Alternative titles; symbols
HGNC Approved Gene Symbol: NR2F2
Cytogenetic location: 15q26.2 Genomic coordinates (GRCh38): 15:96,326,046-96,340,263 (from NCBI)
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
---|---|---|---|---|
15q26.2 | 46XX sex reversal 5 | 618901 | Autosomal dominant | 3 |
Congenital heart defects, multiple types, 4 | 615779 | Autosomal dominant | 3 |
Ladias and Karathanasis (1991) identified ARP1 (apolipoprotein regulatory protein-1) as a novel member of the steroid/thyroid nuclear receptor family of ligand-dependent transcription factors that binds to regulatory elements of apolipoprotein A-I (APOI; 107680). Hepatocyte-specific expression of APOI is dependent on synergistic actions between nuclear proteins bound to distinct sites within a liver-specific enhancer located upstream of the APOA1 transcription start site (Widom et al., 1991).
Chicken ovalbumin upstream promoter transcription factors (COUP-TFs) are members of the steroid/thyroid hormone receptor superfamily. They are often called orphan receptors, since their ligands have not been identified. COUP-TF homologs have been cloned in many species, from Drosophila to human. The protein sequences are highly homologous across species, suggesting functional conservation. ARP1, also called COUP-TFII, and COUP-TFI (132890) were cloned from the human, and their genomic organization characterized. Qiu et al. (1995) isolated the mouse genes encoding COUP-TFs I and II and characterized their genomic structures. Both have relatively simple structures similar to those of their human counterparts.
By immunohistochemical analysis of mature mouse retina, Inoue et al. (2010) found that Coup-Tfi was expressed in almost all cells in the inner nuclear layer (INL). In contrast, Coup-Tfii was expressed broadly on the dorsal side of the INL and only in a subset of cells, mainly glycinergic amacrine cells, on the ventral side. Weak expression of Coup-Tfii was detected in the outer nuclear layer on the dorsal side.
Tang et al. (2010) found that both Coup-Tfi and Coup-Tfii were expressed in dorso-distal optic vesicles and in a 'ventral high-dorsal low' gradient in the presumptive retinal pigment epithelium (RPE) in mouse at embryonic day 9.5 (E9.5). The 2 proteins showed differences in expression in some early eye structures, and Coup-Tfii was generally more abundant than Coup-Tfi.
Al Turki et al. (2014) used whole-mount in situ hybridization and optical projection tomography to map the pattern of Nr2f2 mRNA expression in the developing mouse embryo and observed expression in the atria of the heart, branchial arches, somites, and olfactory placode at 10.5 days postcoitum. In addition, they demonstrated expression of NR2F2 in several structures of the developing human fetal heart, including the atria, coronary vessels, and aorta.
High et al. (2016) analyzed RNA from the diaphragmatic pleuroperitoneal folds of mice at embryonic day 11.5, and observed expression of COUP-TFII variant 1. The authors noted that this observation confirmed expression at the time point when the insult leading to diaphragmatic hernia is believed to occur.
Bashamboo et al. (2018) studied human fetal ovaries and observed widespread presence of COUP-TF2 in the stromal cells at gestational weeks 9+1 and 9+5, whereas FOXL2 (605597) was limited to somatic cells of the fetal ovary. In addition, FOXL2 and COUP-TF2 appeared to be mutually exclusive at the cellular level by coimmunofluorescence.
Using a 3.9-kb fragment, Modi et al. (1991) assigned the NR2F2 gene to chromosome 15q26.1-q26.2 by Southern analysis of human-rodent somatic cell hybrid DNAs and in situ chromosomal hybridization.
Qiu et al. (1995) used interspecific backcross analysis to map Tcfcoup1 to mouse chromosome 13 and Tcfcoup2 to mouse chromosome 7. By isotopic in situ hybridization, they mapped the human counterparts to chromosomes 5q14 and 15q26, in regions that show homology of synteny between mouse and human.
