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Previous genome-wide association studies have demonstrated that single nucleotide polymorphisms in T-box (TBX)5 are associated with increased susceptibility to atrial fibrillation (AF), and a recent study has causally linked a TBX5 mutation to atypical Holt-Oram syndrome and paroxysmal AF. However, the prevalence and spectrum of TBX5 mutations in patients with AF remain to be elucidated. In the present study, a cohort of 190 unrelated patients with idiopathic AF were prospectively recruited, with 400 unrelated healthy individuals recruited as controls. The coding exons and flanking introns of the TBX5 gene were sequenced in the participants. The functional characteristics of the mutant TBX5 were delineated in contrast with its wild-type counterpart using a dual-luciferase reporter assay system. As a result, a novel heterozygous TBX5 mutation, p.P132S, was identified in an index patient with AF, with a mutational prevalence of ~0.53%. Genetic analysis of the proband's family showed that the mutation co-segregated with AF, and was transmitted in an autosomal dominant pattern. The missense mutation was absent in the 800 control chromosomes, and the altered amino acid was completely evolutionarily conserved across species. Functional analyses revealed that the mutant TBX5 had significantly reduced transcriptional activity. Furthermore, the mutation markedly decreased the synergistic activation between TBX5 and NK2 homeobox 5, another transcription factor which has been causatively linked to AF. The present study was the first, to the best of our knowledge, to report on the association between a TBX5 loss-of-function mutation and increased susceptibility to AF. These results provide novel insight into the molecular mechanism underpinning AF, and have potential implications in the development of novel prophylactic and therapeutic strategies for AF, the most common form of sustained cardiac arrhythmia. [ABSTRACT FROM AUTHOR]

The article presents a study which explores how interleukin (IL)-6/Signal transducer and activator of transcription 3 (STAT3)/mineralocorticoid receptor (MR)/Fibroblast growth factor 21 (FGF21) axis mediates heart-liver cross-talk after myocardial infarction . It mentions the protective role of liver in myocardial infarction.

Background: The zinc finger transcription factor CASZ1 plays a key role in cardiac development and postnatal adaptation, and in mice, deletion of the CASZ1 gene leads to dilated cardiomyopathy (DCM). However, in humans whether genetically defective CASZ1 contributes to DCM remains unclear. Methods: The coding exons and splicing junction sites of the CASZ1 gene were sequenced in 138 unrelated patients with idiopathic DCM. The available family members of the index patient harboring an identified CASZ1 mutation and 200 unrelated, ethnically matched healthy individuals used as controls were genotyped for CASZ1. The functional characteristics of the mutant CASZ1 were analyzed in contrast to its wild-type counterpart using a luciferase reporter assay system. Results: A novel heterozygous CASZ1 mutation, p.K351X, was identified in an index patient with DCM. Genetic analysis of the mutation carrier's family showed that the mutation co-segregated with DCM, which was transmitted in an autosomal dominant pattern with complete penetrance. The nonsense mutation, which was absent in 400 referential chromosomes, altered the amino acid that was highly conserved evolutionarily. Biological investigations revealed that the mutant CASZ1 had no transcriptional activity. Conclusions: The current study reveals CASZ1 as a new gene responsible for human DCM, which provides novel mechanistic insight and potential therapeutic target for CASZ1-associated DCM, implying potential implications in improved prophylactic and therapeutic strategies for DCM, the most common type of primary myocardial disease. [ABSTRACT FROM AUTHOR]

