The cardiac T-box transcription factor TBX5 is crucial for proper cardiovascular development, and mutations in TBX5 have been associated with various congenital heart diseases and arrhythmias in humans. However, whether mutated TBX5 contributes to dilated cardiomyopathy (DCM) remains unclear. In this study, the coding exons and flanking introns of the TBX5 gene were sequenced in 190 unrelated patients with idiopathic DCM. The available family members of the index patient carrying an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were genotyped for TBX5. The functional characteristics of the mutant TBX5 were explored in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system. As a result, a novel heterozygous TBX5 mutation, p.S154A, was identified in a family with DCM inherited in an autosomal dominant pattern, which co-segregated with DCM in the family with complete penetrance. The missense mutation was absent in 400 control chromosomes and the altered amino acid was completely conserved evolutionarily across various species. Functional assays revealed that the mutant TBX5 had significantly decreased transcriptional activity. Furthermore, the mutation markedly diminished the synergistic activation of TBX5 with NKX2-5 or GATA4, other two transcription factors causatively linked to DCM. This study firstly associates TBX5 loss-of-function mutation with enhanced susceptibility to DCM, providing novel insight into the molecular mechanisms of DCM, and suggesting the potential implications in the development of new treatment strategies for this common form of myocardial disorder.

The findings expand the spectrum of mutations in connexin40 linked to AF and provide new insight into the molecular aetiology involved in the pathogenesis of AF.

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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The renin-angiotensin-aldosterone system (RAAS) plays a key role in atrial structural and electrical remodeling. The aim of this study was to investigate the potential associations of angiotensin-converting enzyme (ACE) gene insertion/ deletion (I/D) and aldosterone synthase (CYP11B2) gene −344T/C polymorphisms with the risk and recurrence of lone atrial fibrillation (AF). One hundred and ninety-three patients who underwent successful catheter ablation for lone AF were recruited. Two hundred and ninety-seven sinus rhythm subjects without a history of arrhythmia served as controls. The subjects were genotyped for ACE gene I/D and CYP11B2 gene −344T/C polymorphisms. Results showed that the ACE gene DD genotype and D allele were associated with a greater prevalence of lone AF (both P<0.01). In addition, the ACE gene DD genotype had a significantly larger left atrial dimension (LAD; 41.6±5.7 mm vs. 39.6±5.2 mm; P=0.043) and higher risk of AF recurrence [44.7% vs. 23.2%; odds ratio (OR), 2.68; 95% confidence interval (CI), 1.28–5.61; P=0.008] compared with the II+ID genotype in lone AF patients. After adjustment for a variety of risk factors, the ACE gene DD genotype had a 1.97-fold increased risk for lone AF (OR, 1.97; 95% CI, 1.15–3.37; P= 0.013) and 2.35-fold increased risk for AF recurrence (RR, 2.35; 95% CI, 1.10–5.04; P=0.028) compared with the ACE gene II+ID genotype. However, no correlation between the CYP11B2 gene −344T/C polymorphism and lone AF or its recurrence was observed in this cohort. In conclusion, the ACE gene DD genotype was associated with an increased incidence of lone AF and its recurrence following ablation, which was partly mediated by LAD.

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Objective Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia associated with substantial morbidity and significant mortality. The familial aggregation of AF elsewhere in the world has been documented. This investigation sought to evaluate familial aggregation of lone AF in the Chinese population. Methods The study population included 382 unrelated patients with lone AF, and their 6,856 relatives. The controls were 15,507 age-sex-matched individuals from the general population. The prevalence of AF in each class of relatives was compared to that in each subgroup of the age-and sex-comparable control individuals. Results The relatives of patients with lone AF had a significantly increased risk of the arrhythmia as compared to the general population. The relative risk (95% confidence intervals) of AF for relatives compared to the general population was: 37.36 (12.71-109.9) for sons, 166.6 (22.06-1258) for daughters, 27.39 (14.63-51.26) for brothers, 24.49 (14.01-42.83) for sisters, 4.87 (2.84-8.35) for mothers, and 4.78 (3.00-7.59) for fathers. Conclusion These findings provide evidence suggesting that there is a significant familial aggregation of lone AF among Chinese families and a Mendelian genetic component involved in the pathogenesis of this prevalent disorder.

The structural, single-crystal and polycrystalline elastic and thermodynamic properties of cubic perovskite BaHfO3 under pressure were investigated using the first-principles total energy calculations in the frame of the generalized gradient approximation (GGA) combined with the quasi-harmonic Debye model in which the phonon effects are considered. The calculated ground-state quantities, such as the lattice constant, Young’s modulus, shear modulus, shear and longitudinal sound velocities and Debye temperature, were in reasonable agreement with previous theoretical and experimental data. Based on the elastic constants, bulk modulus, shear modulus and Young’s modulus, the structural stability, hardness, stiffness and the brittle and ductile behaviors, along with the binding characteristic of BaHfO3 under pressure effects, have been discussed. More importantly, the temperature and pressure dependencies of the lattice constant, bulk modulus, the Debye temperature, heat capacities, volume expansion coefficient and lattice thermal conductivity are predicted successfully in the wide temperature and pressure ranges. It was found that the effects of pressure and temperature are inversely proportional. The obtained specific heat capacities at constant pressure, at the thermal expansion coefficient and at the thermal conductivity match well with the experimental data available in the range of 300–1300 K.