The Experts below are selected from a list of 549 Experts worldwide ranked by ideXlab platform

Dawood Darbar - One of the best experts on this subject based on the ideXlab platform.

  • Abstract 407: Modeling Atrial Fibrillation in a Dish Using Atrial iPSC Derived Cardiomyocytes
    Circulation Research, 2019
    Co-Authors: Liang Hong, Ambili Menon, Arvind Sridhar, Seockwon Youn, Meihong Zhang, Erin Lambers, Brandon Chalazan, Joseph C. Wu, Jalees Rehman, Dawood Darbar
    Abstract:

    Mutations in multiple genes have been linked with Familial Atrial Fibrillation (AF) but the underlying pathophysiologic mechanisms and implications for therapy remain poorly understood. To characte...

  • electrophysiologic and molecular mechanisms of a frameshift nppa mutation linked with Familial Atrial Fibrillation
    Journal of Molecular and Cellular Cardiology, 2019
    Co-Authors: Ambili Menon, Marcia Blair, Liang Hong, Eleonora Saviogalimberti, Arvind Sridhar, Seockwon Youn, Meihong Zhang, Sabina Kupershmidt, Dawood Darbar
    Abstract:

    Abstract A frameshift (fs) mutation in the natriuretic peptide precursor A (NPPA) gene, encoding a mutant Atrial natriuretic peptide (Mut-ANP), has been linked with Familial Atrial Fibrillation (AF) but the underlying mechanisms by which the mutation causes AF remain unclear. We engineered 2 transgenic (TG) mouse lines expressing the wild-type (WT)-NPPA gene (H-WT-NPPA) and the human fs-Mut-NPPA gene (H-fsMut-NPPA) to test the hypothesis that mice overexpressing the human NPPA mutation are more susceptible to AF and elucidate the underlying electrophysiologic and molecular mechanisms. Transthoracic echocardiography and surface electrocardiography (ECG) were performed in H-fsMut-NPPA, H-WT-NPPA, and Non-TG mice. Invasive electrophysiology, immunohistochemistry, Western blotting and patch clamping of membrane potentials were performed. To examine the role of the Mut-ANP in ion channel remodeling, we measured plasma cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) activity in the 3 groups of mice. In H-fsMut-NPPA mice mean arterial pressure (MAP) was reduced when compared to H-WT-NPPA and Non-TG mice. Furthermore, injection of synthetic fs-Mut-ANP lowered the MAP in H-WT-NPPA and Non-TG mice while synthetic WT-ANP had no effect on MAP in the 3 groups of mice. ECG characterization revealed significantly prolonged QRS duration in H-fsMut-NPPA mice when compared to the other two groups. Trans-Esophageal (TE) Atrial pacing of H-fsMut-NPPA mice showed increased AF burden and AF episodes when compared with H-WT-NPPA or Non-TG mice. The cardiac Na+ (NaV1.5) and Ca2+ (CaV1.2/CaV1.3) channel expression and currents (INa, ICaL) and action potential durations (APD90/APD50/APD20) were significantly reduced in H-fsMut-NPPA mice while the rectifier K+ channel current (IKs) was markedly increased when compared to the other 2 groups of mice. In addition, plasma cGMP levels were only increased in H-fsMut-NPPA mice with a corresponding reduction in plasma cAMP levels and PKA activity. In summary, we showed that mice overexpressing an AF-linked NPPA mutation are more prone to develop AF and this risk is mediated in part by remodeling of the cardiac Na+, Ca2+ and K+ channels creating an electrophysiologic substrate for reentrant AF.

  • examining rare and low frequency genetic variants previously associated with lone or Familial forms of Atrial Fibrillation in an electronic medical record system a cautionary note
    Circulation-cardiovascular Genetics, 2015
    Co-Authors: Peter Weeke, Dawood Darbar, Joshua C Denny, Lisa Basterache, Christian M Shaffer, Erica Bowton, Christie Ingram, Dan M Roden
    Abstract:

    Background—Studies in individuals or small kindreds have implicated rare variants in 25 different genes in lone and Familial Atrial Fibrillation (AF) using linkage and segregation analysis, functio...

  • abstract 11864 examining rare and low frequency genetic variants previously associated with lone or Familial forms of Atrial Fibrillation in an electronic medical record system a cautionary note
    Circulation, 2014
    Co-Authors: Peter Weeke, Dawood Darbar, Joshua C Denny, Lisa Basterache, Christian M Shaffer, Erica Bowton, Christiana D Ingram, Dan M Roden
    Abstract:

    Introduction: Studies in individuals or small kindreds have implicated rare variants in 25 different genes in lone and Familial Atrial Fibrillation (AF) using linkage and segregation analysis, functional characterization, and rarity in public databases. Here we used a cohort of 20,204 patients of European ancestry (EA) or African ancestry (AA) (n=18,424 and n=1,780, respectively) with electronic medical records (EMRs) and exome chip data to compare the frequency of AF among carriers and non-carriers of these rare variants. Methods and Results: The exome chip included 19/115 rare variants, in 9 genes, previously associated with lone or Familial AF. Using validated algorithms querying a combination of clinical notes, structured billing codes, ECG reports, and procedure codes, we identified 1,056 AF cases (>18 years) and 19,148 non-AF controls (>50 years) with available genotype data on the Illumina HumanExome BeadChip v.1.0 in the Vanderbilt EMR-linked DNA repository, BioVU. While known correlations between...

