.…”

Section: Connexinsmentioning

confidence: 62%

A Contemporary Review on the Genetic Basis of Atrial Fibrillation

Roberts¹,

Gollob

2014

Methodist DeBakey Cardiovascular Journal

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Atrial fibrillation is the most common sustained cardiac arrhythmia, and affected individuals suffer from increased rates of heart failure, stroke, and death. Despite the enormous clinical burden that it exerts on patients and health care systems, contemporary treatment strategies have only modest efficacy that likely stems from our limited understanding of its underlying pathophysiology. Epidemiological studies have provided unequivocal evidence that the arrhythmia has a substantial heritable component. Subsequent investigations into the genetics underlying atrial fibrillation have suggested that there is considerable interindividual variability in the pathophysiology characterizing the arrhythmia. This heterogeneity may partly account for the poor treatment efficacy of current therapies. Subdividing atrial fibrillation into mechanistic subtypes on the basis of genotype illustrates the heterogeneous nature of the arrhythmia and may ultimately help guide treatment strategies. A pharmacogenetic approach to the management of atrial fibrillation may lead to dramatic improvements in treatment efficacy and improved patient outcomes

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A Novel SCN5A Gain-of-Function Mutation M1875T Associated With Familial Atrial Fibrillation

Cited by 180 publications

References 26 publications

The genetic basis of Brugada syndrome: A mutation update

The genetic basis of Brugada syndrome: A mutation update

Novel KCNA5 loss-of-function mutations responsible for atrial fibrillation

A Contemporary Review on the Genetic Basis of Atrial Fibrillation

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