Atrial Fibrillation Is Associated With Accumulation of Aging-Related Common Type Mitochondrial DNA Deletion Mutation in Human Atrial Tissue*

Lai, Ling‐Ping; Tsai, Chien Chen; Su, Ming‐Jai; Lin, Jiunn Lee; Chen, Yih‐Sharng; Tseng, Yung Zu; Huang, Shoei K. Stephen

doi:10.1378/chest.123.2.539

Cited by 52 publications

(33 citation statements)

References 26 publications

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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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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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“…The common deletion (mtDNA 4977 ) was genotyped in a subset of 157 patients for whom DNA was of sufficient quality, using a nested PCR protocol. 16 The amplification target was the segment between 8224 and 13501 bp. The primer pairs for mtDNA 4977 and wild-type mtDNA were used in the same tube of reaction (coamplification).…”

Section: Blood Samplesmentioning

confidence: 99%

Mitochondrial DNA Injury and Mortality in Hemodialysis Patients

Madhumathi

Demello

et al. 2009

Journal of the American Society of Nephrology

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The role of mitochondrial injury in the pathogenesis of complications of uremia is incompletely defined, although diminished bioenergetic capacity and the accumulation of mitochondrial DNA (mtDNA) mutations have been reported. This study was undertaken to evaluate the prevalence of mtDNA injury in 180 patients who had ESRD and were enrolled into the baseline phase of the HEMO study and to relate these markers to all-cause mortality. The mitochondrial injury markers studied in peripheral blood mononuclear cells were the mtDNA copy number per cell, measured by quantitative PCR, and the presence of the mtDNA 4977 mutation. After frequency-matching healthy control subjects for age, mtDNA copy number was lower among older dialysis patients compared with older healthy subjects (P ϭ 0.01). A one-log increase in mtDNA copy number was independently associated with a decreased hazard for mortality (adjusted hazard ratio 0.64; 95% confidence interval 0.46 to 0.89). The mtDNA 4977 deletion was present in 48 (31%) patients and was independently associated with a decreased hazard for mortality (adjusted hazard ratio 0.33; 95% confidence interval 0.19 to 0.56). In summary, the mtDNA 4977 seems to predict survival in ESRD, but a reduced mitochondrial copy number seems to predict a poor outcome. Although further exploration of these associations is needed, evaluation of mitochondrial DNA copy number and somatic mtDNA mutations may provide simple genomic biomarkers to predict clinical outcomes among patients with ESRD. The uremic syndrome is characterized by abnormalities in energy metabolism, manifest as changes in basal metabolic rate, relative catabolism, negative nitrogen balance, protein energy malnutrition, insulin resistance, and dyslipidemia. 1 Mitochondria are integral to these metabolic processes, which they probably influence through cytokine-and adipokine-mediated mechanisms. 2 Early studies with 31-phosphorus nuclear magnetic resonance demonstrated that mitochondrial oxidative capacity was diminished in muscle of patients established on dialysis. 3 More recent studies showed a high prevalence of somatic mitochondrial DNA (mtDNA) mutations, specifically the "common deletion" (a 4977-bp deletion between nucleotide positions 8470 and 13,447 [mtDNA 4977 ]) in skeletal muscle of patients with ESRD. 4 Human mtDNA is particularly prone to oxidant injury because mitochondria generate reactive oxygen species during ATP production. 5 mtDNA injury may be qualitativedeletion or point mutations-or quantitative-abnormalities of mtDNA copy number per cell, mtDNA being polyploid. 6 mtDNA mutations are classically studied in skeletal muscle tissue, but recent observations suggested that the use of periph-

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“…18 Mitochondrial mutations, another form of tissue specific variation, have been reported in multiple small series of AF subjects, as for many other conditions associated with ageing. 19 The issues surrounding the validation of somatic mutation in non-clonal tissues are complex, but it should prove possible to prove this disease mechanism through in vivo modeling.…”

Section: Novel Genetic Mechanismsmentioning

confidence: 99%

Genetics of atrial fibrillation: Rare mutations, common polymorphisms, and clinical relevance

Darbar

2008

Heart Rhythm

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The limited success in therapy of AF is likely the result of heterogeneity of the underlying electrical substrate and incomplete understanding of fundamental mechanisms in disease pathogenesis. In addition, there is increasing evidence of a heritable component to some forms of AF, and in particular to idiopathic or lone AF. Recent data also suggests that AF in the setting of underlying disease may also be under genetic control. These findings suggest that there may be an inherited intrinsic threshold for vulnerability to the arrhythmia. Ultimately, the identification of genetic loci for AF may provide insight into the pathogenesis of AF and eventually may lead to improved, patient-specific rhythm control strategies to treat this common and morbid condition. Heritability of lone AFThe heterogeneous clinical presentations of AF suggest multiple mechanisms for the arrhythmia. Heritability of AF is suggested by two recent population-based studies demonstrating that the presence of AF in first-degree relatives was associated with an increased risk of developing AF. 1, 2 We and others have also found a family history of AF in one-third of patients with lone AF indicating that familial AF is more common than previously recognized. 3, 4While most AF is seen in association with other cardiac or systemic conditions, 10-30% of patients have lone AF. These relatively homogeneous subsets of the arrhythmia can serve as a unique population for understanding the genetic contributions to AF. Since Wolff's original description of three brothers with AF in 1943, 5 , there have been multiple families identified in which AF segregates as a monogenic trait. Studies in such kindreds have been used to map genetic loci in AF. Recently, we identified a novel AF locus on chromosome 5p15 and demonstrated that affected individuals with AF and mutation carriers can be identified by a prolonged signal-averaged P-wave duration. 6 Identification of the intermediate or endophenotype not only aided ascertainment of additional family members but has helped in the fine mapping of the AF locus. Collectively, these reports support the idea that familial AF is a genetically heterogeneous disorder. Ion channel mutations and AFRecently, the first genes for AF have been identified, providing a link between ion channelopathies and the disease. KCNQ1 was the first disease gene linked to adult-onset

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Atrial Fibrillation Is Associated With Accumulation of Aging-Related Common Type Mitochondrial DNA Deletion Mutation in Human Atrial Tissue*

Cited by 52 publications

References 26 publications

Connexin40 nonsense mutation in familial atrial fibrillation

Connexin40 nonsense mutation in familial atrial fibrillation

Mitochondrial DNA Injury and Mortality in Hemodialysis Patients

Genetics of atrial fibrillation: Rare mutations, common polymorphisms, and clinical relevance

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