Alternative titles; symbols
HGNC Approved Gene Symbol: TBX2
Cytogenetic location: 17q23.2 Genomic coordinates (GRCh38): 17:61,399,843-61,409,466 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q23.2 | Vertebral anomalies and variable endocrine and T-cell dysfunction | 618223 | Autosomal dominant | 3 |
The TBX2 gene encodes a transcription factor that belongs to the family of T-box factor proteins that bind DNA, including TBX1 (602054) and TBX3 (601621). TBX2 is expressed in a variety of tissues and organs during embryogenesis (summary by Harrelson et al., 2004).
While identifying genes expressed during embryonic development of the mouse kidney, Campbell et al. (1995) isolated a 2.3-kb cDNA clone that appeared to represent a member of the gene family of DNA-binding proteins. They identified and cloned the human homolog (TBX2), which exhibited strong sequence homology with the Drosophila 'optomotor-blind' (omb) gene and lesser homology to the DNA-binding domain of the murine brachyury or T gene. The Drosophila omb gene and murine T gene share a conserved putative DNA-binding motif. Unlike omb, which is expressed in neural tissue, or T, which is not expressed in adult animals, TBX2 is expressed primarily in adult in kidney, lung, and placenta as multiple transcripts of between 2 and 4 kb. At least part of the transcript heterogeneity appeared to be due to alternative polyadenylation. This was the first reported human member of the family of highly conserved DNA-binding proteins, the Tbx or T-box proteins.
Sowden et al. (2001) examined the role of omb-related T-box genes in the development of human and mouse retina. Murine Tbx2, Tbx3, and Tbx5 (601620) and human TBX2 cDNAs were isolated from retina cDNA libraries by hybridization to the Drosophila omb gene. Human and mouse TBX2, TBX3, and TBX5 were expressed asymmetrically across the embryonic neural retina, with highest levels of mRNA within dorsal and peripheral retina. The dorsoventral gradient of TBX2 expression disappeared before the ganglion cell layer (GCL) formed. Its expression became restricted to the inner neuroblastic retina and later to the GCL and inner nuclear layer (INL). The dorsal expression domains of TBX5 and TBX3 were maintained during formation of the GCL. As the retina matured, TBX3 expression was restricted to the INL, and TBX5 was expressed within the GCL. The authors concluded that the expression patterns of TBX2, TBX3, and TBX5 within the developing retina support the idea that the encoded transcription factors play a role in providing positional information important for topographic mapping in differentiation of distinct cell types across the laminar axis of the retina.
Campbell et al. (1998) reported the exon/intron boundaries of TBX2 and a polymorphism within intron 2 of the gene. They noted that the exon/intron boundaries of TBX2 are highly conserved within the T-box domain with those of both the T (601397) and TBX5 genes.
By fluorescence in situ hybridization, Campbell et al. (1995) mapped the TBX2 gene to 17q23.
Bollag et al. (1994) mapped the Tbx2 gene to mouse chromosome 11 in a region of conserved synteny with human 17q21-q23. (They also identified 2 other related genes, Tbx1 and Tbx3, which they mapped to mouse chromosomes 5 and 16, respectively.) For this reason, Law et al. (1995) focused their search for the human homolog to 17q. Studying a chromosome 17 monochromosome hybrid, the TBX2 gene was isolated from a YAC contig containing markers D17S792, D17S794, and D17S948, located at 17q21-q22.
To identify new immortalizing genes with potential roles in tumorigenesis, Jacobs et al. (2000) performed a genetic screen aimed to bypass the rapid and tight arrest of senescence in primary fibroblasts deficient for the oncogene BMI1 (164831). They identified TBX2 as a potent immortalizing gene that acts by downregulating CDKN2A (600160). TBX2 represses the CDKN2A(p19ARF) promoter and attenuates the induction of CDKN2A mediated by E2F1 (189971), MYC (190080), or HRAS (190020). Jacobs et al. (2000) found that TBX2 was amplified in a subset of primary human breast cancers, indicating that it might contribute to breast cancer development.
