Genetic Analysis of Essential Cardiac Transcription Factors in 256 Patients With Non-Syndromic Congenital Heart Defects

Kodo, Kazuki; Nishizawa, Tsutomu; Furutani, Michiko; Arai, Shoichi; Ishihara, Kazuaki; Oda, Mayumi; Makino, Shinji; Fukuda, Keiichi; Takahashi, Tsuyoshi; Matsuoka, Rumiko; Nakanishi, Toshio; Yamagishi, Hiroyuki

doi:10.1253/circj.cj-11-1389

Cited by 73 publications

(57 citation statements)

References 44 publications

(21 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Implications of a MEF2C-TDGF1 pathway for congenital heart disease Importantly, the data presented here establish a direct transcriptional relationship between two genes associated with OFT alignment defects (Kodo et al, 2012;Roessler et al, 2008;Wang et al, 2011). This direct transcriptional relationship suggested the possibility that Mef2c and Tdgf1 might exhibit a genetic interaction.…”

Section: Analyses Of Mef2csupporting

confidence: 55%

“…MEF2C has also been implicated as having a possible role in OFT defects in humans. Kodo et al (2012) identified a single sequence variant in human MEF2C (A103V) in a single patient with isolated congenital heart disease. Although this observation is not conclusive, taken together with the work presented here it supports a role for an MEF2C-TDGF1 pathway in human congenital OFT defects.…”

Section: ;Tdgf1mentioning

confidence: 99%

“…This morphogenetic defect has been interpreted as a failure of cells from the AHF to be properly deployed to the heart (Nakazawa et al, 2011;Verzi et al, 2005). MEF2C has also been associated with congenital OFT defects in human patients (Kodo et al, 2012), but the specific function and transcriptional targets of MEF2C in the AHF and its derivatives are largely unknown.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

MEF2C regulates outflow tract alignment and transcriptional control of Tdgf1

et al. 2016

View full text Add to dashboard Cite

Congenital heart defects are the most common birth defects in humans, and defects that affect the proper alignment of the outflow tracts and septation of the ventricles are a highly significant cause of morbidity and mortality in infants. A late differentiating population of cardiac progenitors, referred to as the anterior second heart field (AHF) gives rise to the outflow tract and the majority of the right ventricle and provides an embryological context for understanding cardiac outflow tract alignment and membranous ventricular septal defects. However, the transcriptional pathways controlling AHF development and their roles in congenital heart defects remain incompletely elucidated. Here, we inactivated the gene encoding the transcription factor MEF2C in the AHF in mice. Loss of Mef2c function in the AHF results in a spectrum of outflow tract alignment defects ranging from overriding aorta to double-outlet right ventricle and dextro-transposition of the great arteries. We identify Tdgf1, the gene that encodes the Nodal co-receptor Cripto, as a direct transcriptional target of MEF2C in the outflow tract via an AHF-restricted Tdgf1 enhancer. Importantly, both the MEF2C and TDGF1 genes are associated with congenital heart defects in humans. Thus, these studies establish a direct transcriptional pathway between the core cardiac transcription factor MEF2C and the human congenital heart disease gene TDGF1. Moreover, we found a range of outflow tract alignment defects resulting from a single genetic lesion, supporting the idea that AHF-derived outflow tract alignment defects may be an embryological spectrum rather than distinct anomalies.

show abstract

Section: Analyses Of Mef2csupporting

confidence: 55%

Section: ;Tdgf1mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

MEF2C regulates outflow tract alignment and transcriptional control of Tdgf1

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Furthermore, genetic analysis suggested that NKX2.5 and GATA-6 together with these three transcription factors are essential for cardiac development [5] [6].…”

Section: Introductionmentioning

confidence: 99%

The Cytomegalovirus Enhancer Induces an Immediate Response to the Myosin Light Chain 2v Promoter during P19CL6 Cell Differentiation

Wakayama¹,

Ohashi²,

Fujimoto³

et al. 2017

AJMB

View full text Add to dashboard Cite

The P19CL6 mouse embryonic carcinoma cells efficiently differentiate into cardiac muscle cells in the presence of DMSO. A reporter plasmid for cardiac muscle differentiation was constructed by connecting the CMV enhancer and a 250 bp MLC-2v promoter in front of the GFP gene to further evaluate the role of the CMV enhancer. This plasmid (pCBVenh/MLC-2v pro /EGFP) was stably introduced into P19CL6 cells, and the transfectant differentiated into cardiomyocytes with DMSO. Upon DMSO addition, GFP was immediately transcribed (within 2 days) and the amount of the transcript increased with cultivation. Concomitantly, GFP fluorescence was detected in the cells under a microscope. However, native MLC-2v was transcribed later on day 4. This expression time course is different from that of GFP. Clearly the CMV enhancer responded immediately to DMSO. Since GATA DNA-binding proteins play crucial roles in the initiation of cardiomyocyte differentiation, such a response could be ascribed to the presence of multiple GATA motifs in the enhancer sequence but not in the native MLC-2v promoter. Thus the CMV enhancer may be not only useful for gene therapy and monitoring cell differentiation but also the study of the role of GATA transcription factors expressed in P19CL6 cells.

show abstract

“…GATA6 gene mutations have been reported in familial and isolated CHD patients in different ethnic populations, including atrial septal defect, atrioventricular septal defect, persistent truncus arteriosus, tetralogy of Fallot and ventricular septal defect (VSD) [16][17][18][19][20][21][22][23][24][25]. Mutations in GATA6 gene include missense mutations, deletions and copy number variants.…”

Section: Introductionmentioning

confidence: 99%

Novel and functional DNA sequence variants within the GATA5 gene promoter in ventricular septal defects

et al. 2014

View full text Add to dashboard Cite

Congenital heart disease (CHD) is the most common birth defect in humans. Genetic causes and underlying molecular mechanisms for isolated CHD remain largely unknown. Studies have demonstrated that GATA transcription factor 6 (GATA6) plays an essential role in the heart development. Mutations in GATA6 gene have been associated with diverse types of CHD. As GATA6 functions in a dosage-dependent manner, we speculated that changed GATA6 levels, resulting from DNA sequence variants (DSVs) within the gene regulatory regions, may mediate the CHD development. In the present study, GATA6 gene promoter was genetically and functionally analyzed in large groups of patients with ventricular septal defect (VSD) (n = 359) and ethnic-matched healthy controls OPEN ACCESS Int. J. Mol. Sci. 2014, 15 12678(n = 365). In total, 11 DSVs, including four SNPs, were identified in VSD patients and controls. Two novel and heterozygous DSVs, g.22169190A>T and g.22169311C>G, were identified in two VSD patients, but in none of controls. In cultured cardiomyocytes, the activities of the GATA6 gene promoter were significantly reduced by the DSVs g.22169190A>T and g.22169311C>G. Therefore, our findings suggested that the DSVs within the GATA6 gene promoter identified in VSD patients may change GATA6 levels, contributing to the VSD development as a risk factor.

show abstract

Genetic Analysis of Essential Cardiac Transcription Factors in 256 Patients With Non-Syndromic Congenital Heart Defects

Cited by 73 publications

References 44 publications

MEF2C regulates outflow tract alignment and transcriptional control of Tdgf1

MEF2C regulates outflow tract alignment and transcriptional control of Tdgf1

The Cytomegalovirus Enhancer Induces an Immediate Response to the Myosin Light Chain 2v Promoter during P19CL6 Cell Differentiation

Novel and functional DNA sequence variants within the GATA5 gene promoter in ventricular septal defects

Contact Info

Product

Resources

About