Alternative titles; symbols
HGNC Approved Gene Symbol: TBX20
Cytogenetic location: 7p14.2 Genomic coordinates (GRCh38): 7:35,202,430-35,254,100 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7p14.2 | Atrial septal defect 4 | 611363 | 3 |
Members of the phylogenetically conserved family of T-box genes share a common DNA-binding domain, the T-box. T-box genes, such as TBX20, encode transcription factors involved in the regulation of developmental processes (summary by Meins et al., 2000).
By searching genome databases for sequences similar to the Drosophila H15 gene, Meins et al. (2000) isolated a novel member of the T-box gene family, which they designated TBX20, from a BAC clone mapping to chromosome 7p15-p14. They also isolated the mouse homolog from heart and eye RNA samples. Human TBX20 encodes a deduced 297-amino acid protein that shares approximately 71% sequence identity with the T-box domain of the Drosophila H15 protein. H15 is expressed in leg imaginal discs and is thought to play a role in early patterning events. RT-PCR analysis showed that human TBX20 is expressed in the fetal heart, eye, and limb. In situ hybridization showed that during embryogenesis in the mouse, Tbx20 is expressed in the developing heart, eye, ventral neural tube, and limbs, indicating a possible role in regulating development of these tissues. Tbx20 is also present in adult heart.
Stennard et al. (2003) cloned 3 mouse Tbx20 splice variants, which they called Tbx20a, Tbx20b, and Tbx20c, and by database analysis they identified a fourth variant, Tbx20d. Tbx20a encodes a deduced 445-amino acid protein with a central T-box, followed by a transactivation domain and a C-terminal transrepression domain. Compared with Tbx20a, Tbx20b and Tbx20c are C-terminally truncated after the T-box, and Tbx20d is truncated within the T-box. Tbx20b corresponds to the human TBX20 variant cloned by Meins et al. (2000). Epitope-tagged Tbx20a was expressed in nuclei of transfected mouse fibroblasts. In situ hybridization revealed Tbx20 expression in both myocardial and endocardial layers of mouse heart from early stages of development.
By RT-PCR of HEK293 cells and myocardium, Hammer et al. (2008) cloned a human TBX20 splice variant homologous to mouse Tbx20a. The deduced 447-amino acid human TBX20A protein contains a predicted transactivation domain and transrepression domain C-terminal to the T-box. Real-time PCR showed stronger expression of TBX20A than TBX20B in all 4 human heart chambers.
Meins et al. (2000) determined that the TBX20 gene contains 6 exons spanning 22 kb of genomic DNA.
Hammer et al. (2008) determined that the TBX20 gene contains 8 exons. The core promoter region contains several GC boxes.
Meins et al. (2000) identified the TBX20 gene within a BAC clone that had been mapped to chromosome 7p15-p14.
Hammer et al. (2008) identified a TBX20 pseudogene on chromosome 12 that includes only TBX20 exons 5 through 8.
By deletion analysis, Stennard et al. (2003) found that the C-terminal region of mouse Tbx20a contained strong transactivation and transrepression domains. The C terminus of Tbx20a was also required to induce markers of ventrolateral mesoderm and endoderm in Xenopus embryos, resulting in partial secondary axis and protrusions containing ectopic beating heart tissue. Tbx20a, Tbx20b, and Tbx20c interacted via their T-box with the cardiac transcription factors Nkx2-5 (600584), Gata4 (600576), and Gata5 (611496). The shorter Tbx20 isoforms, but not Tbx20a, synergized with Nkx2-5 and Gata4 to activate cardiac gene expression. However, Tbx20a, as well as the shorter isoforms, could synergize with Nkx2-5 and Gata5 to activate transcription.
Using reporter gene assays, Hammer et al. (2008) found that the GC box-binding transcription factors TFAP2A (107580), TFAP2B (601601), and TFAP2C (601602), but not SP1 (189906) or E2F (see 189971), bound to the TBX20 core promoter and repressed TBX20 expression in a dose-dependent manner. Binding assays confirmed that TFAP2 bound to the TBX20 promoter in transfected HEK293 cells and HL1 mouse atria cardiomyocytes. Real-time PCR showed overexpression of TBX20, but not TBX5 (601620), in heart biopsies from patients with tetralogy of Fallot (TOF; 187500), but not in those from patients with ventricular septal defects (see 614429). Overexpression of TBX20 in TOF patients correlated with downregulation of TFAP2C.
