Alternative titles; symbols
HGNC Approved Gene Symbol: TFAP2A
SNOMEDCT: 449821007;
Cytogenetic location: 6p24.3 Genomic coordinates (GRCh38): 6:10,396,677-10,419,659 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p24.3 | Branchiooculofacial syndrome | 113620 | Autosomal dominant | 3 |
AP2-alpha is a 52-kD retinoic acid-inducible and developmentally regulated activator of transcription that binds to a consensus DNA-binding sequence CCCCAGGC in the SV40 and metallothionein (156350) promoters (Mitchell et al., 1987; Williams et al., 1988).
Williams et al. (1988) isolated and characterized human TFAP2A, which they designated AP2, encoding a 436-amino acid protein.
Buettner et al. (1993) described an alternatively spliced form of AP2 that does not bind the AP2 consensus site and strongly inhibits binding of endogenous AP2, thus acting as a dominant-negative inhibitor. Gestri et al. (2009) noted that alternative splicing of exon 5a results in a TFAP2A isoform of 365 amino acids with an alternative C-terminal sequence.
Gestri et al. (2009) analyzed TFAP2A expression in mouse and human embryos and human fetal stage F2. Expression in the mouse was seen in the nasal process, palate, and within the CNS. During human embryonic development, TFAP2A was first seen in the anterior epithelium of the lens at cleavage stage (CS) 15. At CS18, TFAP2A was expressed more strongly in the anterior epithelium of the lens and also in the ganglion layer of the neural retina, and at CS22, in the equatorial region of the lens epithelium, secondary lens fibers, and throughout the ganglion cell layer of the neural retina. TFAP2A expression was still visible but weaker in the retina of F2 human eyes.
Bauer et al. (1994) described the genomic organization of the TFAP2A gene, including the promoter. The mature AP2 mRNA is spliced from 7 exons distributed over 18 kb of genomic DNA. They demonstrated that the promoter of the AP2TF gene is subject to positive autoregulation by its own gene product. A consensus AP2 binding site was located at position -622 with respect to the ATG initiation codon.
Gestri et al. (2009) noted that TFAP2A has 3 alternative transcription start sites designated exons 1a, 1b, and 1c as well as an alternative exon 5a.
By analysis of somatic cell hybrids and in situ hybridization to chromosomes, Gaynor et al. (1991) mapped the TFAP2A gene to chromosome 6p24-p22.3. Williamson et al. (1996) identified 2 other members of this gene family, AP2-beta (TFAP2B; 601601) and AP2-gamma (TFAP2C; 601602). Using FISH, Warren et al. (1996) mapped the homologous mouse gene, Tcfap2a, to chromosome 13A5-B1. Williamson et al. (1996) obtained human and mouse genomic clones for AP2-alpha and used FISH to confirm the location of the gene to human chromosome 6p24 and to mouse 13A5-B1.
Davies et al. (1999) reported a child with microphthalmia and corneal clouding and a number of other dysmorphic features, including hypertelorism, micrognathia, dysplastic ears, thin limbs, and congenital cardiac defects. This child had an interstitial deletion of 6p25-p24 that included AP2-alpha. Davies et al. (1999) suggested that AP2-alpha may be involved in anterior eye chamber development.
Zhu et al. (2001) found that SV40 transformation of human lung fibroblast cell lines was associated with cytosine methylation of the AP2-alpha promoter at 2 sites, including the KLF12 (607531)-binding site. They concluded that hypermethylation at the KLF12 site would tend to relieve KLF12-mediated suppression of AP2 promoter activity.
