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Gene Review

TBX5  -  T-box 5

Homo sapiens

Synonyms: T-box protein 5, T-box transcription factor TBX5
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Disease relevance of TBX5


High impact information on TBX5

  • Human mutations in TBX5, a gene encoding a T-box transcription factor, and SALL4, a gene encoding a zinc-finger transcription factor, cause similar upper limb and heart defects [6].
  • Heterozygous Tbx5(del/+) mice were generated to study the mechanisms by which TBX5 haploinsufficiency causes cardiac and forelimb abnormalities seen in Holt-Oram syndrome [7].
  • Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation [8].
  • Deletion analysis showed that both the N-terminal domain and T-box of Tbx5 were important for this transactivation [8].
  • A G80R mutation of Tbx5, which causes substantial cardiac defects with minor skeletal abnormalities in HOS, did not activate Nppa or show synergistic activation, whereas R237Q, which causes upper-limb malformations without cardiac abnormalities, activated the Nppa promoter to a similar extent to that of wildtype Tbx5 [8].

Biological context of TBX5

  • In this study we describe functional defects in DNA binding, transcriptional activity, protein-protein interaction, and cellular localization of mutant TBX5 with these missense mutations (Q49K, I54T, G80R, G169R, R237Q, R237W, and S252I) [1].
  • 5. The second group of mutations includes Q49K, I54T, G169R, and S252I, which have no or moderate effect on DNA-binding activity and the function of transcription activation of TBX5 but cause the complete loss of synergistic transcription activity between TBX5 and NKX2 [1].
  • TBX5 is a T-box transcription factor that plays a critical role in organogenesis [1].
  • Partial dysfunction of TBX5 in mouse also causes HOS phenotype [9].
  • Here, we report that ectopic expression of TBX5 inhibited colony formation, induced apoptosis, and decreased the growth rate of cells [9].

Anatomical context of TBX5

  • In embryonic and adult heart, TBX5 is expressed throughout the epicardium and in cardiomyocyte nuclei in myocardium of all four cardiac chambers [10].
  • Endocardial expression of TBX5 is only present in left ventricle [10].
  • P19CL6 cell lines overexpressing wildtype Tbx5 started to beat earlier and expressed cardiac-specific genes more abundantly than did parental P19CL6 cells, whereas cell lines expressing the G80R mutant did not differentiate into beating cardiomyocytes [8].
  • Co-transfection of Nkx2-5 and Tbx5 into COS-7 cells showed that they also associate with each other in mammalian cells [8].
  • Blocking cell cycle progression by TBX5 depletion leads to a decrease in cardiac cell number, an alteration in the timing of the cardiac differentiation program, defects in cardiac sarcomere formation, and ultimately, to cardiac programmed cell death [11].

Other interactions of TBX5

  • CONCLUSIONS: The expression pattern of TBX2, TBX3, and TBX5 within the developing retina supports the idea that the encoded transcription factors play a role in providing positional information important for topographic mapping and in differentiation of distinct cell types across the laminar axis of the retina [12].
  • GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5 [13].
  • 5. All seven missense mutations greatly reduced the interaction of TBX5 with NKX2.5 in vivo and in vitro [1].
  • Specifically, there is overlap of clinical features with other conditions, most notably Holt-Oram syndrome, a condition resulting from mutation of the TBX5 locus and Townes-Brocks syndrome, known to be caused by mutations in the SALL1 gene [14].
  • Thus, it is thought that Tbx5 and Tbx4 might be involved in determining limb identity [15].

