Genetic basis of congenital heart disease

Gelb, Bruce D.

doi:10.1097/00001573-200403000-00007

Cited by 70 publications

(38 citation statements)

References 29 publications

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“…Several genes have been identified as being responsible for various congenital heart diseases (23). It has been shown that mutations of most congenital heart diseases genes can engender more than one cardiac phenotype.…”

Section: Discussionmentioning

confidence: 99%

The Heart of Children with Steroid-Resistant Nephrotic Syndrome

Frishberg

Feinstein²,

Rinat³

et al. 2006

Journal of the American Society of Nephrology

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Mutations in the gene NPHS2 encoding podocin are responsible for a recessive form of steroid-resistant nephrotic syndrome (SRNS). The common phenotype is of massive proteinuria in early childhood that tends to progress to end-stage renal failure. Extrarenal manifestations have not been described. Twenty-two children with SRNS from six unrelated Arab families were found to be homozygous for the R138X mutation in NPHS2. Eighteen patients underwent cardiac evaluation at diagnosis of SRNS while they had normal BP and preserved renal function. Cardiac anomalies were detected in 16 (89%) children: Left ventricular hypertrophy in eight, pulmonary stenosis in six, discrete subaortic stenosis in two, and Ebstein anomaly and ventricular septal defect in one each. The remaining four affected individuals were assessed only once they had end-stage renal failure. They had severe left ventricular hypertrophy and experienced repeated episodes of heart failure. Two control groups were equally evaluated. The first consisted of 37 siblings without nephrotic syndrome, of whom only one carrier had a cardiac defect (P < 0.001). None of the second group, which included 22 children with persistent nephrotic syndrome as a result of other causes, had a cardiac anomaly (P < 0.001). Cardiac disorders in homozygotes for mutations in NPHS2 cannot be attributed to an association by chance or to a state of persistent nephrotic syndrome. Because human podocin mRNA is expressed in fetal heart, it is speculated that it may have a role in normal cardiac development. Cardiac evaluation is recommended at the time of diagnosis of SRNS due to mutations in podocin.

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Section: Discussionmentioning

confidence: 99%

The Heart of Children with Steroid-Resistant Nephrotic Syndrome

Frishberg

Feinstein²,

Rinat³

et al. 2006

Journal of the American Society of Nephrology

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“…(78,79) Both misalignment of cardiac regions and deficient tissue fusion cause heart malseptation, a frequent component of syndromic and non-syndromic congenital heart disease. (80) Another important tissue fusion event affects the development of the epicardium, the outermost layer of the heart, which develops once the single-looped heart tube primordium is formed. The epicardial progenitors are found in the proepicardium, a coelomic cell mass located at the caudalmost region of the heart tube.…”

Section: Development Of the Hypophysismentioning

confidence: 99%

Tissue fusion and cell sorting in embryonic development and disease: biomedical implications

2006

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Throughout embryonic development, segregated epithelial and/or mesenchymal cell populations make contact and fuse to shape new tissue units. This process, known as tissue fusion, is a key event in many essential morphogenetic mechanisms and its disruption can lead to congenital malformations. Another mechanism whereby complex tissues can arise involves a cell sorting process in which originally intermixed cells de-mix to generate distinct phases or layers. Different organisms use a combination of tissue fusion and cell sorting to acquire shape. Although the two processes appear to differ mechanistically, they are intricately linked inasmuch as they both involve the same molecular determinants and contribute to the same body plan. We aim to discuss the role of adhesion molecules and cell dynamics in tissue fusion and cell sorting, providing examples of their impact in embryonic development. Finally, we will advance the concept that malignant invasion may be viewed as cell sorting in reverse. Supplementary material for this article can be found on the BioEssays website (http://www.interscience.wiley.com/jpages/0265-9247/suppmat/index.html).

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“…The etiology of TOF is multifactorial, implying contributions from sequence variations, anomalous gene expression, and epigenetic factors, as well as environmental contributions. Functional mutations of several important cardiac-related transcriptional factor genes and chromosomal abnormality were identified in patients with TOF, supporting a genetic contribution (4)(5)(6). In spite of the expanding knowledge of the genetic mechanisms involved in cardiac formation, there remain nearly 80% of children with congenital heart defects who do not have a known genetic defect.…”

mentioning

confidence: 94%

Elevated methylation of the RXRA promoter region may be responsible for its downregulated expression in the myocardium of patients with TOF

Zhang

Wang

et al. 2014

Pediatr Res

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Background:As an important component of retinoid acid signaling pathway, the retinoid X receptor α (RXRA) is considered to play an important role in the pathogenesis of tetralogy of Fallot (TOF). Methods: The expression level of RXRA mRNA and the methylation status of the RXRA promoter region in 26 patients with TOF and 6 controls were detected using real-time PCR and bisulfite-specific PCR and cloning-based sequencing, respectively. Dual-luciferase reporter assays, combined with in vitro methylation assay, were performed to determine the transcriptional regulatory activity of unmethylated and methylated CpG regions in the RXRA promoter. results: The mRNA expression of RXRA in the right ventricular outflow tract (RVOT) myocardium was significantly decreased in patients with TOF compared with that in the controls. The methylation status of region −1453 to −1000 containing CpG sites 1-23 in the RXRA promoter region was higher in patients with TOF than that in the controls. This region contained several transcription factor sites. In addition, dual-luciferase reporter assays combined with methylation assay in vitro showed that this region had transcriptional regulatory activity, which can be depressed by the methylation of this region. conclusion: The elevated methylation at RXRA promoter may be responsible for the downregulated mRNA expression in RVOT myocardium of patients with TOF.

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Genetic basis of congenital heart disease

Cited by 70 publications

References 29 publications

The Heart of Children with Steroid-Resistant Nephrotic Syndrome

The Heart of Children with Steroid-Resistant Nephrotic Syndrome

Tissue fusion and cell sorting in embryonic development and disease: biomedical implications

Elevated methylation of the RXRA promoter region may be responsible for its downregulated expression in the myocardium of patients with TOF

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