  • Selective Targeting of Gain-of-Function KCNQ1 Mutations Predisposing to Atrial Fibrillation
    Circulation-arrhythmia and Electrophysiology, 2013
    Co-Authors: Courtney M. Campbell, Dawood Darbar, Eleonora Savio Galimberti, Jonathan D. Campbell, Christopher H. Thompson, Carlos G. Vanoye, Alfred L. George
    Abstract:

    Background Atrial Fibrillation is the most common sustained cardiac arrhythmia in adults. We hypothesized that gain-of-function KCNQ1 mutations previously associated with Familial Atrial Fibrillation have distinct pharmacological properties that may enable targeted inhibition. Methods and Results Wild-type (WT) KCNQ1 or the Familial Atrial Fibrillation mutation KCNQ1-S140G was heterologously coexpressed with KCNE1 to enable electrophysiological recording of the slow delayed rectifier current ( I Ks) and investigation of pharmacological effects of the I Ks selective blocker HMR-1556. Coexpression of KCNQ1-S140G with KCNE1 generated potassium currents (S140G- I Ks) that exhibited greater sensitivity to HMR-1556 than WT- I Ks. Enhanced HMR-1556 sensitivity was also observed for another gain-of-function Atrial Fibrillation mutation, KCNQ1-V141M. Heteromeric expression of KCNE1 with both KCNQ1-WT and KCNQ1-S140G generated currents (HET- I Ks) with gain-of-function features, including larger amplitude, a constitutively active component, hyperpolarized voltage dependence of activation, and extremely slow deactivation. A low concentration of HMR-1556, which had little effect on WT- I Ks but was capable of inhibiting the mutant channel, reduced both instantaneous and steady state HET- I Ks to levels that were not significantly different from WT- I Ks and attenuated use-dependent accumulation of the current. In cultured adult rabbit left Atrial myocytes, expression of S140G- I Ks shortened action potential duration compared with WT- I Ks. Application of HMR-1556 mitigated S140G- I Ks–induced action potential duration shortening and did not alter action potential duration in cells expressing WT- I Ks. Conclusions The enhanced sensitivity of KCNQ1 gain-of-function mutations for HMR-1556 suggests the possibility of selective therapeutic targeting, and, therefore, our data illustrate a potential proof of principle for genotype-specific treatment of this heritable arrhythmia.

Yiqing Yang - One of the best experts on this subject based on the ideXlab platform.

  • a novel pitx2c gain of function mutation p met207val in patients with Familial Atrial Fibrillation
    American Journal of Cardiology, 2019
    Co-Authors: Asma Mechakra, Yiqing Yang, Tim Footz, Michael A Walter, A Aranega, Francisco Hernandeztorres, Elodie Morel, Gilles Millat, Mohamed Chahine, Philippe Chevalier
    Abstract:

    Genome-wide studies have associated several genetic variants upstream of PITX2 on chromosome 4q25 with Atrial Fibrillation (AF), suggesting a potential role of PITX2 in AF. Our study aimed at identifying rare coding variants in PITX2 predisposing to AF. The Polymerase chain reaction sequencing of PITX2c was performed in 60 unrelated patients with idiopathic AF. The p.Met207Val variant was identified in 1 of 60 French patients with early onset AF and in none of 389 French referents. This variant, located in the inhibitory domain 1 distal to the homeodomain, was evaluated by the software MutationTaster as a disease-causing mutation with a probability of 0.999. Reporter gene assays demonstrated that p.Met207Val caused a 3.1-fold increase in transactivation activity of PITX2c in HeLa cells in comparison with its wild-type counterpart. When the variant was coexpressed with wild-type PITX2c in the HL-1 immortalized mouse Atrial cell line, this gain-of-function caused an increase in the mRNA level of KCNH2 (2.6-fold), SCN1B (1.9-fold), GJA5 (3.1-fold), GJA1 (2.1-fold), and KCNQ1 in the homozygous form (1.8-fold). These genes encode for the IKr channel α subunit, the β-1 Na+ channel subunit, connexin 40, connexin 43 and the IKs channel α subunit, respectively. These conditions may contribute to the propensity to AF found in patients carrying the p.Met207Val variant. In conclusion, the present report is the first to associate a gain-of-function mutation of PITX2c with increased vulnerability to AF, therefore, restoration of normal PITX2c function may be a potential therapeutic target in AF patients.