By deletion analysis of the 5-prime-flanking region of the TFAP2A gene, Cheng and Handwerger (2003) determined that the proximal 152 bp are essential for minimal promoter activity and that a 140-bp fragment from nucleotides -1279 to -1139 acts as an enhancer of basal transcriptional activity. Ligation of the 140-bp fragment to a minimal TFAP2A promoter or a heterologous simian virus 40 promoter luciferase reporter plasmid conferred enhancer activity in trophoblast cells. In deoxyribonuclease I footprint studies, nuclear extracts from trophoblast cells protected 2 regions of the 140-bp fragment, E2 and E3. Site-directed mutagenesis of an ETS1 (164720)-binding site in E2 significantly inhibited TFAP2A enhancer activity. Gel shift and supershift assays indicated that ETS1 binds to the ETS site in E2, and overexpression of ETS1 in transfection studies induced TFAP2A promoter activity. As the transcription factor ETS1 is abundant in trophoblast cells, Cheng and Handwerger (2003) concluded that these investigations strongly suggested that TFAP2A gene expression in the placenta is enhanced by a cis-acting element at nucleotides -1279 to -1139 that contains a critical ETS1-binding site.
Zarelli and Dawid (2013) found that human and zebrafish KCTD15 (615240) inhibited AP2-alpha-dependent expression of a reporter gene. KCTD15 did not prevent AP2-alpha dimer formation or binding of AP2-alpha to chromatin. KCTD15 directly bound a proline-rich region in the N-terminal activation domain of zebrafish AP2-alpha. Mutation of pro59 within this region inhibited KCTD15 binding, but it had no effect on DNA binding by AP2-alpha or AP2-alpha transactivation activity. KCTD15 inhibited AP2-alpha-dependent expression of neural crest markers in Xenopus animal cap assays. Zarelli and Dawid (2013) concluded that KCTD15 is a negative regulator of AP2-alpha that regulates neural crest formation during embryonic development.
Montagnac et al. (2013) reported that clathrin-coated pits control microtubule acetylation through a direct interaction of alpha-tubulin acetyltransferase (ATAT1; 615556) with the clathrin adaptor AP2. Montagnac et al. (2013) observed that about one-third of growing microtubule ends contact and pause at clathrin-coated pits and that loss of clathrin-coated pits decreases lys40 acetylation levels. Montagnac et al. (2013) showed that ATAT1 localizes to clathrin-coated pits through a direct interaction with AP2 that is required for microtubule acetylation. In migrating cells, the polarized orientation of acetylated microtubules correlates with clathrin-coated pit accumulation at the leading edge, and interaction of ATAT1 with AP2 is required for directional migration. Montagnac et al. (2013) concluded that microtubules contacting clathrin-coated pits become acetylated by ATAT1. In migrating cells, this mechanism ensures the acetylation of microtubules oriented toward the leading edge, thus promoting directional cell locomotion and chemotaxis.
Ye et al. (2016) noted that TFAP2A transcriptionally regulates PITX2c (see 601542), the dominant PITX2 isoform in the developing and adult left atrium. They identified a SNP in PITX2, rs2595104, that lies in an enhancer region approximately 10 kb upstream of the PITX2c transcription site, and that TFAP2A binds PITX2 at the site of the SNP. They also showed that CITED2 (602937), a TFAP2A binding partner that had been implicated in synergistic regulation of PITX2c, was differentially recruited to rs2595104. Ye et al. (2016) showed that binding of TFAP2A at rs2595104, and interaction with CITED2, regulate PITX2c in human cardiomyocytes, and suggested that this pathway could influence susceptibility to atrial fibrillation at the 4q25 locus (ATFB5; 611494).
Milunsky et al. (2008) studied a mother and son with branchiooculofacial syndrome (BOFS; 113620) and detected a 3.2-Mb deletion at chromosome 6p24.3. Sequencing of candidate genes in that region in 4 additional unrelated BOFS patients revealed 4 different de novo missense mutations in the highly conserved exons 4 and 5 of the TFAP2A gene (see, e.g., 107580.0001 and 107580.0002).
Gestri et al. (2009) analyzed the TFAP2A gene in 37 patients with developmental eye defects plus variable defects associated with BOFS and identified 2 heterozygous mutations in 2 patients (107580.0003 and 107580.0004, respectively). In addition, multiplex ligation-dependent probe amplification (MPLA) revealed a heterozygous deletion of the TFAP2A gene in 2 sibs with BOFS and their mildly affected father, previously reported by Fielding and Fryer (1992).
