HGNC Approved Gene Symbol: TFAP2B
SNOMEDCT: 703534001;
Cytogenetic location: 6p12.3 Genomic coordinates (GRCh38) : 6:50,818,355-50,847,619 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p12.3 | Char syndrome | 169100 | Autosomal dominant | 3 |
| Patent ductus arteriosus 2 | 617035 | Autosomal dominant | 3 |
Families of related transcription factors are often expressed in the same cell lineages but at different times or sites in the developing embryo. Williamson et al. (1996) stated that the AP-2 family appears to regulate the expression of genes required for development of tissues of ectodermal origin, such as neural crest and skin. AP-2 may also be involved in the overexpression of c-erbB-2 (164870) in human breast cancer cells (Bosher et al., 1995).
Williamson et al. (1996) isolated an AP-2-related cDNA that is the apparent homolog of the mouse AP-2-beta described by Moser et al. (1995). The predicted protein differs from AP-2-alpha (107580) and -gamma (601602) in the N-terminal activation domain, but is 75 to 85% conserved within the DNA-binding and dimerization domains. All 3 gene products (AP-2-alpha, -beta, and -gamma) bind the GCCNNNGGC motif. Williamson et al. (1996) also obtained a genomic clone for AP-2-beta (designated TFAP2B).
Moser et al. (1997) demonstrated that Tcfap2b in the developing mouse is expressed in the lateral head mesenchyme and neural folds at 8.5 days postcoitum, coincident with the location of the neural crest cells. During later embryogenesis, Tcfap2b is expressed in the facial mesenchyme, cornea, and kidney.
Williamson et al. (1996) found that the structure of the AP-2-beta gene is similar to that of TFAP2A.
By fluorescence in situ hybridization, Williamson et al. (1996) mapped the TFAP2B gene to chromosome 6p12. A mouse genomic clone was used to map the mouse Tcfap2b locus to 1A2-4.
The TFAP2B gene plays an important role in retinoic acid-induced differentiation, particularly in cells derived from the neuroectoderm.
Char Syndrome
In affected members of 2 families with Char syndrome (CHAR; 169100), Satoda et al. (2000) identified heterozygous missense mutations in the TFAP2B gene altering conserved residues (601601.0001-601601.0002). Mutant TFAP2B proteins dimerized properly in vitro, but showed abnormal binding to TFAP2 target sequence. Dimerization of both mutants with normal TFAP2B adversely affected transactivation, demonstrating a dominant-negative mechanism. Satoda et al. (2000) concluded that TFAP2B has a role in ductal, facial, and limb development and suggested that Char syndrome results from derangement of neural crest cell derivatives.
Zhao et al. (2001) studied 8 patients with Char syndrome and identified 4 novel mutations in the TFAP2B gene; 3 occurred in the basic domain (601601.0003-601601.0005) and the other affected a conserved PY motif in the transactivation domain (601601.0006). Zhao et al. (2001) found that all 4 mutations, as well as 2 previously identified mutations in the basic domain, had dominant-negative effects when expressed in eukaryotic cells.
In 2 unrelated families segregating autosomal dominant Char syndrome, Mani et al. (2005) identified heterozygosity for 2 different splice site mutations in the TFAP2B gene (see, e.g., 601601.0007). The authors noted that in contrast to previously reported dominant-negative TFAP2B mutations in Char syndrome, the mechanism of disease in these 2 kindreds was likely to be haploinsufficiency.
Type 2 Diabetes
Maeda et al. (2005) performed a genomewide, case-control association study using gene-based SNPs in Japanese patients with type 2 diabetes (125853) and Japanese controls and identified several variations within the TFAP2B gene that were significantly associated with type 2 diabetes: an intron 1 VNTR (p = 0.0009), intron 1 +774G-T (p = 0.0006), and intron 1 +2093A-C (p = 0.0004). The association of TFAP2B with type 2 diabetes was also observed in a U.K. population. Maeda et al. (2005) suggested that the TFAP2B gene may confer susceptibility to type 2 diabetes.