  • a shox2 loss of function mutation underlying Familial Atrial Fibrillation
    International Journal of Medical Sciences, 2018
    Co-Authors: Ning Li, Xinhua Wang, Ruogu Li, Zhangsheng Wang, Yingjia Xu, Qi Qiao, Xiumei Li, Ruomin Di, Min Zhang, Yiqing Yang
    Abstract:

    : Atrial Fibrillation (AF), as the most common sustained cardiac arrhythmia, is associated with substantially increased morbidity and mortality. Aggregating evidence demonstrates that genetic defects play a crucial role in the pathogenesis of AF, especially in Familial AF. Nevertheless, AF is of pronounced genetic heterogeneity, and in an overwhelming majority of cases the genetic determinants underlying AF remain elusive. In the current study, 162 unrelated patients with Familial AF and 238 unrelated healthy individuals served as controls were recruited. The coding exons and splicing junction sites of the SHOX2 gene, which encodes a homeobox-containing transcription factor essential for proper development and function of the cardiac conduction system, were sequenced in all study participants. The functional effect of the mutant SHOX2 protein was characterized with a dual-luciferase reporter assay system. As a result, a novel heterozygous SHOX2 mutation, c.580C>T or p.R194X, was identified in an index patient, which was absent from the 476 control chromosomes. Genetic analysis of the proband's pedigree revealed that the nonsense mutation co-segregated with AF in the family with complete penetrance. Functional assays demonstrated that the mutant SHOX2 protein had no transcriptional activity compared with its wild-type counterpart. In conclusion, this is the first report on the association of SHOX2 loss-of-function mutation with enhanced susceptibility to Familial AF, which provides novel insight into the molecular mechanism underpinning AF, suggesting potential implications for genetic counseling and individualized management of AF patients.

  • nkx2 6 mutation predisposes to Familial Atrial Fibrillation
    International Journal of Molecular Medicine, 2014
    Co-Authors: Jun Wang, Weiyi Fang, Daifu Zhang, Ruogu Li, Xinkai Qu, Yiqing Yang
    Abstract:

    : Atrial Fibrillation (AF) is the most common form of sustained cardiac arrhythmia and is associated with substantially increased morbidity and mortality rates. Aggregating evidence demonstrates that genetic defects are involved in the pathogenesis of AF and a number of AF-associated genes have been identified. Nevertheless, AF is a genetically heterogeneous disorder and the genetic components underpinning AF in an overwhelming majority of patients remain unclear. In this study, the entire coding exons and splice junction sites of the NK2 homeobox 6 (NKX2-6) gene, which encodes a homeodomain transcription factor important for cardiovascular development, were sequenced in 150 unrelated patients with lone AF, and a novel heterozygous NKX2-6 mutation, p.Q175H, was identified in an index patient. Genetic analysis of the available family members of the mutation carrier revealed that the mutation co-segregated with AF transmitted in an autosomal dominant pattern. The missense mutation was absent in the 200 unrelated ethnically matched healthy individuals used as controls and the altered amino acid was completely conserved evolutionarily among species. Due to unknown transcriptional targets of NKX2-6, the functional characteristics of the mutation as regards transcriptional activity were analyzed using NKX2-5 as a surrogate. Alignment between human NKX2-6 and NKX2-5 proteins displayed that the Q175H-mutant NKX2-6 was equivalent to the Q181H-mutant NKX2-5, and the introduction of Q181H into NKX2-5 significantly decreased its transcriptional activity at the Atrial natriuretic factor promoter. The present study firstly associates genetically defective NKX2-6 with enhanced susceptibility to AF, providing novel insight into the molecular mechanisms underlying AF and suggesting potential strategies for the antenatal prophylaxis and personalized treatment of AF.

  • a novel pitx2c loss of function mutation associated with Familial Atrial Fibrillation
    European Journal of Medical Genetics, 2014
    Co-Authors: Jun Wang, Daifu Zhang, Yiqing Yang
    Abstract:

    Abstract Atrial Fibrillation (AF) represents the most prevalent form of sustained cardiac arrhythmia and contributes substantially to cardiovascular morbidity and mortality. Aggregating evidence demonstrates that genetic risk factors play an important role in the pathogenesis of AF. However, AF is a genetically heterogeneous disease and the genetic defects responsible for AF in an overwhelming majority of patients remain unclear. In the present study, the whole coding region and splice junction sites of the PITX2c gene, which encodes a paired-like homeobox transcription factor essential for normal cardiovascular development, were sequenced in 160 unrelated patients with lone AF, and a novel heterozygous mutation, c.349C > T equivalent to p.P117S, was identified in a patient with positive family history of AF. The missense mutation, which co-segregated with AF in the family with complete penetrance and was absent in 700 unrelated ethnically matched healthy individuals, altered the amino acid completely conserved evolutionarily across species and was predicted to be pathogenic by MutationTaster and PolyPhen-2. Biological assays revealed that the mutant PITX2c protein was associated with significantly decreased transcriptional activity when compared with its wild-type counterpart. The findings implicate PITX2c loss-of-function mutation in Familial AF for the first time, providing novel insight into the molecular pathology of AF.