During heart development, chamber myocardium forms locally from the embryonic myocardium of the tubular heart, and expression of the ANF gene (NPPA; 108780) is one of the first hallmarks of chamber formation. Habets et al. (2002) found that Tbx2 expression in the developing mouse heart was restricted to areas complementary to Anf expression. Tbx2 and Nkx2.5 (600584) formed a complex on the Anf promoter and repressed Anf activity.
Ballif et al. (2010) reported 7 unrelated patients with chromosome 17q23.1-q23.2 deletions (613355). All had mild to moderate developmental delay; other common features included facial dysmorphism as well as cardiac and skeletal defects. The authors postulated that the conserved transcription factors TBX2 and TBX4 (601719) located within this chromosome region might be involved, since they are known to play numerous roles in development.
Radio et al. (2010) reported a 4-year-old boy with mild mental retardation and multiple congenital anomalies associated with a de novo 131-kb duplication at chromosome 17q23.2. He was born at 38 weeks' gestation due to oligohydramnios and intrauterine growth retardation, and had severe respiratory distress in the neonatal period. He had multiple congenital heart defects, including intraventricular septal defect, patent foramen ovale, anomalous pulmonary return, tricuspid valve insufficiency, mitral valve stenosis, and aortic coarctation. Brain imaging showed enlarged ventricles, a hypoplastic corpus callosum and cerebellum, hypoplasia of the pons and medulla, and severe hypoplasia of the sixth cranial nerve, resulting in Duane anomaly. Other findings included laryngomalacia, pseudovolvulus, pectus excavatum, and winged scapulae. He had mild dysmorphic facial features, such as long face with pointed chin, long, flat philtrum, and large, low-set ears. Skeletal anomalies included hypoplastic or absent distal phalanges of the hands and feet and milder defects of a vertebral arch and ribs. He had delayed psychomotor development, absent speech, self-destructive behavior, and an IQ of 60. The 131-kb duplication included part of the BCAS3 gene (607470), the entire TBX2 gene (600747), and C17ORF82, but the TBX4 gene was not involved. Radio et al. (2010) noted that the phenotype in their patient overlapped somewhat with that reported by Ballif et al. (2010) in patients with a deletion of chromosome 17q23, but those patients also had deletion of the TBX4 gene. The authors also noted that the cardiac defects in their patient were similar to the cardiac phenotype seen in Tbx2-null mice, supporting a role for abnormal TBX2 dosage in congenital heart defects. Radio et al. (2010) concluded that the defects in their patient resulted mainly from duplication of TBX2, but also suggested that alterations in expression of TBX4 may be involved.
In a mother and 2 children with vertebral anomalies and variable endocrine and T-cell dysfunction (VETD; 618223), Liu et al. (2018) identified heterozygosity for a missense mutation in the TBX2 gene (R20Q; 600747.0001) that was not found in the unaffected father. In an unrelated boy with VETD, they identified heterozygosity for a de novo missense mutation in TBX2 (R305H; 600747.0002). In vitro analyses showed that both variants resulted in reduced protein levels and transcriptional repressor activity of TBX2.
Associations Pending Confirmation
Using targeted sequencing, Xie et al. (2018) identified 3 potentially damaging variants in the TBX2 gene (R608W, T249I, and R616Q) in 7 of 588 patients with conotruncal heart defects (see 217095), and none in 300 controls without heart defects. The variants occurred at positions highly conserved among vertebrates. Quantitative RT-PCR analysis showed that each of these variants resulted in higher mRNA expression than wildtype (p less than 0.05). On Western blot analysis, protein expression of R608W and R616Q was greater than that of wildtype TBX2. Functional analysis of the R608W and R1616Q variant proteins found that they failed to activate the promoter of PEA3 (ETV4; 600711), a downstream gene of TBX2. The authors hypothesized that these TBX2 variants might contribute to the etiology of conotruncal heart defects.
Harrelson et al. (2004) noted that in the developing mouse heart, Tbx2 is expressed in the outflow tract, inner curvature, atrioventricular canal and inflow tract, corresponding to a myocardial zone that is excluded from chamber differentiation at 9.5 days post coitus (dpc). Using targeted mutagenesis, the authors found that mice heterozygous for a Tbx2-null mutation appeared normal. However, homozygosity for the mutation was embryonic lethal apparently due to cardiovascular insufficiency. Homozygous embryos had morphologic defects in the development of the atrioventricular canal and septation of the outflow tract. The findings supported a model in which Tbx2 is required to repress chamber differentiation in the atrioventricular canal during embryonic life and also highlighted a role for Tbx2 in limb and digit development.
