Novel de novo pathogenic variant in the <i>NR2F2</i> gene in a boy with congenital heart defect and dysmorphic features

Upadia, Jariya; Gonzales, Patrick R.; Robin, Nathaniel H.

doi:10.1002/ajmg.a.38700

Cited by 17 publications

(15 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mapping a 5.8 Mb deletion in a patient with CHD, Nakamura et al [117] identified COUP-TFII as a putative candidate gene. Association of COUP-TFII to CHD was later confirmed by other groups [118][119][120][121][122]. Interestingly, deletion of 15q is not the only possible mutation happening in CHD in the COUP-TFII locus but single point missense mutations of the NR are sufficient to induce the pathogenic phenotype [120,122].…”

Section: Cardiovascular Diseasesmentioning

confidence: 80%

COUP-TFII in Health and Disease

Polvani

Pepe

Milani

et al. 2019

Cells

View full text Add to dashboard Cite

The nuclear receptors (NRs) belong to a vast family of evolutionary conserved proteins acting as ligand-activated transcription factors. Functionally, NRs are essential in embryogenesis and organogenesis and in adulthood they are involved in almost every physiological and pathological process. Our knowledge of NRs action has greatly improved in recent years, demonstrating that both their expression and activity are tightly regulated by a network of signaling pathways, miRNA and reciprocal interactions. The Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII, NR2F2) is a NR classified as an orphan due to the lack of a known natural ligand. Although its expression peaks during development, and then decreases considerably, in adult tissues, COUP-TFII is an important regulator of differentiation and it is variably implicated in tissues homeostasis. As such, alterations of its expression or its transcriptional activity have been studied and linked to a spectrum of diseases in organs and tissues of different origins. Indeed, an altered COUP-TFII expression and activity may cause infertility, abnormality in the vascular system and metabolic diseases like diabetes. Moreover, COUP-TFII is actively investigated in cancer research but its role in tumor progression is yet to be fully understood. In this review, we summarize the current understanding of COUP-TFII in healthy and pathological conditions, proposing an updated and critical view of the many functions of this NR.

show abstract

Section: Cardiovascular Diseasesmentioning

confidence: 80%

COUP-TFII in Health and Disease

Polvani

Pepe

Milani

et al. 2019

Cells

View full text Add to dashboard Cite

show abstract

“…Furthermore, the expression and functional profile of NR2F2 overlap at least partially with those of the well-established BAV-associated genes GATA4, GATA5 and NKX2-5 during embryonic cardiogenesis (27)(28)(29). Pathogenic mutations in NR2F2, GATA4-6 and NKX2-5 have been reported to cause similar cardiovascular developmental anomalies in animals and humans, including defects in the cardiac outflow tract, septum and endocardial cushion (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40). These findings suggest NR2F2 as a preferred candidate gene of human BAV and provide a theoretical basis for screening of the gene.…”

Section: Nr2f2 Loss-of-function Mutation Is Responsible For Congenital Bicuspid Aortic Valvementioning

confidence: 97%

NR2F2 loss‑of‑function mutation is responsible for congenital bicuspid aortic valve

Wang

Abhinav

et al. 2019

Int J Mol Med

View full text Add to dashboard Cite

congenital bicuspid aortic valve (BAV) represents the most common type of cardiac birth defect affecting 0.4-2% of the general population, and accounts for a markedly increased incidence of life-threatening complications, including valvulopathy and aortopathy. Accumulating evidence has demonstrated the genetic basis of BAV. However, the genetic basis for BAV in the majority of cases remains to be elucidated. In the present study, the coding regions and splicing donors/acceptors of the nuclear receptor subfamily 2 group F member 2 (NR2F2) gene, which encodes a transcription factor essential for proper cardiovascular development, were sequenced in 176 unrelated cases of congenital BAV. The available family members of the proband carrying an identified NR2F2 mutation and 280 unrelated, sex-and ethnicity-matched healthy individuals as controls were additionally genotyped for NR2F2. The functional effect of the mutation was characterized using a dual-luciferase reporter assay system. As a result, a novel heterozygous NR2F2 mutation, NM_021005.3: c.288c>A; p.(cys96 * ), was identified in a family with BAV, which was transmitted in an autosomal dominant mode with complete penetrance. The nonsense mutation was absent from the 560 control chromosomes. Functional analysis identified that the mutant NR2F2 protein had no transcriptional activity. Furthermore, the mutation disrupted the synergistic transcriptional activation between NR2F2 and transcription factor GATA-4, another transcription factor that is associated with BAV. These findings suggested NR2F2 as a novel susceptibility gene of human BAV, which reveals a novel molecular pathogenesis underpinning BAV.