Patent Ductus Arteriosus 2
In affected members of a consanguineous Kuwaiti family segregating autosomal dominant patent ductus arteriosus (PDA2; 617035), Khetyar et al. (2008) identified heterozygosity for a splice site mutation in the TFAP2B gene (601601.0008). None of the affected family members exhibited features of Char syndrome.
In 5 affected members of a Chinese family with isolated PDA, Chen et al. (2011) identified heterozygosity for a splice site mutation (601601.0007) in the TFAP2B gene. The authors noted that the same splice site mutation had previously been reported in a large family with Char syndrome (Mani et al., 2005), and stated that the reasons for differences in expression patterns remained unclear. In a mother and daughter from an unrelated Chinese family, Chen et al. (2011) identified heterozygosity for a 4-bp deletion in TFAP2B (601601.0009). Chen et al. (2011) also analyzed the TFAP2B gene in 100 unrelated Chinese children with isolated PDA and 100 healthy unrelated Chinese children (controls) and identified a novel SNP 34 bp upstream of the TFAP2B transcription initiation site (c.1-34G-A). The A allele was found significantly more frequently among affected individuals than among controls (p = 0.012). The AA genotype was found in 8 affected individuals and in no controls. The authors suggested that this variant should be considered as a potential risk factor for PDA.
Zhao et al. (2001) found that individuals with Char syndrome who had a PY motif mutation had a high prevalence of patent ductus arteriosus (PDA; see 607411), but only mild facial and hand abnormalities as compared to those with basic domain (DNA-binding) mutations. The authors concluded that this correlation supports the existence of TFAP2 coactivators that have tissue specificity and are important for ductal development but less critical for craniofacial and limb development.
Moser et al. (1997) generated mice deficient in AP2B by targeted disruption. Ap2b -/- mice completed embryonic development but died at postnatal days 1 and 2 because of polycystic kidney disease. Analyses of kidney development revealed that induction of epithelial conversion, mesenchyme condensation, and further glomerular and tubular differentiation occurred normally in Ap2b-deficient mice. At the end of embryonic development, expression of bcl-XL, bcl-w, and bcl-2 is downregulated in parallel to massive apoptotic death of collecting duct and distal tubular epithelia. Moser et al. (1997) demonstrated that transfection of AP2 into cell lines in vitro strongly suppresses c-myc-induced apoptosis, pointing to a function of AP2 in programming cell survival during embryogenesis.
Satoda et al. (2000) identified a heterozygous C-to-A transversion at nucleotide 791 in the TFAP2B gene, resulting in a substitution of aspartic acid for alanine at codon 264, in the family with Char syndrome (CHAR; 169100) described by Satoda et al. (1999). All affected individuals inherited the ala264-to-asp allele but this allele was not observed in any unaffected individual. The mutation was not identified in 100 control individuals of European descent, and comparison within the TFAP2 family transcript factor showed that the alanine at position 264 was entirely conserved.
Satoda et al. (2000) identified a C-to-T transition at nucleotide 865 in the TFAP2B gene, resulting in an arginine to cysteine substitution at codon 289, in a family with Char syndrome (CHAR; 169100), previously described by Davidson (1993). The mutation was not identified in more than 100 control individuals of European descent, and was a change of a conserved residue within the protein.
In a Palestinian boy with Char syndrome (CHAR; 169100) who had patent ductus arteriosus, clinodactyly, typical facial features, and a supernumerary nipple, Zhao et al. (2001) identified a heterozygous C-to-T transition at nucleotide 673 in the TFAP2B gene, resulting in an arg225-to-cys (R225C) substitution. The mutation is located in the basic domain, which is responsible for DNA binding. The mutation was not found in the parents or in over 100 Israeli Arab controls. Functional analysis of this mutant protein showed that it failed to bind target sequences in vitro.