In a 4-year-old Turkish girl with sensorineural hearing loss and features of BOFS, Tekin et al. (2009) identified a heterozygous deletion/insertion mutation in the TFAP2A gene (107580.0005).
In 2 families and 3 sporadic patients with BOFS, Reiber et al. (2010) identified 4 heterozygous mutations, all within the highly conserved exons 4 through 6 of the TFAP2A gene, respectively (see, e.g., 107580.0001 and 107580.0006-107580.0007). The authors noted that these exons are almost free of any single-nucleotide polymorphisms and are evolutionarily highly conserved.
For discussion of a possible role of TFAP2A in cleft lip/palate, see CLP1 (119530).
To study the role of AP2 during embryogenesis, Schorle et al. (1996) undertook a targeted mutagenesis of the Ap2 gene in the mouse. They reported that Ap2 -/- mice died perinatally with cranioabdominoschisis and severe dysmorphogenesis of the face, skull, sensory organs, and cranial ganglia. Failure of cranial closure between days 9 and 9.5 postcoitum coincided with increased apoptosis in the midbrain, anterior hindbrain, and proximal mesenchyme of the first branchial arch, but did not involve loss of expression of 'Twist' (601622) or Pax3 (606597), 2 other regulatory genes known to be required for cranial closure.
Homozygous knockout mice for Ap2-alpha were shown by Zhang et al. (1996) to have observable neural tube defects at day 9.5 which were followed by craniofacial and body wall abnormalities later in embryogenesis. This is consistent with the developmental expression of AP2-alpha in tissues of ectodermal origin.
Lim et al. (2005) tested the role of the transcription factor AP2-alpha in regulating Fmr1 (309550) expression. Chromatin immunoprecipitation showed that AP2-alpha associated with the Fmr1 promoter in vivo. Fmr1 transcript levels were reduced approximately 4-fold in homozygous null AP2-alpha mutant mice at embryonic day 18.5 when compared with normal littermates. AP2-alpha exhibited a strong gene dosage effect, with heterozygous mice showing a approximately 2-fold reduction in Fmr1 levels. Examination of conditional AP2-alpha mutant mice indicated that the transcription factor played a major role in regulating Fmr1 expression in embryos, but not in adults. Overexpression of a dominant-negative AP2-alpha in Xenopus embryos led to reduced Fmr1 levels. Exogenous wildtype AP2-alpha rescued Fmr1 expression in embryos where endogenous AP2-alpha had been suppressed. Lim et al. (2005) concluded that AP2-alpha associates with the Fmr1 promoter in vivo and selectively regulates Fmr1 transcription during embryonic development.
After morpholino knockdown of tfap2a function in zebrafish, Gestri et al. (2009) observed a range of eye anomalies, which were frequently asymmetric and included microphthalmia, mild coloboma, and severe coloboma in which ventral retinal tissue, including retinal pigment epithelium, protruded from the back of the eye towards the midline of the brain. Pharyngeal cartilages were also affected in tfap2a morphants with the ceratohyal reduced in size and oriented medially instead of rostrally. Less severe defects were seen in more posterior arches.
Bassett et al. (2010) showed that patterning and morphogenetic defects in the Ap2-alpha knockout optic neuroepithelium began at the optic vesicle stage. During subsequent optic cup formation, ectopic neural retina and optic stalk-like tissue replaced regions of retinal pigment epithelium. Ap2-alpha knockout eyes also displayed coloboma in the ventral retina, and a rare phenotype in which the optic stalk completely failed to extend, causing the optic cups to be drawn inward to the midline. There was increased sonic hedgehog (SHH; 600725) signaling in the Ap2-alpha knockout forebrain neuroepithelium, which likely contributed to multiple aspects of the ocular phenotype, including expansion of Pax2 (167409)-positive optic stalk-like tissue into the optic cup. The authors suggested that loss of AP2-alpha in multiple tissues in the craniofacial region leads to severe optic cup and optic stalk abnormalities by disturbing the tissue-tissue interactions required for ocular development.