  • mutations of the scn4b encoded sodium channel β4 subunit in Familial Atrial Fibrillation
    International Journal of Molecular Medicine, 2013
    Co-Authors: Ruogu Li, Weiyi Fang, Xinkai Qu, Yingjia Xu, Min Zhang, Qian Wang, Yiqing Yang
    Abstract:

    : Atrial Fibrillation (AF) represents the most common form of sustained cardiac arrhythmia and accounts for substantial morbidity and mortality. Mutations in the cardiac sodium channel α, β1, β2 and β3 subunit genes (SCN5A, SCN1B, SCN2B and SCN3B) have been associated with AF, which suggests that mutations in the sodium channel β4 subunit gene, SCN4B, are also involved in the pathogenesis of AF. To examine this hypothesis, the coding exons and exon-intron boundaries of SCN4B were sequenced in 170 unrelated index patients with Familial AF. The available relatives of the probands carrying the identified mutations and 200 unrelated ethnically matched healthy individuals used as the controls were subsequently genotyped. The pathogenic potential of a SCN4B sequence variation was predicted using MutationTaster. As a result, 2 novel heterozygous SCN4B mutations, p.V162G and p.I166L, were identified in 2 unrelated families with AF transmitted in an autosomal dominant pattern, respectively. In each family the mutation co-segregated with AF and was absent in the 400 control chromosomes. The mutations altered the amino acids evolutionarily highly conserved across species and were both predicted to be disease-causing. To the best of our knowledge, this is the first study to demonstrate an association of SCN4B mutations with AF, suggesting SCN4B as a novel AF susceptibility gene.

Dan M Roden - One of the best experts on this subject based on the ideXlab platform.

  • examining rare and low frequency genetic variants previously associated with lone or Familial forms of Atrial Fibrillation in an electronic medical record system a cautionary note
    Circulation-cardiovascular Genetics, 2015
    Co-Authors: Peter Weeke, Dawood Darbar, Joshua C Denny, Lisa Basterache, Christian M Shaffer, Erica Bowton, Christie Ingram, Dan M Roden
    Abstract:

    Background—Studies in individuals or small kindreds have implicated rare variants in 25 different genes in lone and Familial Atrial Fibrillation (AF) using linkage and segregation analysis, functio...

  • abstract 11864 examining rare and low frequency genetic variants previously associated with lone or Familial forms of Atrial Fibrillation in an electronic medical record system a cautionary note
    Circulation, 2014
    Co-Authors: Peter Weeke, Dawood Darbar, Joshua C Denny, Lisa Basterache, Christian M Shaffer, Erica Bowton, Christiana D Ingram, Dan M Roden
    Abstract:

    Introduction: Studies in individuals or small kindreds have implicated rare variants in 25 different genes in lone and Familial Atrial Fibrillation (AF) using linkage and segregation analysis, functional characterization, and rarity in public databases. Here we used a cohort of 20,204 patients of European ancestry (EA) or African ancestry (AA) (n=18,424 and n=1,780, respectively) with electronic medical records (EMRs) and exome chip data to compare the frequency of AF among carriers and non-carriers of these rare variants. Methods and Results: The exome chip included 19/115 rare variants, in 9 genes, previously associated with lone or Familial AF. Using validated algorithms querying a combination of clinical notes, structured billing codes, ECG reports, and procedure codes, we identified 1,056 AF cases (>18 years) and 19,148 non-AF controls (>50 years) with available genotype data on the Illumina HumanExome BeadChip v.1.0 in the Vanderbilt EMR-linked DNA repository, BioVU. While known correlations between...

  • whole exome sequencing in Familial Atrial Fibrillation
    European Heart Journal, 2014
    Co-Authors: Marcia Blair, Raafia Muhammad, Peter Weeke, Christian M Shaffer, Jessica T Delaney, Jonathan D Mosley, Laura Short, Tanya Stubblefield, Dan M Roden
    Abstract:

    Aims Positional cloning and candidate gene approaches have shown that Atrial Fibrillation (AF) is a complex disease with Familial aggregation. Here, we employed whole-exome sequencing (WES) in AF kindreds to identify variants associated with Familial AF. Methods and results WES was performed on 18 individuals in six modestly sized Familial AF kindreds. After filtering very rare variants by multiple metrics, we identified 39 very rare and potentially pathogenic variants [minor allele frequency (MAF) ≤0.04%] in genes not previously associated with AF. Despite stringent filtering >1 very rare variants in the 5/6 of the kindreds were identified, whereas no plausible variants contributing to Familial AF were found in 1/6 of the kindreds. Two candidate AF variants in the calcium channel subunit genes (CACNB2 and CACNA2D4) were identified in two separate families using expression data and predicted function. Conclusion By coupling family data with exome sequencing, we identified multiple very rare potentially pathogenic variants in five of six families, suggestive of a complex disease mechanism, whereas none were identified in the remaining AF pedigree. This study highlights some important limitations and challenges associated with performing WES in AF including the importance of having large well-curated multi-generational pedigrees, the issue of potential AF misclassification, and limitations of WES technology when applied to a complex disease.