Zhao et al. (2001) studied the English family described by Sweeney et al. (2000) with typical facial features and hand anomalies of Char syndrome (CHAR; 169100) but no cardiovascular abnormalities, and identified a heterozygous C-to-A transversion at nucleotide 673 in the TFAP2B gene, resulting in an arg225-to-ser (R225S) substitution in the basic domain, which is responsible for DNA binding. The mutation was not found in over 100 controls. Functional analysis of this mutant protein showed that it failed to bind target sequences in vitro.
In 4 affected members of an Australian family with Char syndrome (CHAR; 169100) who had markedly anomalous facial appearances and PDAs, but no hand anomalies, Zhao et al. (2001) identified a G-to-A transition at nucleotide 821 in the TFAP2B gene, resulting in an arg274-to-gln (R274Q) substitution in the basic domain, which is responsible for DNA binding.
In affected members of a large family from Minnesota segregating Char syndrome (CHAR; 169100) described by Sletten and Pierpont (1995), Zhao et al. (2001) identified a heterozygous C-to-G transversion at nucleotide 185 in the TFAP2B gene, resulting in a pro62-to-arg (P62R) substitution in a conserved PY motif of the transactivation domain. Affected members of this family had a high prevalence of patent ductus arteriosus, mildly anomalous facial features, and normal hands. One affected individual had a muscular ventricular septal defect, and another died of complex cyanotic heart disease in adulthood.
In a large 3-generation family segregating autosomal dominant Char syndrome (CHAR; 169100), Mani et al. (2005) identified heterozygosity for a G-to-A transition at position +5 of the splice donor site of intron 3, a highly conserved nucleotide in the TFAP2B gene. The mutation was detected in 22 affected individuals and in 1 unaffected obligate carrier, but was not found in 17 additional unaffected family members or in 200 unrelated control chromosomes. Transfection studies in COS7 cells revealed abnormal splicing with the mutant but not wildtype TFAP2B. Of the 22 affected family members, 9 had PDA with facial dysmorphism and clinodactyly, and 13 exhibited only dysmorphic facies and clinodactyly, but none had PDA alone.
In 5 affected members over 2 generations of a Chinese family with isolated patent ductus arteriosus (PDA2; 617035), Chen et al. (2011) identified heterozygosity for the same splice site mutation in the TFAP2B gene, which they designated as c.601+5G-A. Nested PCR revealed that the mutation resulted in a 61-bp deletion within exon 3. The mutation was not found in unaffected family members or in 100 ethnically matched controls. None of the affected individuals in the Chinese family exhibited the craniofacial or fifth-finger anomalies of Char syndrome, and Chen et al. (2011) stated that the reasons for differences in expression patterns between this family and the family reported by Mani et al. (2005) remained unclear.
In 6 affected members of a consanguineous Kuwaiti family segregating autosomal dominant patent ductus arteriosus (PDA2; 617035), Khetyar et al. (2008) identified heterozygosity for a transversion in intron 2 (IVS2-2A-T) of the TFAP2B gene, predicted to disrupt the acceptor splice site of exon 3 and cause a frameshift resulting in a premature termination codon (Lys170fsTer178). The mutation was not found in 6 unaffected family members.
In a Chinese mother and daughter with isolated patent ductus arteriosus (PDA2; 617035), Chen et al. (2011) identified heterozygosity for a 4-bp deletion (c.435_438delCCGG) in exon 2 of the TFAP2B gene, causing a frameshift predicted to result in a premature termination codon (Arg145ArgfsTer45). The mutation was not found in unaffected family members or in 100 ethnically matched controls.