The embryonic expression of COUP-TFII suggests that it may participate in mesenchymal-epithelial interactions required for organogenesis. Pereira et al. (1999) found that targeted deletion of the COUP-TFII gene in mice resulted in embryonic lethality with defects in angiogenesis and heart development. Angiopoietin-1 (601667), a proangiogenic soluble factor thought to mediate the mesenchymal-endothelial interactions during heart development and vascular remodeling, was downregulated in the mutant mice. This downregulation suggested that COUP-TFII may be required for bidirectional signaling between endothelial and mesenchymal compartments essential for proper angiogenesis and heart development.
Using yeast 2-hybrid analysis, Avram et al. (2000) identified mouse Ctip1 (BCL11A; 606557) and Ctip2 (BCL11B; 606558) as proteins expressed in brain that interacted with Arp1. Cotransfection experiments in HEK293 cells showed that Ctip1 potentiated Arp1-mediated transcriptional repression independently of trichostatin A-sensitive histone deacetylation. Confocal microscopy demonstrated punctate nuclear expression of Ctip1 and recruitment of Arp1 to these foci.
You et al. (2005) showed that COUP-TFII is specifically expressed in venous but not arterial endothelium. Ablation of COUP-TFII in mouse endothelial cells enabled veins to acquire arterial characteristics, including the expression of arterial markers NP1 (602069) and Notch (see 190198) signaling molecules, and the generation of hematopoietic cell clusters. Furthermore, ectopic expression of COUP-TFII in endothelial cells resulted in the fusion of veins and arteries in transgenic mouse embryos. Thus, You et al. (2005) concluded that COUP-TFII has a critical role in repressing Notch signaling to maintain vein identity, which suggests that vein identity is under genetic control and is not derived by a default pathway.
Vilhais-Neto et al. (2010) found that Rere (605226) forms a complex with Nr2f2, p300 (602700), and a retinoic acid receptor, which is recruited to the retinoic acid regulatory element of retinoic acid targets, such as the Rarb (180220) promoter. Furthermore, the knockdown of Nr2f2 and/or Rere decreases retinoic acid signaling, suggesting that this complex is required to promote transcriptional activation of retinoic acid targets. The symmetrical expression of Nr2f2 in the presomitic mesoderm overlaps with the symmetry of the retinoic acid signaling response, supporting its implication in the control of somitic symmetry. Vilhais-Neto et al. (2010) suggested that misregulation of this mechanism could be involved in symmetry defects of the human spine, such as those observed in patients with scoliosis.
Inoue et al. (2010) found that forced expression of Coup-Tfi or Coup-Tfii in embryonic mouse retinal explant cultures reduced the number of cells expressing markers of rod photoreceptors. In contrast, the Coup-Tfs increased the number of cells expressing markers of cone photoreceptors and increased the number of glycinergic amacrine cells.
Tang et al. (2010) found that knockdown of both COUP-TFI and COUP-TFII in ARPE-19 human RPE cells via small interfering RNA increased expression of PAX6 (607108) and reduced expression of OTX2 (600037) and MITF (156845), which are key RPE genes, as well as VAX2 (604295), a negative regulator of PAX6. In contrast, overexpression of COUP-TFs repressed PAX6 expression. Chromatin immunoprecipitation experiments and reporter gene assays showed that both COUP-TFs bound a direct repeat element in the PAX6 promoter and downregulated PAX6 and OTX2 expression.
Qin et al. (2013) demonstrated that COUP-TFII, a member of the nuclear receptor superfamily, serves as a key regulator to inhibit SMAD4 (600993)-dependent transcription, and consequently overrides the TGF-beta (190180)-dependent checkpoint for PTEN (601728)-null indolent tumors. Overexpression of COUP-TFII in the mouse prostate epithelium cooperates with PTEN deletion to augment malignant progression and produce an aggressive metastasis-prone tumor. The functional counteraction between COUP-TFII and SMAD4 is reinforced by genetically engineered mouse models in which conditional loss of SMAD4 diminishes the inhibitory effects elicited by COUP-TFII ablation. The biologic significance of COUP-TFII in prostate carcinogenesis is substantiated by patient sample analysis, in which COUP-TFII expression or activity is tightly correlated with tumor recurrence and disease progression, whereas it is inversely associated with TGF-beta signaling. Qin et al. (2013) concluded that the destruction of the TGF-beta-dependent barrier by COUP-TFII is crucial for the progression of PTEN-mutant prostate cancer into a life-threatening disease.
