Progress in the pathogenesis of congenital bicuspid aortic valves and the associated complications / 国际儿科学杂志

Congenital bicuspid aortic valves(BAV)is one of the most common congenital heart diseases.It is generally diagnosed by echocardiography when deterioration of the abnormal leaflets becomes clinically evident.Patients with BAV are at increased risks of developing serious complications, including aortic stenosis, aortic regurgitation, aortic dilation, aortic dissection and/or aneurysm, which seriously threatens the health of patients.Although its diagnosis and surgical treatment have been clear, the specific pathogenesis has not been completely revealed.Recently, studies have found that gene mutations and related signaling pathway abnormalities are associated with BAV and its complications.And epigenetics and environmental factors are involved in the development and progress of BAV.Understanding the underlying cellular and molecular basis of normal and pathological aortic valve development may improve the preventative and therapeutic approaches to valve degeneration.

Novel mutations of the SRF gene in Chinese sporadic conotruncal heart defect patients.

BACKGROUND: Conotruncal heart defects (CTDs) are a group of congenital heart malformations that cause anomalies of cardiac outflow tracts. In the past few decades, many genes related to CTDs have been reported. Serum response factor (SRF) is a ubiquitous nuclear protein that acts as transcription factor, and SRF was found to be a critical factor in heart development and to be strongly expressed in the myocardium of the developing mouse and chicken hearts. The targeted inactivation of SRF during heart development leads to embryonic lethality and myocardial defects in mice. METHODS: To illustrate the relationship between SRF and human heart defects, we screened SRF mutations in 527 CTD patients, a cross sectional study. DNA was extracted from peripheral leukocyte cells for target sequencing. The mutations of SRF were detected and validated by Sanger sequencing. The affection of the mutations on wild-type protein was analyzed by in silico softwares. Western blot and real time PCR were used to analyze the changes of the expression of the mutant mRNA and protein. In addition, we carried out dual luciferase reporter assay to explore the transcriptional activity of the mutant SRF. RESULTS: Among the target sequencing results of 527 patients, two novel mutations (Mut1: c.821A > G p.G274D, the adenine(A) was mutated to guanine(G) at position 821 of the SRF gene coding sequences (CDS), lead to the Glycine(G) mutated to Asparticacid(D) at position 274 of the SRF protein amino acid sequences; Mut2: c.880G > T p.G294C, the guanine(G) was mutated to thymine (T) at position 880 of the SRF CDS, lead to the Glycine(G) mutated to Cysteine (C) at position 294 of the SRF protein amino acid sequences.) of SRF (NM_003131.4) were identified. Western blotting and real-time PCR showed that there were no obvious differences between the protein expression and mRNA transcription of mutants and wild-type SRF. A dual luciferase reporter assay showed that both SRF mutants (G274D and G294C) impaired SRF transcriptional activity at the SRF promoter and atrial natriuretic factor (ANF) promoter (p < 0.05), additionally, the mutants displayed reduced synergism with GATA4. CONCLUSION: These results suggest that SRF-p.G274D and SRF-p.G294C may have potential pathogenic effects.

Association between MeCP2 and proliferative vitreoretinopathy under the regulation of tumor necrosis factor / 中华实验眼科杂志

Proliferative vitreoretinopathy (PVR) is an ocular fundus disease involving multiple cytokines.Its important pathological process is epithelial-mesenchymal transition (EMT) of retinal pigment epithelium (RPE) cells.Tumor necrosis factor (TNF) is an important inflammatory response inducing factor, which can be produced by activated RPE cells, microglia, monocytes and macrophages, and then participate in the occurrence and development of PVR.In addition to cytokines, epigenetic factors such as DNA methylation also play an important role in the development of PVR, in which methyl-CpG binding protein 2(MeCP2) is involved in EMT and fibrosis, and is highly expressed in PVR membrane.The positive expression of MeCP2 is also found in transformed RPE cells and microglia.It is speculated that MeCP2 plays an important role in the occurrence and development of PVR.TNF can also stimulate the expression of MeCP2.This article reviews the role of MeCP2 and the interaction between TNF and MeCP2 in the formation of PVR.

The correlation between mutations in the promoter region of TBX 1 gene and conotruncal heart defects / 临床儿科杂志

Objective To explore the correlation between mutations in the promoter region of TBX1 gene and conotruncal heart defects. Methods A total of 621 children with conotruncal heart defects were recruited. Multiplex ligation-dependent probe ampliifcation (MLPA) was used to detect the copy numbers of chromosomal region 22 q 11 . 2 . Children with 22 q 11 . 2 deletion were excluded. Polymerase chain reaction ampliifcation (PCR) and gene sequencing were applied to analyze promoter region of TBX 1 (-2000 ..+1 ) in 605 children with conotruncal heart defects without 22 q 11 . 2 deletion and 588 healthy children. Bioinformatics software was used to predict and analyze the function of the variable loci. Results There were mutations in the promoter region of TBX 1 gene in children with conotruncal heart defects, including 3 single nucleotide polymorphisms (SNP) sites and 7 rare loci. The incidence of mutation was 1 . 7%. The analysis of 7 rare loci by AliBaba 2 . 1 to showed that 3 of them may inlfuence the combination of trans-acting factors and cis-acting elements of the promoter of TBX 1 gene. Conclusion The mutation in the TBX 1 promoter region may be related to the occurrence of conotruncal heart defects.