Kirk et al. (2007) reported missense (I152M; 606061.0001) and nonsense (Q195X; 606061.0002) germline mutations within the T-box DNA-binding domain of human TBX20 that were associated with a family history of congenital heart disease and a complex spectrum of developmental anomalies, including defects in septation, chamber growth, and valvulogenesis (ASD4; 611363). Biophysical characterization of wildtype and mutant proteins indicated that the missense mutation disrupted the structure and function of the TBX20 T-box. Dilated cardiomyopathy is a feature of the TBX20 mutant phenotype in humans and mice, suggesting that mutations in developmental transcription factors can provide a sensitized template for adult-onset heart disease. The clinical spectrum of congenital heart disease due to distinct mutations in the same gene, or mutations in different genes acting in the conserved pathway, can vary greatly within and among families. Conversely, defects in different cardiac developmental processes can give rise to similar forms of congenital heart disease. In TBX20 mutation-positive families, there is additional complexity in that TBX20 is essential for both myogenic and valvular development and that mutations are associated with myocardial dysfunction and dilated cardiomyopathy.
Posch et al. (2010) analyzed the TBX20 gene in 170 patients with ostium secundum atrial septal defects and identified heterozygosity for a missense mutation (I121M; 606061.0003) in 1 proband. Functional analysis showed that the mutant protein had a more dynamic structure than wildtype and significantly enhanced transcriptional activity.
Stennard et al. (2005) found that deletion of Tbx20 in mouse was embryonic lethal. Tbx20 -/- embryos showed grossly abnormal cardiac development and arrested yolk sac vascular remodeling. Ectopic activation of Tbx2 (600747) occurred across the whole heart myogenic field in Tbx20 -/- embryos, likely due to loss of Tbx20 repressive function.
Sakabe et al. (2012) stated that conditional ablation of Tbx20 in adult mouse cardiomyocytes results in functional abnormalities within 5 days and rapid progression to heart failure within 15 days. They coupled chromatin immunoprecipitation with transcriptome analyses and identified over 4,000 genes that were differentially expressed between wildtype and Tbx20 -/- adult hearts. About 20% of these genes appeared to be direct Tbx20 targets based on the proximity of putative Tbx20-binding sites. Of the putative direct targets, genes involved preferentially in cardiovascular biology and energy metabolism were downregulated in adult Tbx20 -/- hearts, and genes involved in noncardiac tissues, immune response, and cell cycle and proliferation were upregulated in Tbx20 -/- hearts. Sakabe et al. (2012) identified a low-affinity Tbx20-binding motif in promoter regions of Tbx20 target genes in addition to the classic T-box DNA-binding motif. They also found evidence that Tbx20 cooperates with other transcription factors to regulate distinct genetic pathways.
Qian and Bodmer (2009) utilized a Drosophila heart model involving mutation of pannier (pnr) to examine the function of GATA4 (600576) in adult heart physiology. Heterozygous pnr mutants had defective cardiac performance in response to electrical pacing of the heart as well as in elevated arrhythmias. Adult-specific disruption of pnr function using a dominant-negative form revealed a cardiac autonomous requirement of pnr in regulating heart physiology. Neuromancer (nmr), the Drosophila homolog of TBX20, was identified as a potential downstream mediator of pnr in regulating cardiac performance and rhythm regularity, based on the finding that overexpression of nmr, but not of tinman (NKX2-5; 600584), partially rescued adult defects in pnr mutants. Qian and Bodmer (2009) concluded that pnr and TBX20/nmr play important roles in establishing and/or maintaining proper heart function.
In 1 woman in each successive generation of a family with congenital heart disease and a complex spectrum of other developmental cardiac anomalies (ASD4; 611363), Kirk et al. (2007) found a heterozygous 456C-G transversion in the TBX20 gene that resulted in an ile152-to-met (I152M) substitution. Ile152 is a highly conserved amino acid in the T-box DNA-binding domain, and biophysical studies of the purified bacterially expressed T-box domain confirmed direct effects of this mutation on tertiary protein structure, thermal stability, and DNA binding.
In a family in which 6 members in 3 generations had a history of various cardiac anomalies (ASD4; 611363), Kirk et al. (2007) found that 2 living members carried a 583C-T transition in the TBX20 gene that resulted in a gln195-to-stop (Q195X) substitution. The mutation resulted in a TBX20 protein that was truncated within the T-box and lacked the potent C-terminal trans activation and trans repression domains.