  • chromosome 4q25 variants are genetic modifiers of rare ion channel mutations associated with Familial Atrial Fibrillation
    Journal of the American College of Cardiology, 2012
    Co-Authors: Marylyn D Ritchie, Marcia Blair, Dan M Roden, Tanya Stubblefield, Shane Rowan, Gayle Kucera, Shannon Carter, Dawood Darbar
    Abstract:

    Objectives The aim of this study was to test the hypothesis that 2 common polymorphisms in the chromosome 4q25 region that have been associated with Atrial Fibrillation (AF) contribute to the variable penetrance of Familial AF. Background Although mutations in ion channels, gap junction proteins, and signaling molecules have been described for Mendelian forms of AF, penetrance is highly variable. Recent studies have consistently identified 2 common single-nucleotide polymorphisms in the chromosome 4q25 region as independent AF susceptibility alleles. Methods Eleven families in which AF was present in ≥2 members who also shared a candidate gene mutation were studied. These mutations were identified in all subjects with Familial lone AF (n = 33) as well as apparently unaffected family members (age >50 years with no AF; n = 17). Results Mutations were identified in SCN5A (n = 6), NPPA (n = 2), KCNQ1 (n = 1), KCNA5 (n = 1), and NKX2.5 (n = 1). In genetic association analyses, unstratified and stratified according to age of onset of AF and unaffected age >50 years, there was a highly statistically significant association between the presence of both common (rs2200733 and rs10033464) and rare variants and AF (unstratified p = 1 × 10−8, stratified [age of onset 50 years] p = 7.6 × 10−5) (unstratified p 50 years] p Conclusions Common AF-associated 4q25 polymorphisms modify the clinical expression of latent cardiac ion channel and signaling molecule gene mutations associated with Familial AF. These findings support the idea that the genetic architecture of AF is complex and includes both rare and common genetic variants.

  • Chromosome 4q25 variants are genetic modifiers of rare ion channel mutations associated with Familial Atrial Fibrillation.
    Journal of the American College of Cardiology, 2012
    Co-Authors: Marylyn D Ritchie, Marcia Blair, Dan M Roden, Tanya Stubblefield, Shane Rowan, Gayle Kucera, Shannon Carter, Dawood Darbar
    Abstract:

    Atrial Fibrillation (AF) is an important and increasing public health problem. The prevalence of AF doubles for each advancing decade of life and there is widespread agreement that the prevalence is increasing over time (1,2). The risk factors for AF are multi-factorial and include male sex, advancing age, coronary artery disease, congestive heart failure and valvular heart disease. However, a substantial portion of the variability in risk for AF remains unexplained, leading investigators to search for genetic factors. Investigators at the Framingham Heart Study have observed that the odds ratio (OR) of developing AF was 1.8 times higher for individuals with at least one parent diagnosed with AF compared to those without such a parental history (3). The OR increased further (3.2) if one parent was affected before 75 years of age. In a population-based cohort of over 5,000 AF patients from Iceland, first-degree relatives of AF patients were 1.77-fold more likely to have AF than the general population, with a relative risk of 4.67 in first-degree relatives of patients less than 60 years of age (4). Familial aggregation of AF is particularly prominent in individuals with idiopathic or so-called lone AF, i.e., early-onset AF without structural heart disease, for which as many as 30% of probands have a first-degree relative with the arrhythmia (5–7). Although a Mendelian pattern of inheritance has been reported, large AF kindreds such as those used to identify disease genes in other inherited arrhythmia syndromes, e.g., congenital long QT syndrome, are unusual. A common presentation of the Mendelian form of the arrhythmia is a proband with Familial lone AF (6). Mutations in genes encoding cardiac ion channels, gap junction proteins, Atrial natriuretic peptide (ANP) and nucleoporins (NUP155) have been reported in isolated cases and small kindreds (8). Although traditional linkage analysis or candidate gene approaches have been successful in identifying monogenic forms of Familial lone AF, the mode of transmission for most forms of AF remains unclear supporting the idea that AF inheritance is complex. In 2007, a genome-wide association study (GWAS) in Icelanders identified a locus on chromosome 4q25 associated with AF in subjects of all ages (9). Within this locus, two non-coding single nucleotide polymorphisms (SNPs) were independently associated with AF and these findings were replicated in two populations of European descent and one of Asian descent. The SNP most strongly associated with AF, rs2200733, conferred a 1.71-fold increased risk of AF while the other SNP, rs10033464, conferred a 1.42-fold increased risk. Recently, this association was replicated in a study of 4 large populations with ambulatory AF (10). This association has also been reported for post-cardiac surgery AF a setting thought to be related to inflammation (11) and has recently been reported to predict the likelihood of successful AF ablation (12). Although mutations in ion channels, gap junction proteins and signaling molecules have been identified in isolated kindreds with two or more individuals affected with Familial lone AF, penetrance in these families is highly variable. One potential explanation for this phenomenon is the coexistence of modifier gene alleles, possibly common SNPs altering AF susceptibility. Here we tested the hypothesis that 4q25 genotypes contribute to the variable penetrance of the AF phenotype in Familial AF.