Dilated cardiomyopathy (DCM) is the most common form of primary myocardial disease. It is the most common cause of chronic congestive heart failure and the most frequent reason for heart transplantation in young adults. There is increasing evidence demonstrating that genetic defects are involved in the pathogenesis of idiopathic DCM. Recent studies have shown that genetically defective LRRC10 predisposes animals to DCM. However, the association of LRRC10 with DCM in humans has not been reported. In the current study, the whole coding region and flanking splice junction sites of the LRRC10 gene were sequenced in 220 unrelated patients with idiopathic DCM. The available relatives of the index patients harboring identified mutations and 200 unrelated ethnically matched healthy individuals used as controls were also genotyped for LRRC10. The functional effect of the LRRC10 mutations was analyzed in silico. As a result, two novel heterozygous LRRC10 mutations, p.L41V and p.L163I, were identified in two families with DCM, respectively, with a mutational prevalence of ~0.91%. Genetic analyses of the pedigrees showed that in each family, the mutation co-segregated with DCM was transmitted as an autosomal dominant trait with complete penetrance. The missense mutations were absent in 400 control chromosomes and the altered amino acids were completely conserved evolutionarily across various species. Functional analysis in silico indicated that the LRRC10 mutations were causative. This study firstly reports the association of LRRC10 mutations with enhanced susceptibility to DCM in humans, which provides novel insight into the molecular mechanism underpinning DCM, and contributes to the development of novel prophylactic and therapeutic strategies for DCM. [ABSTRACT FROM AUTHOR]

Congenital atrial septal defect (ASD) and progressive atriventricular block (AVB) are the two most common phenotypes linked to NK2 homeobox 5 (NKX2.5) mutations in animals and humans. However, the prevalence and spectrum of NKX2.5 mutation in patients with ASD and AVB remain to be elucidated. In the present study, the coding exons and flanking introns of the NKX2.5 gene, which encodes a homeobox-containing transcription factor essential for development of the heart, were sequenced in a cohort of 62 unrelated patients with ASD and AVB, and subsequently in a mutation carrier's available family members. As controls, 300 unrelated, ethnically-matched healthy individuals were recruited, who were also genotyped for NKX2.5. The functional consequence of the mutant NKX2.5 was evaluated in contrast to its wild-type counterpart using a dual-luciferase reporter assay system. As a result, a novel heterozygous NKX2.5 mutation, p.Q181X, was identified in an index patient with ASD and AVB, with a prevalence of ~1.61%. Genetic analysis of the proband's pedigree revealed that the mutation co-segregated with ASD and AVB with complete penetrance. The nonsense mutation, which eliminated partial homeobox and the carboxyl terminus, was absent in the 600 control chromosomes. Functional evaluation showed that the NKX2.5 mutant had no transcriptional activity. Furthermore, the mutation disrupted the synergistic activation between NKX2.5 and GATA binding protein 4, another cardiac core transcription factor associated with ASD. The results of the present study expand the spectrum of NKX2.5 mutations linked to ASD and AVB, and indicated that NKX2.5 loss-of-function mutations are an uncommon cause of ASD and AVB in humans. [ABSTRACT FROM AUTHOR]

Background: The basic helix-loop-helix transcription factor HAND1 is essential for cardiac development and structural remodeling, and mutations in HAND1 have been causally linked to various congenital heart diseases. However, whether genetically compromised HAND1 predisposes to dilated cardiomyopathy (DCM) in humans remains unknown. Methods: The whole coding region and splicing junctions of the HAND1 gene were sequenced in 140 unrelated patients with idiopathic DCM. The available family members of the index patient carrying an identified mutation and 260 unrelated ethnically matched healthy individuals used as controls were genotyped for HAND1. The functional effect of the mutant HAND1 was characterized in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system. Results: A novel heterozygous HAND1 mutation, p.R105X, was identified in a family with DCM transmitted as an autosomal dominant trait, which co-segregated with DCM in the family with complete penetrance. The nonsense mutation was absent in 520 control chromosomes. Functional analyses unveiled that the mutant HAND1 had no transcriptional activity. Furthermore, the mutation abolished the synergistic activation between HAND1 and GATA4, another crucial cardiac transcription factors that has been associated with various congenital cardiovascular malformations and DCM. Conclusions: This study firstly reports the association of HAND1 loss-of-function mutation with increased susceptibility to DCM in humans, which provides novel insight into the molecular mechanisms underpinning DCM. [ABSTRACT FROM AUTHOR]