show abstract

“…NR2F1 and NR2F2 are both expressed in human atrial cardiomyocytes [128]. However, to this point, only mutations in NR2F2 in humans have been associated with CHDs [1,2,119,120,129,130] (Table 1). NR2F1 and NF2F2 are required for the differentiation of atrial cardiomyocytes in human embryonic stem cells (hESCs) [128].…”

Section: Zebrafish As a Model For Human Atrial And San Defectsmentioning

confidence: 99%

“…However, nr2f1a mutants also have an expanded AVC [70], which we posit could lead to AVSDs from improper alignment and valve specification. Interestingly, although Nr2fs have historically been associated with atrial development, human NR2F2 mutations are also associated with CHDs affecting the ventricle, including VSDs, left ventricular outflow tract obstruction (LVOTO), and double outlet right ventricle (DORV) [1,2,119,120]. Additionally, mutations in NR2F1 and NR2F2 have been associated with craniofacial defects in humans [120,130].…”

Section: Zebrafish As a Model For Human Atrial And San Defectsmentioning

confidence: 99%

“…Interestingly, although Nr2fs have historically been associated with atrial development, human NR2F2 mutations are also associated with CHDs affecting the ventricle, including VSDs, left ventricular outflow tract obstruction (LVOTO), and double outlet right ventricle (DORV) [1,2,119,120]. Additionally, mutations in NR2F1 and NR2F2 have been associated with craniofacial defects in humans [120,130]. Interestingly, our work has revealed that zebrafish Nr2f1a and Nr2f2 function redundantly to restrict the number of ventricular cardiomyocytes and promote pharyngeal muscle specification at earlier stages, but do not overtly function redundantly in promoting atrial cardiomyocyte differentiation [118].…”

Section: Zebrafish As a Model For Human Atrial And San Defectsmentioning

confidence: 99%

See 1 more Smart Citation

Atrial and Sinoatrial Node Development in the Zebrafish Heart

Martin

Waxman

2021

JCDD

View full text Add to dashboard Cite

Proper development and function of the vertebrate heart is vital for embryonic and postnatal life. Many congenital heart defects in humans are associated with disruption of genes that direct the formation or maintenance of atrial and pacemaker cardiomyocytes at the venous pole of the heart. Zebrafish are an outstanding model for studying vertebrate cardiogenesis, due to the conservation of molecular mechanisms underlying early heart development, external development, and ease of genetic manipulation. Here, we discuss early developmental mechanisms that instruct appropriate formation of the venous pole in zebrafish embryos. We primarily focus on signals that determine atrial chamber size and the specialized pacemaker cells of the sinoatrial node through directing proper specification and differentiation, as well as contemporary insights into the plasticity and maintenance of cardiomyocyte identity in embryonic zebrafish hearts. Finally, we integrate how these insights into zebrafish cardiogenesis can serve as models for human atrial defects and arrhythmias.

show abstract

Novel de novo pathogenic variant in the NR2F2 gene in a boy with congenital heart defect and dysmorphic features

Cited by 17 publications

References 24 publications

COUP-TFII in Health and Disease

COUP-TFII in Health and Disease

NR2F2 loss‑of‑function mutation is responsible for congenital bicuspid aortic valve

Atrial and Sinoatrial Node Development in the Zebrafish Heart

Contact Info

Product

Resources

About