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Chen, Y.-W., Zhao, W., Zhang, Z.-F., Fu, Q., Shen, J., Zhang, Z., Ji, W., Wang, J., Li, F. Familial nonsyndromic patent ductus arteriosus caused by mutations in TFAP2B. Pediat. Cardiol. 32: 958-965, 2011. [PubMed: 21643846] [Full Text: https://doi.org/10.1007/s00246-011-0024-7]
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Maeda, S., Tsukada, S., Kanazawa, A., Sekine, A., Tsunoda, T., Koya, D., Maegawa, H., Kashiwagi, A., Babazono, T., Matsuda, M., Tanaka, Y., Fujioka, T., and 14 others. Genetic variations in the gene encoding TFAP2B are associated with type 2 diabetes mellitus. J. Hum. Genet. 50: 283-292, 2005. [PubMed: 15940393] [Full Text: https://doi.org/10.1007/s10038-005-0253-9]
Mani, A., Radhakrishnan, J., Farhi, A., Carew, K. S., Warnes, C. A., Nelson-Williams, C., Day, R. W., Pober, B., State, M. W., Lifton, R. P. Syndromic patent ductus arteriosus : evidence for haploinsufficient TFAP2B mutations and identification of a linked sleep disorder. Proc. Nat. Acad. Sci. 102: 2975-2979, 2005. [PubMed: 15684060] [Full Text: https://doi.org/10.1073/pnas.0409852102]
Moser, M., Imhof, A., Pscherer, A., Bauer, R., Amselgruber, W., Sinowatz, F., Hofstadter, F., Schule, R., Buettner, R. Cloning and characterization of a second AP-2 transcription factor: AP-2-beta. Development 121: 2779-2788, 1995. [PubMed: 7555706] [Full Text: https://doi.org/10.1242/dev.121.9.2779]
Moser, M., Pscherer, A., Roth, C., Becker, J., Mucher, G., Zerres, K., Dixkens, C., Weis, J., Guay-Woodford, L., Buettner, R., Fassler, R. Enhanced apoptotic cell death of renal epithelial cells in mice lacking transcription factor AP-2B. Genes Dev. 11: 1938-1948, 1997. [PubMed: 9271117] [Full Text: https://doi.org/10.1101/gad.11.15.1938]
Moser, M., Ruschoff, J., Beuttner, R. Comparative analysis of AP-2-alpha and AP-2-beta gene expression during murine embryogenesis. Dev. Dyn. 208: 115-124, 1997. [PubMed: 8989526] [Full Text: https://doi.org/10.1002/(SICI)1097-0177(199701)208:1<115::AID-AJA11>3.0.CO;2-5]
Satoda, M., Pierpont, M. E. M., Diaz, G. A., Bornemeier, R. A., Gelb, B. D. Char syndrome, an inherited disorder with patent ductus arteriosus, maps to chromosome 6p12-p21. Circulation 99: 3036-3042, 1999. [PubMed: 10368122] [Full Text: https://doi.org/10.1161/01.cir.99.23.3036]
Satoda, M., Zhao, F., Diaz, G. A., Burn, J., Goodship, J., Davidson, H. R., Pierpont, M. E. M., Gelb, B. D. Mutations in TFAP2B cause Char syndrome, a familial form of patent ductus arteriosus. Nature Genet. 25: 42-46, 2000. [PubMed: 10802654] [Full Text: https://doi.org/10.1038/75578]
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Sweeney, E., Fryer, A., Walters, M. Char syndrome: a new family and review of the literature emphasising the presence of symphalangism and the variable phenotype. Clin. Dysmorph. 9: 177-182, 2000. [PubMed: 10955477] [Full Text: https://doi.org/10.1097/00019605-200009030-00005]
Williamson, J. A., Bosher, J. M., Skinner, A., Sheer, D., Williams, T., Hurst, H. C. Chromosomal mapping of the human and mouse homologues of two new members of the AP-2 family of transcription factors. Genomics 35: 262-264, 1996. [PubMed: 8661133] [Full Text: https://doi.org/10.1006/geno.1996.0351]
Zhao, F., Weismann, C. G., Satoda, M., Pierpont, M. E. M., Sweeney, E., Thompson, E. M., Gelb, B. D. Novel TFAP2B mutations that cause Char syndrome provide a genotype-phenotype correlation. Am. J. Hum. Genet. 69: 695-703, 2001. [PubMed: 11505339] [Full Text: https://doi.org/10.1086/323410]