Congenital heart disease (CHD) is the most common developmental abnormality, and is the leading noninfectious cause of mortality in neonates. Increasing evidence demonstrates that genetic defects play an important role in the pathogenesis of CHD. However, CHD exhibits substantial heterogeneity, and the genetic determinants for CHD remain unknown in the overwhelming majority of cases. In the current study, the coding exons and flanking introns of the HAND2 gene, which encodes a basic helix-loop-helix transcription factor essential for normal cardiovascular development, were sequenced in 192 unrelated patients with CHD, and a novel heterozygous mutation, p.S65I, was identified in a patient with congenital ventricular septal defect (VSD). Genetic analysis of the index patient's pedigree revealed that the mutation was present in all seven affected family members available, but absent in the 13 unaffected family members examined. Besides, in addition to VSD, five of the proband's close relatives also had pulmonary stenosis (PS), and the proband's son also had double outlet right ventricle (DORV). The missense mutation, which altered an evolutionarily conserved amino acid, was absent in 300 unrelated, ethnically matched healthy individuals. Biological analyses using a dual-luciferase reporter assay system showed that the mutant HAND2 was associated with significantly diminished transcriptional activity. Furthermore, the mutation abolished the synergistic activation between HAND2 and GATA4, as well as NKX2.5--two other cardiac core transcriptional factors that have been causally linked to CHD. These findings indicate that HAND2 loss-of-function mutation contributes to human CHD, perhaps via its interaction with GATA4 and NKX2.5. [ABSTRACT FROM AUTHOR]

Bicuspid aortic valve (BAV) is the most common form of congenital cardiovascular defect in humans and is associated with substantial morbidity and mortality. Emerging evidence demonstrates that genetic risk factors play an important role in the pathogenesis of BAV. However, BAV is a genetically heterogenous disorder, and the genetic defects underpinning BAV in most patients remain to be identified. In the present study, the coding exons and flanking introns of the NKX2.5 gene, which encodes a homeodomain-containing transcrip-tion factor essential for the normal development of the aortic valve, were sequenced in 142 unrelated patients with BAV. The available relatives of the mutation carrier and 200 unre-lated healthy subjects used as controls were also genotyped for NKX2.5. The functional characteristics of the mutation were delineated by using a dual-luciferase reporter assay system. As a result, a novel heterozygous NKX2.5 mutation, p.K192X, was identified in a family with BAV transmitted in an autosomal dominant pattern. The nonsense mutation was absent in 400 control chromosomes. Functional analyses revealed that the mutant NKX2.5 had no transcriptional activity compared with its wild-type counterpart. Furthermore, the mutation abolished the synergistic transcriptional activation between NKX2.5 and GATA5, another transcription factor crucial for the aortic valvular morphogenesis. In conclusion, this study is the first to link an NKX2.5 loss-of-function mutation to enhanced susceptibility to human BAV, providing novel insight into the molecular mechanism of BAV and suggesting potential implications for genetic counseling and clinical care of families presenting with BAV. [ABSTRACT FROM AUTHOR]

Dilated cardiomyopathy (DCM) is the most frequent type of primary myocardial disorder responsible for substantial morbidity and mortality. DCM is the third most common cause of heart failure and the most common reason for heart transplantation. A recent study has implicated GATA4 mutation in the pathogenesis of familial DCM. However, the prevalence and spectrum of GATA4 mutations associated with sporadic DCM remain unclear. In this study, the coding exons and exon-intron boundaries of the GATA4 gene, which encodes a cardiac transcription factor crucial for normal cardiogenesis, were sequenced in 220 unrelated patients with sporadic DCM. A total of 200 unrelated ethnically-matched healthy individuals used as controls were genotyped. The functional characteristics of the mutant GATA4 were assayed in contrast to its wild-type counterpart using a luciferase reporter assay system. As a result, 3 novel heterozygous GATA4 mutations, p.V39L, p.P226Q and p.T279S, were identified in 3 unrelated patients with sporadic DCM, with a mutational prevalence of approximately 1.36%. The missense mutations were absent in 400 control chromosomes and the altered amino acids were completely conserved evolutionarily across species. Functional analysis showed that the GATA4 mutants were consistently associated with significantly decreased transcriptional activity and markedly reduced the synergistic activation between GATA4 and NKX2-5. This study firstly links GATA4 mutations to increased susceptibility to sporadic DCM and provides novel insight into the molecular etiology underlying DCM, suggesting the potential implications for the early prophylaxis and allele-specific treatment of this common form of cardiomyopathy. [ABSTRACT FROM AUTHOR]