Genome-Wide Linkage Scan Identifies a Novel Genetic Locus on Chromosome 5p13 for Neonatal Atrial Fibrillation Associated With Sudden Death and Variable Cardiomyopathy

Oberti, Carlos; Wang, Lejin; Li, Lin; Dong, Jiamei; Rao, Shaoqi; Du, Wei; Wang, Qing Kenneth

doi:10.1161/01.cir.0000150333.87176.c7

Cited by 113 publications

(60 citation statements)

References 25 publications

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“…Increasing evidence demonstrates the familial aggregation of AF and an enhanced vulnerability to AF in the close relatives of patients with AF, suggesting that genetic defects may be involved in the pathogenesis of AF in a subset of patients (10)(11)(12)(13)(14)(15)(16). Genome-wide genetic linkage analysis with highly polymorphic microsatellite markers mapped susceptibility loci for AF on human chromosomes 10q22, 6q14-16, 11p15.5, 5p13, 10p11-q21 and 5p15, of which AF-causing mutations in two genes, KCNQ1 on chromosome 11p15.5 and NUP155 on chromosome 5p13, were identified and functionally characterized (17)(18)(19)(20)(21)(22)(23). In addition, genetic screening of candidate genes revealed an increasing number of AF associated mutations in genes encoding potassium channel subunits (KCNH2, KCNA5, KCNJ2, KCNJ8 and KCNE1-5), sodium channel subunits (SCN5A and SCN1B-3B), signaling peptide (NPPA), gap junctions (GJA1 and GJA5), and others .…”

Section: Introductionmentioning

confidence: 99%

A novel NKX2.5 loss-of-function mutation responsible for familial atrial fibrillation

Huang

Xue

et al. 2013

International Journal of Molecular Medicine

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Abstract. Atrial fibrillation (AF) represents the most common form of sustained cardiac arrhythmia and accounts for substantial morbidity and mortality. Increasing evidence demonstrates that abnormal cardiovascular development is involved in the pathogenesis of AF. In this study, the coding exons and splice sites of the NKX2.5 gene, which encodes a homeodomain-containing transcription factor pivotal for normal cardiovascular morphogenesis, were sequenced in 110 unrelated index patients with familial AF. The available relatives of the mutation carrier and 200 unrelated ethnically-matched healthy individuals serving as controls were subsequently genotyped. The disease-causing potential of the identified NKX2.5 variation was predicted by MutationTaster. The functional characteristics of the mutant NKX2.5 protein were analyzed using a dual-luciferase reporter assay system. As a result, a novel heterozygous NKX2.5 mutation, p.F145S, was identified in a family with AF transmitted as an autosomal dominant trait, which co-segregated with AF in the family with complete penetrance. The detected substitution, which altered the amino acid completely conserved evolutionarily across species, was absent in 400 control chromosomes and was automatically predicted to be causative. Functional analysis demonstrated that the NKX2.5 mutant was associated with significantly decreased transcriptional activity compared with its wild-type counterpart. To the best of our knowledge, this is the first report on the association of the NKX2.5 lossof-function mutation with increased susceptibility to familial AF. The findings of the present study provide novel insights into the molecular mechanism underlying AF, suggesting the potential implications for the early prophylaxis and allelespecific therapy of AF.

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Section: Introductionmentioning

confidence: 99%

A novel NKX2.5 loss-of-function mutation responsible for familial atrial fibrillation

Huang

Xue

et al. 2013

International Journal of Molecular Medicine

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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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“…While the structural heart diseases or systemic disorders, such as coronary artery disease, rheumatic heart disease, cardiomyopathy, congenital heart defects, pericarditis, congestive heart failure, hypertension, hyperthyroidism, and electrolyte imbalance, predispose to AF (4), AF also occurs in individuals without any known risk factors and growing evidence points to a genetic basis for the pathogenesis of AF (5)(6)(7)(8)(9)(10)(11)(12)(13). Furthermore, several chromosomal loci linked to AF have been mapped and AF-related mutations in multiple genes, including the connexin40 encoding cardiac gap junction membrane channel protein ·5, have been identified (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). However, AF is a genetically heterogeneous disorder and the molecular basis of AF remains unknown in the majority of cases (27).…”

Section: Introductionmentioning

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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Genome-Wide Linkage Scan Identifies a Novel Genetic Locus on Chromosome 5p13 for Neonatal Atrial Fibrillation Associated With Sudden Death and Variable Cardiomyopathy

Cited by 113 publications

References 25 publications

A novel NKX2.5 loss-of-function mutation responsible for familial atrial fibrillation

A novel NKX2.5 loss-of-function mutation responsible for familial atrial fibrillation

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

Connexin40 nonsense mutation in familial atrial fibrillation

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