epidermal-growth-factor and Heart-Septal-Defects--Ventricular

Congenital heart defects are the most common birth defects in humans, and those 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, which encodes a Nodal co-receptor (also known as 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 constitute an embryological spectrum rather than distinct anomalies.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Epidermal Growth Factor; Female; Gene Deletion; Gene Expression Regulation, Developmental; Heart; Heart Defects, Congenital; Heart Septal Defects, Ventricular; Heart Ventricles; Humans; In Situ Hybridization; Male; MEF2 Transcription Factors; Membrane Glycoproteins; Mice; Morphogenesis; Neoplasm Proteins; Organogenesis; Sequence Analysis, RNA; Tissue Distribution; Transcription, Genetic; Transposition of Great Vessels

Nodal modulator 1 (NOMO1), a highly conserved transmembrane protein, has been identified as a part of a protein complex that participates in the Nodal signaling pathway, a critical determinant of heart and visceral organ formation. We previously found that the NOMO1 gene was substantially downregulated in human ventricular septal defect (VSD) myocardium and, thus, may be an important molecular pathway in human heart development. In this study, we aimed to investigate the effects of NOMO1 gene silencing by RNA interference (RNAi) during early mouse cardiac differentiation using P19 cells as a model system. Our results revealed that the differentiated P19 cell population exhibited downregulated NOMO1 levels and expressed lower levels of Nodal signaling mediators, such as Nodal, Cripto and Smad2, than the negative control. Similarly, cardiomyocyte-specific sarcomeric markers, such as cardiac troponin T, as well as expression of cardiogenesis-related transcriptional factors, such as Nkx2.5, Gata4 and Tbx5 were found to be downregulated in P19 differentiated cardiomyocytes in NOMO1-silenced cells when compared to controls. In conclusion, our results indicate that NOMO1 gene knockdown inhibits the differentiation of P19 cells into cardiomyocytes, which highlights a potential role for NOMO1 in early cardiogenesis.

Topics: Animals; Cell Differentiation; Cell Line; Down-Regulation; Epidermal Growth Factor; GATA4 Transcription Factor; Heart; Heart Septal Defects, Ventricular; Homeobox Protein Nkx-2.5; Homeodomain Proteins; Membrane Glycoproteins; Mice; Myocytes, Cardiac; Neoplasm Proteins; Nodal Protein; RNA Interference; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Smad2 Protein; T-Box Domain Proteins; Transcription Factors; Troponin T

The goal of our study was to identify potential pathogenic mutations in the TDGF1 gene in Chinese people with isolated CHD, particularly those with VSD, and to provide further insight into the etiology of CHD. A total of 500 CHD Chinese patients were investigated for mutations in the TDGF1 gene. Thirteen variants were found among the 500 isolated VSD patients and 250 controls, including one non-synonymous variant identified in patients but not in controls. This work firstly provides human genetic evidence of TDGF1 involved in the pathogenesis of VSD, expanding our knowledge of the causative mutations of congenital heart defects, in particular, the causative mutations of VSD.

Topics: Amino Acid Sequence; Asian People; Epidermal Growth Factor; Genetic Predisposition to Disease; GPI-Linked Proteins; Heart Septal Defects, Ventricular; Humans; Intercellular Signaling Peptides and Proteins; Membrane Glycoproteins; Molecular Sequence Data; Neoplasm Proteins; Prevalence

Atrioventricular septal defects (AVSD) are common cardiovascular malformations, occurring in 3.5/10,000 births. Although frequently associated with trisomy 21, autosomal dominant AVSD has also been described. Recently we identified and characterized the cell adhesion molecule CRELD1 (previously known as "cirrin") as a candidate gene for the AVSD2 locus mapping to chromosome 3p25. Analysis of the CRELD1 gene from individuals with non-trisomy 21-associated AVSD identified heterozygous missense mutations in nearly 6% of this population, including mutations in isolated AVSD and AVSD associated with heterotaxy syndrome. CRELD1 is the first human gene to be implicated in the pathogenesis of isolated AVSD and AVSD in the context of heterotaxy, which provides an important step in unraveling the pathogenesis of AVSD.

Topics: Amino Acid Sequence; Animals; Cattle; Cell Adhesion Molecules; Chromosome Mapping; Chromosomes, Human, Pair 21; Chromosomes, Human, Pair 3; Down Syndrome; Epidermal Growth Factor; Exons; Extracellular Matrix Proteins; Heart Septal Defects, Atrial; Heart Septal Defects, Ventricular; Heterozygote; Humans; Mice; Models, Molecular; Molecular Sequence Data; Protein Conformation; Sequence Alignment; Sequence Homology, Amino Acid