Weiyi Fang - One of the best experts on this subject based on the ideXlab platform.

  • nkx2 6 mutation predisposes to Familial Atrial Fibrillation
    International Journal of Molecular Medicine, 2014
    Co-Authors: Jun Wang, Weiyi Fang, Daifu Zhang, Ruogu Li, Xinkai Qu, Yiqing Yang
    Abstract:

    : Atrial Fibrillation (AF) is the most common form of sustained cardiac arrhythmia and is associated with substantially increased morbidity and mortality rates. Aggregating evidence demonstrates that genetic defects are involved in the pathogenesis of AF and a number of AF-associated genes have been identified. Nevertheless, AF is a genetically heterogeneous disorder and the genetic components underpinning AF in an overwhelming majority of patients remain unclear. In this study, the entire coding exons and splice junction sites of the NK2 homeobox 6 (NKX2-6) gene, which encodes a homeodomain transcription factor important for cardiovascular development, were sequenced in 150 unrelated patients with lone AF, and a novel heterozygous NKX2-6 mutation, p.Q175H, was identified in an index patient. Genetic analysis of the available family members of the mutation carrier revealed that the mutation co-segregated with AF transmitted in an autosomal dominant pattern. The missense mutation was absent in the 200 unrelated ethnically matched healthy individuals used as controls and the altered amino acid was completely conserved evolutionarily among species. Due to unknown transcriptional targets of NKX2-6, the functional characteristics of the mutation as regards transcriptional activity were analyzed using NKX2-5 as a surrogate. Alignment between human NKX2-6 and NKX2-5 proteins displayed that the Q175H-mutant NKX2-6 was equivalent to the Q181H-mutant NKX2-5, and the introduction of Q181H into NKX2-5 significantly decreased its transcriptional activity at the Atrial natriuretic factor promoter. The present study firstly associates genetically defective NKX2-6 with enhanced susceptibility to AF, providing novel insight into the molecular mechanisms underlying AF and suggesting potential strategies for the antenatal prophylaxis and personalized treatment of AF.

  • mutations of the scn4b encoded sodium channel β4 subunit in Familial Atrial Fibrillation
    International Journal of Molecular Medicine, 2013
    Co-Authors: Ruogu Li, Weiyi Fang, Xinkai Qu, Yingjia Xu, Min Zhang, Qian Wang, Yiqing Yang
    Abstract:

    : Atrial Fibrillation (AF) represents the most common form of sustained cardiac arrhythmia and accounts for substantial morbidity and mortality. Mutations in the cardiac sodium channel α, β1, β2 and β3 subunit genes (SCN5A, SCN1B, SCN2B and SCN3B) have been associated with AF, which suggests that mutations in the sodium channel β4 subunit gene, SCN4B, are also involved in the pathogenesis of AF. To examine this hypothesis, the coding exons and exon-intron boundaries of SCN4B were sequenced in 170 unrelated index patients with Familial AF. The available relatives of the probands carrying the identified mutations and 200 unrelated ethnically matched healthy individuals used as the controls were subsequently genotyped. The pathogenic potential of a SCN4B sequence variation was predicted using MutationTaster. As a result, 2 novel heterozygous SCN4B mutations, p.V162G and p.I166L, were identified in 2 unrelated families with AF transmitted in an autosomal dominant pattern, respectively. In each family the mutation co-segregated with AF and was absent in the 400 control chromosomes. The mutations altered the amino acids evolutionarily highly conserved across species and were both predicted to be disease-causing. To the best of our knowledge, this is the first study to demonstrate an association of SCN4B mutations with AF, suggesting SCN4B as a novel AF susceptibility gene.

  • mutational spectrum of the gata5 gene associated with Familial Atrial Fibrillation
    International Journal of Cardiology, 2012
    Co-Authors: Yiqing Yang, Xinhua Wang, Min Zhang, Juan Wang, Qian Wang, Fangfang Shen, Jinqi Jiang, Weiyi Fang
    Abstract:

    Atrial Fibrillation (AF) is the most common cardiac arrhythmia seen in clinical practice, with an estimated prevalence of 1-2% in the general population. The incidence of AF increases dramatically with age, ranging from less than 1% in patients under 60 years of age to almost 10% in those aged 80 and over (1). AF is associated with substantial morbidity, mortality and health care burden. AF confers a five-fold increased risk of stroke, and about 15-20% of all strokes result from this tachycardia. AF also accounts for an approximately two-fold increase in risk of death, and a third of all hospitalizations for cardiac rhythm disturbances (1-3). AF frequently arises from diverse cardiac and systemic disorders, including hypertension, coronary artery disease, valvular heart disease, and hyperthyroidism (1). However, in 30% to 45% of AF cases, an underlying cause cannot be detected by routine methods, a condition usually defined as idiopathic or lone AF, of which at least 15% have a positive family history, hence termed Familial AF (1). There is now growing evidence demonstrating that genetic defects play an important role in the pathogenesis of AF and multiple genes involved in AF have been identified (4). Nevertheless, AF is genetically heterogeneous and the genetic determinants of AF remain largely unclear. Recent studies highlight a key role for several cardiac transcrip- tion factors, including NKX2-5, GATA4, GATA5 and GATA6, in the cardiogenesis (5,6), and mutations in NKX2-5, GATA4 and GATA6 have been causally implicated in congenital heart diseases and AF (7-12). GATA5 is another member of the GATA family, and its expression and functions overlap with those of GATA4 and GATA6 during cardiovascular development, especially in regulation of target gene expression synergistically with NKX2-5, which points to the likely association of functionally impaired GATA5 with AF (5,6). To assess the prevalence and spectrum of GATA5 mutations in patients with Familial AF, 130 unrelated index patients with Familial AF identified among the Chinese Han population were included in this study. The control population comprised 200 unrelated ethnically matched healthy individuals. All subjects were appraised by medical history, physical examination, electrocardiography, and echocardiogra- phy. The study subjects were clinically classified using a consistently applied set of definitions (10). The baseline demographic and clinical characteristics of the study population are summarized in Table 1 .T he study protocol was reviewed and approved by the local institutional ethics committee and written informed consent was obtained from all participants prior to study. Peripheral venous blood specimens were taken from all subjects and genomic DNA was extracted as described previously (10). According to the genomic DNA sequence of GATA5 (GenBank accession no. NT_011362), the primer sequences were designed as shown in Table 2. The coding exons (exons 2-7) and their flanking splice junction sites of GATA5 were screened for genetic variations by means of polymerase chain reaction, followed by DNA sequencing with Big Dye chemistry under an ABI 3130 XL DNA Analyzer.

  • prevalence and spectrum of pitx2c mutations associated with Familial Atrial Fibrillation
    International Journal of Cardiology, 2012
    Co-Authors: Yiqing Yang, Ruogu Li, Xinkai Qu, Yingjia Xu, Weiyi Fang
    Abstract:

    Atrial Fibrillation (AF) is the most common form of cardiac arrhythmia seen in clinical practice, accounting for approximately one-third of hospitalizations for heart rhythm disorders. The prevalence of AF is estimated to be 1% in the general population and increases markedly with advancing age, rising from about 0.5% of people in their fifties to nearly 10% of the octogenarians (1) .A F is associated with substantial morbidity and mortality. It confers a 5-fold increased risk of stroke and a double risk of death (1). AF generally occurs secondary to various cardiac and systemic disorders, including hypertension, cor-

  • gata4 loss of function mutations in Familial Atrial Fibrillation
    Clinica Chimica Acta, 2011
    Co-Authors: Yiqing Yang, Xianling Zhang, Xinhua Wang, Weifeng Jiang, Maoya Wang, Weiyi Fang
    Abstract:

    BACKGROUND: Atrial Fibrillation (AF) is the most common sustained cardiac arrhythmia and a major source of the substantially increased morbidity and mortality. Growing studies demonstrate that genetic defects play pivotal roles in a subgroup of AF. However, AF is a genetically heterogeneous disorder and the molecular basis of AF in a majority of cases remains unknown. METHODS: The whole coding region of the GATA4 gene, which encodes a zinc-finger transcription factor essential for cardiogenesis, was analyzed in 130 unrelated probands with AF in contrast to 200 unrelated ethnically matched healthy individuals used as controls. The available family members of the probands harboring the identified mutations were genotyped. The functional effect of the mutant GATA4 was characterized using a luciferase reporter assay system. RESULTS: Two novel heterozygous GATA4 mutations, p.S70T and p.S160T, were identified in 2 unrelated families with AF inherited as an autosomal dominant trait, respectively, which co-segregated with AF in each family with complete penetrance. Functional analysis showed that the mutations of GATA4 were associated with a significantly decreased transcriptional activity. CONCLUSION: The findings provide new insight into the molecular mechanism involved in the pathogenesis of AF, suggesting the potential implications in the genetic diagnosis and gene-specific therapy of this common arrhythmia.

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  • genetics of Familial Atrial Fibrillation
    Europace, 2009
    Co-Authors: Oscar Campuzano, Ramon Brugada
    Abstract:

    Atrial Fibrillation (AF) remains one of the most common and challenging arrhythmias encountered in clinical practice. While Familial forms had remained mostly unknown, in this last decade, the identification of genetic defects, which mainly affect ionic currents, has been the key in our understanding of the pathophysiology of the inherited form of the arrhythmia. Despite the limited prevalence of the Familial disease, elucidation of the molecular mechanisms that cause Familial AF will likely facilitate understanding of the more common acquired forms of the disease. Therefore, as data keep unravelling, clinicians can expect that soon better therapeutic and preventive options for this arrhythmia will emerge from the discoveries in basic science.