Using the development of the 4-digit chick leg as a model system, Suzuki et al. (2004) studied the role of Tbx2 and Tbx3 in specifying digit identities along the anterior-posterior axis. Misexpression of Tbx2 and Tbx3 induced posterior homeotic transformation of digit III to digit IV and digit II to digit III, respectively. Conversely, misexpression of constitutively active mutants induced anterior transformation. In both cases, alterations in the expression of several markers, including Bmp2 (112261), Shh (600725), and HoxD genes (see 142987), were observed. In addition, Tbx2 and Tbx3 rescued Noggin (602991)-mediated inhibition of interdigital BMP signaling, which was pivotal in establishing digit identities. Suzuki et al. (2004) concluded that, in the developing chick, Tbx3 specifies digit III and the combination of Tbx2 and Tbx3 specifies digit IV, acting together with the interdigital BMP signaling cascade.
In a mother and 2 children with vertebral anomalies and variable endocrine and T-cell dysfunction (VETD; 618223), Liu et al. (2018) identified heterozygosity for a c.59G-A transition in the TBX2 gene, resulting in an arg20-to-gln (R20Q) substitution at a highly conserved residue. The mutation, which was not found in the unaffected father, was observed in 1/2,865 internal controls from a hemophilia cohort and was also present in 2/89,521 individuals in the gnomAD database. Analysis of transfected HEK293T cells showed that the R20Q mutant had less than half the transcriptional repressor activity of wildtype (approximately 30% reduction of promoter activity compared to 80% reduction with wildtype TBX2), suggesting that the variant represents a hypomorphic allele. In addition, protein production was reduced to approximately 20% of wildtype with the R20Q mutant. Heterologous overexpression studies in the developing Drosophila visual system as well as adult photoreceptors revealed that the R20Q mutant was much less potent than the wildtype protein, consistent with its being a partial loss-of-function allele.
In a boy with vertebral anomalies and variable endocrine and T-cell dysfunction (VETD; 618223), Liu et al. (2018) identified heterozygosity for a de novo c.914G-A transition in the TBX2 gene, resulting in an arg305-to-his (R305H) substitution at a highly conserved residue within the transcription activation domain. The mutation was not found in his unaffected parents, in 2,865 controls from an internal hemophilia cohort, or in the ExAC or gnomAD databases. Analysis of transfected HEK293T cells showed that the R305H mutant had less than half the transcriptional repressor activity of wildtype (approximately 35% reduction of promoter activity compared to 80% reduction with wildtype TBX2), suggesting that the variant represents a hypomorphic allele. In addition, protein production was reduced to approximately 30% of wildtype with the R305H mutant. Heterologous overexpression studies in the developing Drosophila visual system as well as adult photoreceptors revealed that the R305H mutant was much less potent than the wildtype protein, consistent with its being a partial loss-of-function allele.
