Prolonged Signal-Averaged P-Wave Duration as an Intermediate Phenotype for Familial Atrial Fibrillation

Darbar, Dawood; Hardy, Amanda; Haines, Jonathan L.; Roden, Dan M.

doi:10.1016/j.jacc.2007.11.058

Cited by 53 publications

(39 citation statements)

References 32 publications

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“…Peripheral venous blood specimens were prepared and clinical data including medical records, an electrocardiogram (ECG) and echocardiography reports, were collected. The study participants were clinically classified using a consistently applied set of definitions (27,36). Briefly, the diagnosis of AF was made by a standard 12-lead electrocardiogram demonstrating no P-waves and irregular R-R intervals, regardless of clinical symptoms.…”

Section: Methodsmentioning

confidence: 99%

Connexin40 nonsense mutation in familial atrial fibrillation

Yang

Zhang²,

Wang³

et al. 2010

Int J Mol Med

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Abstract. Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia associated with substantial morbidity and mortality. Genetic variants play important roles in the pathogenesis of AF. However, AF is a genetically heterogeneous disorder, and the genetic determinants in most patients with AF remain to be identified. In this study, the entire coding region of the connexin40 gene, encoding the cardiac gap junction membrane channel protein ·5, was sequenced in 126 unrelated probands with familial AF. A novel heterozygous mutation, c.145C>T, in connexin40, was identified in a proband. The mutation was predicted to introduce a premature stop codon at amino acid position 49 (p.Q49X). This nonsense mutation was present in all the living relatives of the mutation carrier, co-segregating with AF in the family with a penetrance of 100%. However, it was absent in 200 ethnically matched unrelated control individuals. The findings suggest a pathogenic link between the compromised connexin40 function and familial AF, hence providing new insight into the molecular mechanisms involved in AF.

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Section: Methodsmentioning

confidence: 99%

Connexin40 nonsense mutation in familial atrial fibrillation

Yang

Zhang²,

Wang³

et al. 2010

Int J Mol Med

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“…The study subjects were clinically classified using a consistently applied set of definitions. 11,26 Briefly, 'lone AF' was defined as AF in individuals o60 years of age without hypertension or overt structural heart disease by clinical examination, ECG and echocardiography. 'Familial AF' was the lone AF in family members with X2 first-degree relatives with documented lone AF.…”

Section: Study Subjectsmentioning

confidence: 99%

“…6 Emerging evidence has strongly suggested hereditary determinants for AF. 7,8 Genome-wide scan revealed loci on human chromosomes 10q22, 9 6q14-16 10 and 5p15 11 that are linked to familial AF. Specific variations in several genes associated with AF were identified and characterized.…”

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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“…Growing evidence has documented the familial aggregation of AF and an enhanced susceptibility to AF in the close relatives of patients with AF, indicating that hereditary defects may play an important role in the pathogenesis of AF in a subset of patients (8)(9)(10)(11)(12)(13)(14). Genome-wide linkage analysis with polymorphic genetic markers mapped multiple susceptibility loci for AF on human chromosomes 10q22, 6q14-16, 11p15.5, 5p13, 10p11-q21 and 5p15, of which AF-causing mutations in 2 genes, KCNQ1 on chromosome 11p15.5 and NUP155 on chromosome 5p13, were identified and functionally characterized (15)(16)(17)(18)(19)(20)(21). Additionally, a genetic scan of candidate genes revealed a long list of AF associated genes, including KCNE2, KCNE3, KCNE5, KCNH2, KCNJ2, KCNA5, SCN5A, SCN1B, SCN2B, SCN3B, NPPA, GJA1 and GJA5 (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37).…”

Section: Introductionmentioning

confidence: 99%

A novel GATA5 loss-of-function mutation underlies lone atrial fibrillation

Wang

Huang

Wang

et al. 2012

International Journal of Molecular Medicine

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Abstract. Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is associated with significantly increased morbidity and mortality. Cumulative evidence highlights the importance of genetic defects in the pathogenesis of AF. However, AF is of remarkable heterogeneity and the genetic determinants of AF in a vast majority of patients remain illusive. In this study, the coding exons and splice junctions of the GATA5 gene, which encodes a zinc-finger transcription factor essential for normal cardiogenesis, were sequenced in 118 unrelated patients with lone AF. The available relatives of the index patient carrying an identified mutation and 200 unrelated ethnically-matched healthy individuals used as controls were genotyped. The functional effect of the mutant GATA5 was characterized in contrast to its wild-type counterpart using a luciferase reporter assay system. As a result, a novel heterozygous GATA5 mutation, p.W200G, was identified in a family with AF inherited as an autosomal dominant trait. The mutation was absent in 200 control individuals and the altered amino acid was completely conserved evolutionarily across species. Functional analysis showed that the mutation of GATA5 was associated with a significantly decreased transcriptional activity. These findings provide novel insight into the molecular mechanism involved in AF, suggesting potential implications for the early prophylaxis and genespecific therapy of AF.

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Prolonged Signal-Averaged P-Wave Duration as an Intermediate Phenotype for Familial Atrial Fibrillation

Cited by 53 publications

References 32 publications

Connexin40 nonsense mutation in familial atrial fibrillation

Connexin40 nonsense mutation in familial atrial fibrillation

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

A novel GATA5 loss-of-function mutation underlies lone atrial fibrillation

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