  • a mutation in the sodium channel is responsible for the association of long qt syndrome and Familial Atrial Fibrillation
    Heart Rhythm, 2008
    Co-Authors: Begona Benito, Ramon Brugada, Rosa Maria Perich, Eric Lizotte, Juan Cinca, Lluis Mont, Antonio Berruezo, Jose Maria Tolosana, Xavier Freixa, Pedro Brugada
    Abstract:

    Background Type 3 long-QT syndrome (LQT-3) is caused by gain-of-function mutations in the SCN5A encoding the cardiac sodium channel. Familial Atrial Fibrillation (AF), previously considered a potassium channelopathy, has recently been related to sodium genetic variants, both in isolated forms and in patients with underlying heart disease. Objective The purpose of this study was to describe the first family associating LQT-3 and AF due to a gain-of-function mutation in SCN5A and assess the usefulness of the sodium blocker flecainide in individuals with both phenotypes. Methods Complete family screening was performed after identifying a proband showing paroxysmal AF and a long QT interval suggestive of LQT-3. Secondary causes of AF were ruled out in all individuals. Flecainide was used in two patients for LQT-3 diagnosis and therapeutic treatment of AF. Genetic screening was performed by direct sequencing of the exons and exon-intron boundaries of SCN5A. Results We identified a three-generation family (eight members), all of them showing long QT intervals. Paroxysmal AF initiated between 20 and 35 years of age in all three adults. The flecainide test led to shortening of the QTc interval. Flecainide was also effective in acutely restoring sinus rhythm. A Y1795C mutation was identified in all members. Conclusion This is the first report showing an association of Familial AF and LQT-3 due to a mutation in SCN5A. This finding provides further evidence of the role of SCN5A in AF. We also confirm the usefulness of flecainide in this particular complex phenotype, both as a diagnostic tool for LQT-3 and as an acute treatment for AF.

  • Channelopathies: a new category of diseases causing sudden death.
    Herz, 2007
    Co-Authors: Josep Brugada, Ramon Brugada, Pedro Brugada
    Abstract:

    Identification of Familial forms of different diseases has provided a unique opportunity to study how changes in the structure of a gene create a dysfunction in the physiology of the resulting protein. Changes in the genes encoding for ion channels produce modifications in the function of the channel. Changes in the sodium channel are responsible for long QT syndrome, Brugada syndrome and conduction defects. Changes in the potassium channels have been related to long QT syndrome, short QT syndrome and Familial Atrial Fibrillation. Relating genetic modification and dysfunction allows to study the substrate for a disease, understand the physiopathologic mechanism and look for appropriate therapies.

  • Channelopathies: a New Category of Diseases Causing Sudden Death
    Herz Kardiovaskuläre Erkrankungen, 2007
    Co-Authors: Josep Brugada, Ramon Brugada, Pedro Brugada
    Abstract:

    Die Erforschung verschiedener Formen von familiären Erkrankungen gab Aufschluss darüber, wie Genmutationen die physiologische Funktion von Proteinen verändern können. Mutationen an Ionenkanalgenen verändern die Funktion der Kanäle. Mutationen am NatriumkanalgensindursächlichfürdasLong-QT-Syndrom, das Brugada-Syndrom und Erregungsausbreitungsstörungen. Dem Long-QT-Syndrom, dem Short-QT-Syndrom und familiären Formen von Vorhofflimmern hat man Veränderungen am Kaliumkanal als Ursache zugeschrieben. Das Verständnis einer genetischen Modifikation sowie deren folgender Dysfunktion ermöglicht, die Ursache einer Erkrankung zu erforschen, den pathophysiologischen Mechanismus zu verstehen und geeignete Therapieformen zu finden. Identification of Familial forms of different diseases has provided a unique opportunity to study how changes in the structure of a gene create a dysfunction in the physiology of the resulting protein. Changes in the genes encoding for ion channels produce modifications in the function of the channel. Changes in the sodium channel are responsible for long QT syndrome, Brugada syndrome and conduction defects. Changes in the potassium channels have been related to long QT syndrome, short QT syndrome and Familial Atrial Fibrillation. Relating genetic modification and dysfunction allows to study the substrate for a disease, understand the physiopathologic mechanism and look for appropriate therapies.

  • Genetics and arrhythmias.
    Annual Review of Medicine, 2002
    Co-Authors: Robert Roberts, Ramon Brugada
    Abstract:

    : The availability of chromosomal markers that span the human genome and improved high-throughput technology for genotyping and sequencing have led to major advances against genetic diseases. Genes have been identified for several disorders responsible for arrhythmias and sudden death. These genes all encode ion channels and are referred to as channelopathy genes. Congenital long QT syndrome is caused by mutations in genes encoding sodium or potassium channels. Brugada syndrome, only recently described, is due to mutations in a sodium channel and is an important cause of sudden death, particularly in Southeast Asia. Familial polymorphic ventricular tachycardia is due to a defect in the ryanodine receptor. A locus mapped to 10q32 is responsible for Familial Atrial Fibrillation. Treatments based on knowledge of the molecular defect are being implemented for long QT syndrome and will probably provide paradigms for targeted treatment of acquired arrhythmias.