Analytical, diagnostic and therapeutic context of TBX5


  1. Functional analysis of TBX5 missense mutations associated with Holt-Oram syndrome. Fan, C., Liu, M., Wang, Q. J. Biol. Chem. (2003) [Pubmed]
  2. Interaction makes the heart grow stronger. Packham, E.A., David Brook, J. Trends in molecular medicine. (2003) [Pubmed]
  3. TBX5 transcription factor regulates cell proliferation during cardiogenesis. Hatcher, C.J., Kim, M.S., Mah, C.S., Goldstein, M.M., Wong, B., Mikawa, T., Basson, C.T. Dev. Biol. (2001) [Pubmed]
  4. Developmental paradigms in heart disease: insights from tinman. Prall, O.W., Elliott, D.A., Harvey, R.P. Ann. Med. (2002) [Pubmed]
  5. Mutations at the SALL4 locus on chromosome 20 result in a range of clinically overlapping phenotypes, including Okihiro syndrome, Holt-Oram syndrome, acro-renal-ocular syndrome, and patients previously reported to represent thalidomide embryopathy. Kohlhase, J., Schubert, L., Liebers, M., Rauch, A., Becker, K., Mohammed, S.N., Newbury-Ecob, R., Reardon, W. J. Med. Genet. (2003) [Pubmed]
  6. Cooperative and antagonistic interactions between Sall4 and Tbx5 pattern the mouse limb and heart. Koshiba-Takeuchi, K., Takeuchi, J.K., Arruda, E.P., Kathiriya, I.S., Mo, R., Hui, C.C., Srivastava, D., Bruneau, B.G. Nat. Genet. (2006) [Pubmed]
  7. A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease. Bruneau, B.G., Nemer, G., Schmitt, J.P., Charron, F., Robitaille, L., Caron, S., Conner, D.A., Gessler, M., Nemer, M., Seidman, C.E., Seidman, J.G. Cell (2001) [Pubmed]
  8. Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation. Hiroi, Y., Kudoh, S., Monzen, K., Ikeda, Y., Yazaki, Y., Nagai, R., Komuro, I. Nat. Genet. (2001) [Pubmed]
  9. Induction of apoptosis and inhibition of cell growth by developmental regulator hTBX5. He, M.L., Chen, Y., Peng, Y., Jin, D., Du, D., Wu, J., Lu, P., Lin, M.C., Kung, H.F. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  10. Identification and localization of TBX5 transcription factor during human cardiac morphogenesis. Hatcher, C.J., Goldstein, M.M., Mah, C.S., Delia, C.S., Basson, C.T. Dev. Dyn. (2000) [Pubmed]
  11. TBX5 is required for embryonic cardiac cell cycle progression. Goetz, S.C., Brown, D.D., Conlon, F.L. Development (2006) [Pubmed]
  12. Expression of Drosophila omb-related T-box genes in the developing human and mouse neural retina. Sowden, J.C., Holt, J.K., Meins, M., Smith, H.K., Bhattacharya, S.S. Invest. Ophthalmol. Vis. Sci. (2001) [Pubmed]
  13. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Garg, V., Kathiriya, I.S., Barnes, R., Schluterman, M.K., King, I.N., Butler, C.A., Rothrock, C.R., Eapen, R.S., Hirayama-Yamada, K., Joo, K., Matsuoka, R., Cohen, J.C., Srivastava, D. Nature (2003) [Pubmed]
  14. Okihiro syndrome is caused by SALL4 mutations. Kohlhase, J., Heinrich, M., Schubert, L., Liebers, M., Kispert, A., Laccone, F., Turnpenny, P., Winter, R.M., Reardon, W. Hum. Mol. Genet. (2002) [Pubmed]
  15. Tbx5 and Tbx4 genes determine the wing/leg identity of limb buds. Takeuchi, J.K., Koshiba-Takeuchi, K., Matsumoto, K., Vogel-Höpker, A., Naitoh-Matsuo, M., Ogura, K., Takahashi, N., Yasuda, K., Ogura, T. Nature (1999) [Pubmed]
  16. Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Li, Q.Y., Newbury-Ecob, R.A., Terrett, J.A., Wilson, D.I., Curtis, A.R., Yi, C.H., Gebuhr, T., Bullen, P.J., Robson, S.C., Strachan, T., Bonnet, D., Lyonnet, S., Young, I.D., Raeburn, J.A., Buckler, A.J., Law, D.J., Brook, J.D. Nat. Genet. (1997) [Pubmed]
  17. TBX5 nuclear localization is mediated by dual cooperative intramolecular signals. Collavoli, A., Hatcher, C.J., He, J., Okin, D., Deo, R., Basson, C.T. J. Mol. Cell. Cardiol. (2003) [Pubmed]
  18. Three novel TBX5 mutations in Chinese patients with Holt-Oram syndrome. Yang, J., Hu, D., Xia, J., Yang, Y., Ying, B., Hu, J., Zhou, X. Am. J. Med. Genet. (2000) [Pubmed]
  19. Expanding the spectrum of TBX5 mutations in Holt-Oram syndrome: detection of two intragenic deletions by quantitative real time PCR, and report of eight novel point mutations. Borozdin, W., Bravo Ferrer Acosta, A.M., Bamshad, M.J., Botzenhart, E.M., Froster, U.G., Lemke, J., Schinzel, A., Spranger, S., McGaughran, J., Wand, D., Chrzanowska, K.H., Kohlhase, J. Hum. Mutat. (2006) [Pubmed]
  20. Cloning of TBX5, a key gene during heart formation and its expression in rat embryonic heart. Gong, L.G., Qiu, G.R., Xin, N., Xu, X.Y., Sun, K.L. Yi Chuan Xue Bao (2006) [Pubmed]
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