Using single-cell RNA sequencing and mouse genetics, Su et al. (2018) showed that vein cells of the developing heart undergo an early cell fate switch to create a pre-artery population that subsequently builds coronary arteries. Vein cells underwent a gradual and simultaneous switch from venous to arterial fate before a subset of cells crossed a transcriptional threshold into the pre-artery state. Before the onset of coronary blood flow, pre-artery cells appeared in the immature vessel plexus, expressed mature artery markers, and decreased cell cycling. The vein-specifying transcription factor COUP-TF2 prevented plexus cells from overcoming the pre-artery threshold by inducing cell cycle genes. Thus, Su et al. (2018) concluded that vein-derived coronary arteries are built by pre-artery cells that can differentiate independently of blood flow upon the release of inhibition mediated by COUP-TF2 and cell cycle factors.
In a 20-year-old 46,XX man with ovotesticular DSD, coarctation of the aorta, and BPES (SRXX5; 618901), Carvalheira et al. (2019) identified a de novo 3-Mb deletion on chromosome 15q26.2 (chr15:95,127,653_98,146,649, GRCh37), causing partial 15q monosomy of an evolutionarily conserved region. The authors noted that the deleted interval encompasses the NR2F2 and SPATA8 (613948) genes as well as 3 noncoding genes, 3 pseudogenes, and regulatory regions containing more than 15,000 transcription factor binding sites.
Congenital Heart Defects 4
In 10 patients with various types of congenital heart defects (CHTD4; 615779), Al Turki et al. (2014) identified 8 heterozygous variants in the NR2F2 gene, including 5 rare missense mutations (see, e.g., 107773.0001 and 107773.0002) in patients with atrioventricular septal defect (AVSD; see 606215); a 3-bp duplication (107773.0003) that segregated with CHTD in a multiplex family in which 2 affected brothers had AVSD and aortic stenosis with ventricular septal defect (VSD; see 614429), respectively, and their father had tetralogy of Fallot (see 187500); a de novo substitution disrupting a splice donor site (107773.0004) in a patient with hypoplastic left heart syndrome (see 241550); and a de novo balanced chromosomal translocation 46,XY,t(14;15)(q23;q26.3) in a patient with coarctation of the aorta. In 2 of the families, the mutation was inherited from an unaffected parent, suggesting incomplete penetrance. There was significant enrichment of NR2F2 variants in the patient cohorts under study compared to controls (p = 7.7 x 10(-7)). All 6 coding sequence variants significantly altered the activity of NR2F2 on target promoters; the translocation was fine-mapped to the first intron of NR2F2, with the breakpoint predicted to truncate all annotated transcripts and generate a null allele.
In a 5-year-old girl with a large atrial septal defect and left-sided congenital diaphragmatic hernia (CDH), High et al. (2016) identified heterozygosity for a de novo 7-bp deletion in the NR2F2 gene (107773.0005) that was not found in public variant databases. Analysis of WES data from a cohort of 275 patients with CDH revealed 2 patients with isolated CDH who carried heterozygous NR2F2 variants, a c.-60C-T transition in the 5-prime UTR in 1 patient, and a missense change (R213C) in a previously published patient (Longoni et al., 2015). Parental samples were unavailable for segregation analysis.
In an 11-month-old boy with coarctation of the aorta and VSD, Upadia et al. (2018) identified heterozygosity for a de novo 1-bp duplication in the NR2F2 gene (107773.0006). The proband also exhibited microcephaly, dysmorphic features, and developmental delay, and the authors suggested that variation in the NR2F2 gene might cause both syndromic and nonsyndromic heart defects.
In 4 affected individuals from a 3-generation Han Chinese family with double-outlet right ventricle and VSD, Qiao et al. (2018) identified heterozygosity for a nonsense mutation in the NR2F2 gene (G38X; 107773.0007) that segregated fully with disease and was not found in controls or public variant databases.
