Human Molecular Genetics, 2001, Vol. 10, No. 18 1983-1994
© 2001 Oxford University Press
Characterization of the TBX5 binding site and analysis of mutations that cause Holt–Oram syndrome
Institute of Genetics, University of Nottingham, Queen’s Medical Centre, Nottingham NG7 2UH, UK
Holt–Oram syndrome is caused by mutations in TBX5, a member of the T-box gene family. In order to identify DNA sequences to which the TBX5 protein binds, we have performed an in vitro binding site selection assay. We have identified an 8 bp core sequence that is part of the Brachyury consensus-binding site. We show that TBX5 binds to the full palindromic Brachyury binding site and to the half-palindrome, whereas Brachyury does not bind to the TBX5 site. Amino acids 1–237 of TBX5 are required for DNA binding. Analysis of the effects of specific substitution mutations that arise in Holt–Oram patients indicates that G80R and R237Q eliminate binding to the target site. DNA database analysis reveals that target sites are present in the upstream regions of several cardiac-expressed genes including cardiac 
actin, atrial natriuretic factor, cardiac myosin heavy chain , cardiac myosin heavy chain ß, myosin light chain 1A, myosin light chain 1V and Nkx2.5. Cell transfection studies demonstrate that TBX5 activates the transcription of an atrial natriuretic factor reporter construct and this effect is significantly reduced by deletion of the TBX5 binding site.
+ To whom correspondence should be addressed. Tel: +44 115 849 3217; Fax: +44 115 970 9906; Email: david.brook@nottingham.ac.uk
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C. Fan, Q. Chen, and Q. K. Wang Functional Role of Transcriptional Factor TBX5 in Pre-mRNA Splicing and Holt-Oram Syndrome via Association with SC35 J. Biol. Chem., September 18, 2009; 284(38): 25653 - 25663. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Broitman-Maduro, M. Owraghi, W. W. K. Hung, S. Kuntz, P. W. Sternberg, and M. F. Maduro The NK-2 class homeodomain factor CEH-51 and the T-box factor TBX-35 have overlapping function in C. elegans mesoderm development Development, August 15, 2009; 136(16): 2735 - 2746. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. K. Ghosh, F. F. Song, E. A. Packham, S. Buxton, T. E. Robinson, J. Ronksley, T. Self, A. J. Bonser, and J. D. Brook Physical Interaction between TBX5 and MEF2C Is Required for Early Heart Development Mol. Cell. Biol., April 15, 2009; 29(8): 2205 - 2218. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. T. Garnett, T. M. Han, M. J. Gilchrist, J. C. Smith, M. B. Eisen, F. C. Wardle, and S. L. Amacher Identification of direct T-box target genes in the developing zebrafish mesoderm Development, March 1, 2009; 136(5): 749 - 760. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Georges, G. Nemer, M. Morin, C. Lefebvre, and M. Nemer Distinct Expression and Function of Alternatively Spliced Tbx5 Isoforms in Cell Growth and Differentiation Mol. Cell. Biol., June 15, 2008; 28(12): 4052 - 4067. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. V. Postma, J. B.A. van de Meerakker, I. B. Mathijssen, P. Barnett, V. M. Christoffels, A. Ilgun, J. Lam, A. A.M. Wilde, R. H. Lekanne Deprez, and A. F.M. Moorman A Gain-of-Function TBX5 Mutation Is Associated With Atypical Holt-Oram Syndrome and Paroxysmal Atrial Fibrillation Circ. Res., June 6, 2008; 102(11): 1433 - 1442. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Ding, C.-j. Liu, Y. Huang, R. P. Hickey, J. Yu, W. Kong, and P. Lengyel p204 Is Required for the Differentiation of P19 Murine Embryonal Carcinoma Cells to Beating Cardiac Myocytes: ITS EXPRESSION IS ACTIVATED BY THE CARDIAC GATA4, NKX2.5, AND TBX5 PROTEINS J. Biol. Chem., May 26, 2006; 281(21): 14882 - 14892. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Ding, C.-j. Liu, Y. Huang, J. Yu, W. Kong, and P. Lengyel p204 Protein Overcomes the Inhibition of the Differentiation of P19 Murine Embryonal Carcinoma Cells to Beating Cardiac Myocytes by Id Proteins J. Biol. Chem., May 26, 2006; 281(21): 14893 - 14906. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Murakami, M. Nakagawa, E. N. Olson, and O. Nakagawa A WW domain protein TAZ is a critical coactivator for TBX5, a transcription factor implicated in Holt-Oram syndrome PNAS, December 13, 2005; 102(50): 18034 - 18039. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Barron, N. S. Belaguli, S. X. Zhang, M. Trinh, D. Iyer, X. Merlo, J. W. Lough, M. S. Parmacek, B. G. Bruneau, and R. J. Schwartz Serum Response Factor, an Enriched Cardiac Mesoderm Obligatory Factor, Is a Downstream Gene Target for Tbx Genes J. Biol. Chem., March 25, 2005; 280(12): 11816 - 11828. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. W. Vance, S. Carreira, G. Brosch, and C. R. Goding Tbx2 Is Overexpressed and Plays an Important Role in Maintaining Proliferation and Suppression of Senescence in Melanomas Cancer Res., March 15, 2005; 65(6): 2260 - 2268. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Hatcher, N. Y.S.-G. Diman, M.-S. Kim, D. Pennisi, Y. Song, M. M. Goldstein, T. Mikawa, and C. T. Basson A role for Tbx5 in proepicardial cell migration during cardiogenesis Physiol Genomics, July 8, 2004; 18(2): 129 - 140. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. F. Plageman Jr. and K. E. Yutzey Differential Expression and Function of Tbx5 and Tbx20 in Cardiac Development J. Biol. Chem., April 30, 2004; 279(18): 19026 - 19034. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Stanier and G. E. Moore Genetics of cleft lip and palate: syndromic genes contribute to the incidence of non-syndromic clefts Hum. Mol. Genet., April 1, 2004; 13(suppl_1): R73 - R81. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A C B Marcano, K Doudney, C Braybrook, R Squires, M A Patton, M M Lees, A Richieri-Costa, A C Lidral, J C Murray, G E Moore, et al. TBX22 mutations are a frequent cause of cleft palate J. Med. Genet., January 1, 2004; 41(1): 68 - 74. [Full Text] [PDF]
|
|
|
|
 |
|
 A. F. M. MOORMAN and V. M. CHRISTOFFELS Cardiac Chamber Formation: Development, Genes, and Evolution Physiol Rev, October 1, 2003; 83(4): 1223 - 1267. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. E.M.H. Habets, A. F.M. Moorman, and V. M. Christoffels Regulatory modules in the developing heart Cardiovasc Res, May 1, 2003; 58(2): 246 - 263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Packham and J. D. Brook T-box genes in human disorders Hum. Mol. Genet., April 2, 2003; 12(90001): R37 - 44. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Liu, E. Nakamura, V. Knezevic, S. Hunter, K. Thompson, and S. Mackem A role for the mesenchymal T-box gene Brachyury in AER formation during limb development Development, April 1, 2003; 130(7): 1327 - 1337. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C Fan, M A Duhagon, C Oberti, S Chen, Y Hiroi, I Komuro, P I Duhagon, R Canessa, and Q Wang Novel TBX5 mutations and molecular mechanism for Holt-Oram syndrome J. Med. Genet., March 1, 2003; 40(3): e29 - 29. [Full Text] [PDF]
|
|
|
|
|
|
C. Fan, M. Liu, and Q. Wang Functional Analysis of TBX5 Missense Mutations Associated with Holt-Oram Syndrome J. Biol. Chem., February 28, 2003; 278(10): 8780 - 8785. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Agarwal, J. N. Wylie, J. Galceran, O. Arkhitko, C. Li, C. Deng, R. Grosschedl, and B. G. Bruneau Tbx5 is essential for forelimb bud initiation following patterning of the limb field in the mouse embryo Development, February 1, 2003; 130(3): 623 - 633. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Braybrook, S. Lisgo, K. Doudney, D. Henderson, A. C. B. Marcano, T. Strachan, M. A. Patton, L. Villard, G. E. Moore, P. Stanier, et al. Craniofacial expression of human and murine TBX22 correlates with the cleft palate and ankyloglossia phenotype observed in CPX patients Hum. Mol. Genet., October 15, 2002; 11(22): 2793 - 2804. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Pan, B. Hinzmann, W. Yan, F. Wu, J. Morser, and Q. Wu Genomic Structures of the Human and Murine Corin Genes and Functional GATA Elements in Their Promoters J. Biol. Chem., October 4, 2002; 277(41): 38390 - 38398. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. E.M.H. Habets, A. F.M. Moorman, D. E.W. Clout, M. A. van Roon, M. Lingbeek, M. van Lohuizen, M. Campione, and V. M. Christoffels Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the atrioventricular canal: implications for cardiac chamber formation Genes & Dev., May 15, 2002; 16(10): 1234 - 1246. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. G. Bruneau Transcriptional Regulation of Vertebrate Cardiac Morphogenesis Circ. Res., March 22, 2002; 90(5): 509 - 519. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Garrity, S. Childs, and M. C. Fishman The heartstrings mutation in zebrafish causes heart/fin Tbx5 deficiency syndrome Development, January 10, 2002; 129(19): 4635 - 4645. [Abstract] [Full Text] [PDF]
|
|