In a 16-year-old boy of Lebanese origin with an ostium secundum atrial septal defect (ASD4; 611363), Posch et al. (2010) identified heterozygosity for a 374C-G transversion in exon 2 of the TBX20 gene, resulting in an ile121-to-met (I121M) substitution at a highly conserved residue within the T-box DNA-binding region. The mutation was also present in heterozygosity in his mother and sister, who each had large patent foramen ovale with permanent shunt. The mutation was not found in the proband's 2 unaffected brothers, in 680 control alleles, or in 218 control probands from Lebanon. Structural analysis showed that the I121M mutant resulted in a conformation with a more dynamic tertiary structure than the wildtype protein. Functional analysis revealed that the I121M mutant had significantly enhanced transcriptional activity, which was further increased in the presence of cotranscription factors GATA4 (600576)/GATA5 (611496) and NKX2-5 (600584). Posch et al. (2010) suggested that ostium secundum atrial septal defects may be associated with gain-of-function as well as loss-of-function mutations.
Hammer, S., Toenjes, M., Lange, M., Fischer, J. J., Dunkel, I., Mebus, S., Grimm, C. H., Hetzer, R., Berger, F., Sperling, S. Characterization of TBX20 in human hearts and its regulation by TFAP2. J. Cell. Biochem. 104: 1022-1033, 2008. [PubMed: 18275040] [Full Text: https://doi.org/10.1002/jcb.21686]
Kirk, E. P., Sunde, M., Costa, M. W., Rankin, S. A., Wolstein, O., Castro, M. L., Butler, T. L., Hyun, C., Guo, G., Otway, R., Mackay, J. P., Waddell, L. B., and 11 others. Mutations in cardiac T-box factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy. Am. J. Hum. Genet. 81: 280-291, 2007. [PubMed: 17668378] [Full Text: https://doi.org/10.1086/519530]
Meins, M., Henderson, D. J., Bhattacharya, S. S., Sowden, J. C. Characterization of the human TBX20 gene, a new member of the T-box gene family closely related to the Drosophila H15 gene. Genomics 67: 317-332, 2000. [PubMed: 10936053] [Full Text: https://doi.org/10.1006/geno.2000.6249]
Posch, M. G., Gramlich, M., Sunde, M., Schmitt, K. R., Lee, S. H. Y., Richter, S., Kersten, A., Perrot, A., Panek, A. N., Al Khatib, I. H., Nemer, G., Megarbane, A., Dietz, R., Stiller, B., Berger, F., Harvey, R. P., Ozcelik, C. A gain-of-function TBX20 mutation causes congenital atrial septal defects, patent foramen ovale and cardiac valve defects. J. Med. Genet. 47: 230-235, 2010. [PubMed: 19762328] [Full Text: https://doi.org/10.1136/jmg.2009.069997]
Qian, L., Bodmer, R. Partial loss of GATA factor Pannier impairs adult heart function in Drosophila. Hum. Molec. Genet. 18: 3153-3163, 2009. [PubMed: 19494035] [Full Text: https://doi.org/10.1093/hmg/ddp254]
Sakabe, N. J., Aneas, I., Shen, T., Shokri, L., Park, S.-Y., Bulyk, M. L., Evans, S. M., Nobrega, M. A. Dual transcriptional activator and repressor roles of TBX20 regulate adult cardiac structure and function. Hum. Molec. Genet. 21: 2194-2204, 2012. [PubMed: 22328084] [Full Text: https://doi.org/10.1093/hmg/dds034]
Stennard, F. A., Costa, M. W., Elliott, D. A., Rankin, S., Haast, S. J. P., Lai, D., McDonald, L. P. A., Niederreither, K., Dolle, P., Bruneau, B. G., Zorn, A. M., Harvey, R. P. Cardiac T-box factor Tbx20 directly interacts with Nkx2-5, GATA4, and GATA5 in regulation of gene expression in the developing heart. Dev. Biol. 262: 206-224, 2003. [PubMed: 14550786] [Full Text: https://doi.org/10.1016/s0012-1606(03)00385-3]
Stennard, F. A., Costa, M. W., Lai, D., Biben, C., Furtado, M. B., Solloway, M. J., McCulley, D. J., Leimena, C., Preis, J. I., Dunwoodie, S. L., Elliott, D. E., Prall, O. W. J., Black, B. L., Fatkin, D., Harvey, R. P. Murine T-box transcription factor Tbx20 acts as a repressor during heart development, and is essential for adult heart integrity, function and adaptation. Development 132: 2451-2462, 2005. [PubMed: 15843414] [Full Text: https://doi.org/10.1242/dev.01799]