46,XX Sex Reversal 5
Bashamboo et al. (2018) reported 3 unrelated 46,XX children with genital virilization and congenital heart defects (SRXX5; 618901) who were heterozygous for frameshift mutations in the NR2F2 gene: individuals 2 and 3 had the same 7-bp deletion (107773.0008) and individual 1 had a nearly identical 7-bp deletion (107773.0009). The mutations arose de novo in patients 1 and 2, but parents of individual 3 were unavailable for study.
You et al. (2005) generated tissue-specific Coup-TfII -/- mice and observed the development of dorsolateral Bochdalek-type congenital diaphragmatic hernias (CDH; see 142340). The authors noted that in patients with a 5-Mb deletion on chromosome 15q26.1-26.2 Klaassens et al. (2005) had found left-sided Bochdalek-type hernias similar to those seen in the conditional knockout mice. You et al. (2005) suggested that COUP-TFII is a likely contributor to the formation of CDH in patients with 15q deletions.
Petit et al. (2007) found that Coup-TfII heterozygote female mice showed reduced fertility, and Coup-TfII-null mice died during early embryonic development due to angiogenesis and heart defects. Conditional inactivation of Coup-TfII in the ovary and uterus resulted in severely impaired placental formation, leading to miscarriage at days 10 to 12 of pregnancy. Mutant females showed enhanced trophoblast giant cell differentiation, reduction of the spongiotrophoblast layer, and absence of labyrinth formation due to improper vascularization of the placenta.
Tang et al. (2010) noted that both Coup-Tfi-null mice and Coup-Tfii-null mice die early during development. Using conditional deletion of Coup-Tfi and Coup-Tfii in mouse eye and ventral forebrain, Tang et al. (2010) found that the Coup-Tf genes compensated for each other, resulting in mice lacking major eye abnormalities. When all 4 alleles of the Coup-Tf genes were deleted, mutant mice displayed severe coloboma and microphthalmia, which persisted after birth. Examination of double-knockout mice revealed that Coup-Tfi and Coup-Tfii were required for differentiation of the neural retina and ventral and dorsal optic stalk. Double mutants showed increased expression of Pax6 in prospective RPE, followed by transformation of RPE cells into neural retina.
Zhao et al. (2017) discovered that female mouse embryos lacking Coup-tfII in the Wolffian duct mesenchyme became intersex, possessing both female and male reproductive tracts. Retention of Wolffian ducts was not caused by ectopic androgen production or action. Instead, enhanced phosphorylated extracellular signal-regulated kinase (ERK) signaling in Wolffian duct epithelium was responsible for the retention of male structures in an androgen-independent manner. Zhao et al. (2017) suggested that elimination of Wolffian ducts in female embryos is actively promoted by COUP-TFII, which suppresses a mesenchyme-epithelium cross-talk responsible for Wolffian duct maintenance.
In a female patient with a congenital heart defect (CHTD4; 615779), Al Turki et al. (2014) identified heterozygosity for a de novo c.1022C-A transversion (c.1022C-A, NM_021005) in exon 3 of the NR2F2 gene, resulting in a ser341-to-tyr (S341Y) substitution. The patient had complete atrioventricular septal defect. Functional analysis using 2 different promoters in cotransfected HEK293 cells showed a 20 to 52% reduction in transcriptional activity with the mutant compared to wildtype.
In a male patient with a congenital heart defect (CHTD4; 615779), Al Turki et al. (2014) identified heterozygosity for a de novo c.614A-T transversion (c.614A-T, NM_021005) in exon 2 of the NR2F2 gene, resulting in an asn205-to-ile (N205I) substitution. The patient had incomplete atrioventricular septal defect. Functional analysis in cotransfected HEK293 cells using the NGFIA (128990) and APOB (107730) upstream regions showed a 15% increase and an almost 30% decrease in transcriptional activity, respectively, compared to wildtype.
In 2 brothers and their affected father (family 1) with various types of congenital heart defects (CHTD4; 615779), Al Turki et al. (2014) identified heterozygosity for a 3-bp duplication (c.220_222dup, NM_021005) in exon 1b of the NR2F2 gene, resulting in an in-frame duplication (gln75dup). The father had tetralogy of Fallot, 1 brother had atrioventricular septal defect, and the other had aortic stenosis and ventricular septal defect. Functional analysis in cotransfected HEK293 cells using the NGFIA (128990) upstream region showed a 13% increase in transcriptional activity with the mutant compared to wildtype; there was no difference observed when the APOB (107730) upstream region was used.