In an 18-year-old man with branchiooculofacial syndrome (BOFS; 113620), previously studied by Lin et al. (2000), Milunsky et al. (2008) identified a de novo 10529A-G transition in exon 4 of the TFAP2A gene, resulting in an arg255-to-gly (R255G) substitution at a highly conserved residue in the basic region of the DNA-binding domain, a change that replaces a charged polar side chain with a nonpolar side chain with a predicted conformational space change. The mutation was not found in more than 300 controls.
In a mother and daughter with BOFS, as well as an unrelated sporadic BOFS patient, Reiber et al. (2010) identified heterozygosity for the R255G mutation in the TFAP2A gene. Noting that R255G had been found in 3 of 11 unrelated mutation-positive patients, Reiber et al. (2010) suggested that it might represent a recurrent mutation causing BOFS.
In a 17-year-old man with branchiooculofacial syndrome (BOFS; 113620), previously studied by Lin et al. (2000), Milunsky et al. (2008) identified a de novo 12448C-T transition in exon 5 of the TFAP2A gene, resulting in an gly262-to-glu (G262E) substitution at a highly conserved residue in the basic region of the DNA-binding domain, a change that replaces a nonpolar side chain with a charged polar side chain. The mutation was not found in more than 300 controls. Milunsky et al. (2008) stated that this was the first BOFS patient reported with medulloblastoma.
In a 5-year-old boy with branchiooculofacial syndrome (BOFS; 113620), Gestri et al. (2009) identified a de novo heterozygous 12-bp deletion (697del12) in the basic domain of the TFAP2A gene, resulting in deletion of 4 amino acids, from glu233 to arg236. The patient had classic features of BOFS, including high-arched palate, prominent philtrum, narrow ear canals, abnormal pinnae, and periorbital and scalp cysts. His eye findings included a right cystic remnant and mildly microphthalmic left eye with a reduced corneal diameter, iris coloboma, primary aphakia, and a large posterior chorioretinal coloboma.
In a 10-month-old female infant with severe eye defects but a nonclassic branchiooculofacial syndrome phenotype (BOFS; 113620), Gestri et al. (2009) identified a heterozygous 956T-C transition in exon 5a the TFAP2A gene, resulting in a phe319-to-ser (F319S) substitution at a conserved residue in the alternatively spliced isoform of TFAP2A. The mutation, which was not found in 189 control samples, was inherited from her apparently unaffected father and segregated with polydactyly on the paternal side. The patient had right microphthalmia with sclerocornea, primary aphakia, and localized tractional retinal detachment, and an extremely microphthalmic left eye with sclerocornea. Her systemic features, which were not classic for BOFS, included atrial septal defect with an enlarged anomalous blood vessel draining into the right atrium, and facial capillary hemangioma.
In a 4-year-old Turkish girl with sensorineural hearing loss and features of branchiooculofacial syndrome (BOFS; 113620), Tekin et al. (2009) identified heterozygosity for a de novo 18-bp deletion and 6-bp insertion (828delCTGCCTGCAGGGAGACGTinsAGGATT) in exon 5 of the TFAP2A gene, resulting in insertion of arginine and isoleucine residues at codon 276. Tekin et al. (2009) stated that this mutation differed from those previously reported in BOFS patients without sensorineural hearing loss in that it involved both DNA-binding and dimerization domains; they suggested that the patient's inner ear malformation might be related to impaired dimerization of TFAP2A.
In 5 affected members of a family with branchiooculofacial syndrome (BOFS; 113620), originally reported by Lin et al. (1995), Reiber et al. (2010) identified heterozygosity for an 886G-A transition in exon 6 of the TFAP2A gene, resulting in a glu296-to-lys (E296K) substitution at a highly conserved residue.
In a boy with mild branchiooculofacial syndrome (BOFS; 113620) who had a pseudocleft lip consisting only of a philtral ridge, Reiber et al. (2010) identified heterozygosity for a 710G-A transition in exon 4 of the TFAP2A gene, resulting in an arg237-to-gln (R237Q) substitution at a highly conserved residue.
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