Ballif, B. C., Theisen, A., Rosenfeld, J. A., Traylor, R. N., Gastier-Foster, J., Thrush, D. L., Astbury, C., Bartholomew, D., McBride, K. L., Pyatt, R. E., and 14 others. Identification of a recurrent microdeletion at 17q23.1q23.2 flanked by segmental duplications associated with heart defects and limb abnormalities. Am. J. Hum. Genet. 86: 454-461, 2010. [PubMed: 20206336] [Full Text: https://doi.org/10.1016/j.ajhg.2010.01.038]
Bollag, R. J., Siegfried, Z., Cebra-Thomas, J. A., Garvey, N., Davison, E. M., Silver, L. M. An ancient family of embryonically expressed mouse genes sharing a conserved protein motif with the T locus. Nature Genet. 7: 383-389, 1994. [PubMed: 7920656] [Full Text: https://doi.org/10.1038/ng0794-383]
Campbell, C. E., Casey, G., Goodrich, K. Genomic structure of TBX2 indicates conservation with distantly related T-box genes. Mammalian Genome 9: 70-73, 1998. [PubMed: 9434949] [Full Text: https://doi.org/10.1007/s003359900682]
Campbell, C., Goodrich, K., Casey, G., Beatty, B. Cloning and mapping of a human gene (TBX2) sharing a highly conserved protein motif with the Drosophila omb gene. Genomics 28: 255-260, 1995. [PubMed: 8530034] [Full Text: https://doi.org/10.1006/geno.1995.1139]
Habets, P. E. M. H., Moorman, A. F. M., Clout, D. E. W., van Roon, M. A., Lingbeek, M., van Lohuizen, M., Campione, M., Christoffels, V. M. Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the atrioventricular canal: implications for cardiac chamber formation. Genes Dev. 16: 1234-1246, 2002. [PubMed: 12023302] [Full Text: https://doi.org/10.1101/gad.222902]
Harrelson, Z., Kelly, R. G., Goldin, S. N., Gibson-Brown, J. J., Bollag, R. J., Silver, L. M., Papaioannou, V. E. Tbx2 is essential for patterning the atrioventricular canal and for morphogenesis of the outflow tract during heart development. Development 131: 5041-5052, 2004. [PubMed: 15459098] [Full Text: https://doi.org/10.1242/dev.01378]
Jacobs, J. J. L., Keblusek, P., Robanus-Maandag, E., Kristel, P., Lingbeek, M., Nederlof, P. M., van Welsem, T., van de Vijver, M. J., Koh, E. Y., Daley, G. Q., van Lohuizen, M. Senescence bypass screen identifies TBX2, which represses Cdkn2a(p19ARF) and is amplified in a subset of human breast cancers. Nature Genet. 26: 291-299, 2000. [PubMed: 11062467] [Full Text: https://doi.org/10.1038/81583]
Law, D. J., Gebuhr, T., Garvey, N., Agulnik, S. I., Silver, L. M. Identification, characterization, and localization to chromosome 17q21-22 of the human TBX2 homolog, member of a conserved developmental gene family. Mammalian Genome 6: 793-797, 1995. [PubMed: 8597636] [Full Text: https://doi.org/10.1007/BF00539006]
Liu, N., Schoch, K., Luo, X., Pena, L. D. M., Bhavana, V. H., Kukolich, M. K., Stringer, S., Powis, Z., Radtke, K., Mroske, C., Deak, K. L., McDonald, M. T., and 14 others. Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder. Hum. Molec. Genet. 27: 2454-2465, 2018. [PubMed: 29726930] [Full Text: https://doi.org/10.1093/hmg/ddy146]
Pflugfelder, G. O., Roth, H., Poeck, B. A homology domain shared between Drosophila optomotor-blind and mouse Brachyury is involved in DNA binding. Biochem. Biophys. Res. Commun. 186: 918-925, 1992. [PubMed: 1497674] [Full Text: https://doi.org/10.1016/0006-291x(92)90833-7]
Radio, F. C., Bernardini, L., Loddo, S., Bottillo, I., Novelli, A., Mingarelli, R., Dallapiccola, B. TBX2 gene duplication associated with complex heart defect and skeletal malformations. Am. J. Med. Genet. 152A: 2061-2066, 2010. [PubMed: 20635360] [Full Text: https://doi.org/10.1002/ajmg.a.33506]
Sowden, J. C., Holt, J. K. L., Meins, M., Smith, H. K., Bhattacharya, S. S. Expression of Drosophila omb-related T-box genes in the developing human and mouse neural retina. Invest. Ophthal. Vis. Sci. 42: 3095-3102, 2001. [PubMed: 11726608]
Suzuki, T., Takeuchi, J., Koshiba-Takeuchi, K., Ogura, T. Tbx genes specify posterior digit identity through Shh and BMP signaling. Dev. Cell 6: 43-53, 2004. Note: Erratum: Dev. Cell 8: 971-971, 2005. [PubMed: 14723846] [Full Text: https://doi.org/10.1016/s1534-5807(03)00401-5]
Xie, H., Zhang, E., Hong, N., Fu, Q., Li, F., Chen, S., Yu, Y., Sun, K. Identification of TBX2 and TBX3 variants in patients with conotruncal heart defects by target sequencing. Hum. Genomics 12: 44, 2018. [PubMed: 30223900] [Full Text: https://doi.org/10.1186/s40246-018-0176-0]