In a female patient with a congenital heart defect (CHTD4; 615779), Al Turki et al. (2014) identified heterozygosity for a de novo c.970+1G-A transition in intron 2 of the NR2F2 gene, predicted to cause skipping of exon 3. The patient had hypoplastic left heart syndrome (see 241550).
In a 5-year-old girl with a congenital heart defect (CHTD4; 615779), (CHTD4; 615779), High et al. (2016) identified heterozygosity for a de novo 7-bp deletion (c.92_98delGCCCGCC, NM_021005.3) in the NR2F2 gene, causing a frameshift predicted to result in a premature termination codon (Pro33AlafsTer77). The deletion was not found in the 1000 Genomes, NHLBI ESP, dbSNP, or ExAC databases. The authors noted that the transcript variant 1, containing exon 1b which encodes the DNA-binding domain, was the only isoform predicted to be affected by the deletion. The proband had a large atrial septal defect and left-sided congenital diaphragmatic hernia, as well as patent foramen ovale that was still present at 4 years of age. Other features included gastroesophageal reflux requiring gastrostomy tube feeding and mild developmental delay.
In an 11-month-old boy with multiple congenital heart defects (CHTD4; 615779), (CHTD4; 615779), Upadia et al. (2018) identified heterozygosity for a de novo 1-bp duplication (c.856dupG, NM_021005.3) in the NR2F2 gene, causing a frameshift predicted to result in a premature termination codon (Val286GlyfsTer23). The mutation was not found in the NHLBI ESP, ExAC, or gnomAD databases. The proband had coarctation of the aorta, patent foramen ovale, large patent ductus arteriosus with bidirectional shunting, a 3.5-mm diameter muscular ventricular septal defect, and mild pulmonary valve insufficiency. Other features included severe gastroesophageal reflux requiring fundoplication and gastrostomy tube feedings, microcephaly, dysmorphic features, and global developmental delay.
In 4 affected members of a 3-generation Han Chinese family with congenital heart defects (CHTD4; 615779), Qiao et al. (2018) identified heterozygosity for a c.247G-T transversion in the NR2F2 gene, resulting in a gly83-to-ter (G83X) substitution. Affected individuals showed double-outlet right ventricle and ventricular septal defect. The mutation segregated fully with disease in the family and was not found in 230 controls who had normal echocardiograms and no family history of CHTD, or in the dbSNP, 1000 Genomes, Exome Variant Server, or gnomAD databases. Functional analysis in HEK293 cells showed a lack of transcriptional activation with the mutant compared to wildtype NR2F2. In addition, the mutant abrogated synergistic transactivation between NR2F2 and GATA4 (600576).
In 2 unrelated 46,XX children (individuals 2 and 3, of Senegalese and Hungarian ancestry, respectively) with genital virilization and congenital heart defects (SRXX5; 618901), Bashamboo et al. (2018) identified heterozygosity for a 7-bp deletion (c.97_103delCCGCCCG, NM_021005.3) in the NR2F2 gene, causing a frameshift predicted to result in a premature termination codon (Pro33AlafsTer77). The deletion, which was not found in public variant databases, was shown to have arisen de novo in individual 2, but parental DNA was unavailable for individual 3. Individual 2 had persistent ostium secundum and atrial septal defect, whereas individual 3 had ventricular septal defect, and both also exhibited blepharophimosis-ptosis-epicanthus inversus syndrome (BPES).
In a 46,XX Latino infant (individual 1) with genital virilization and congenital heart defects (SRXX5; 618901), Bashamboo et al. (2018) identified heterozygosity for a 7-bp deletion (c.103_109delGGCGCCC, NM_021005.3) in the NR2F2 gene, causing a frameshift predicted to result in a premature termination codon (Gly35ArgfsTer75). The deletion, which was not found in public variant databases, was shown to have arisen de novo in the proband. The patient also exhibited left-sided congenital diaphragmatic hernia, and died shortly after birth due to hypoplasia of the left heart.
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