TBX5 (gene)

T-box 5
Rendering based on PDB 2X6U​.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2X6U​, 2X6V​
Identifiers
Symbols	TBX5 ; HOS
External IDs	OMIM: 601620 MGI: 102541 HomoloGene: 160 ChEMBL: 1687681 GeneCards: TBX5 Gene
Gene ontology Molecular function • RNA polymerase II regulatory region sequence-specific DNA binding • transcriptional activator activity, RNA polymerase II transcription regulatory region sequence-specific binding • DNA binding • transcription factor activity, sequence-specific DNA binding • protein binding • transcription factor binding • sequence-specific DNA binding Cellular component • nucleus • nucleoplasm • cytoplasm Biological process • morphogenesis of an epithelium • bundle of His development • atrioventricular valve morphogenesis • endocardial cushion development • cardiac left ventricle formation • ventricular septum development • transcription initiation from RNA polymerase II promoter • cell-cell signaling • pattern specification process • heart development • negative regulation of cell proliferation • gene expression • negative regulation of epithelial to mesenchymal transition • lung development • embryonic limb morphogenesis • negative regulation of cell migration • embryonic forelimb morphogenesis • forelimb morphogenesis • positive regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase II promoter • positive regulation of cardioblast differentiation • cardiac muscle cell differentiation • pericardium development • negative regulation of cardiac muscle cell proliferation • positive regulation of cardiac muscle cell proliferation • transdifferentiation • atrial septum morphogenesis • cell migration involved in coronary vasculogenesis • positive regulation of secondary heart field cardioblast proliferation • regulation of execution phase of apoptosis Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	6910	21388
Ensembl	ENSG00000089225	ENSMUSG00000018263
UniProt	Q99593	P70326
RefSeq (mRNA)	NM_000192	NM_011537
RefSeq (protein)	NP_000183	NP_035667
Location (UCSC)	Chr 12: 114.35 – 114.41 Mb	Chr 5: 119.83 – 119.89 Mb
PubMed search

T-box transcription factor TBX5 is a protein that in humans is encoded by the TBX5 gene.^[1][2][3]

This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene is closely linked to related family member T-box 3 (ulnar mammary syndrome) on human chromosome 12.

Function

The encoded protein may play a role in heart development and specification of limb identity. Mutations in this gene have been associated with Holt-Oram syndrome, a developmental disorder affecting the heart and upper limbs. Skeletally there may be abnormally bent fingers, sloping shoulders, and phocomelia. Cardiac defects include ventral and atrial septation and problems with the conduction system.^[4] Several transcript variants encoding different isoforms have been described for this gene.^[3]

Clinical significance

In studies done in mutant mice without the TBX5 gene it has been shown that the homozygous mice did not survive gestation due to the heart not developing past E9.5. Also the heterozygous mice were born with morphological problems such as enlarged hearts, atrial and ventral septum defects, and limb malformations similar to those found in the Holt-Oram Syndrome.^[5] Supporting the essential role of TBX5 in the heart development.

Interactions

TBX5 (gene) has been shown to interact with:

• GATA4^[6] and
• NKX2-5.^[6][7]

Other Information

Tbx5 is a gene that is located on the long arm of chromosome 12.^[8] Tbx5 produces a protein called T-box 5 that acts as a transcription factor.^[9] The Tbx5 gene is involved with forelimb and heart development. This gene impacts the early development of the forelimb by triggering FGF-10 (Fibroblast Growth Factor 10).^[10] Tbx5 is involved with the development of the four chambers in the heart, the electrical conducting system, and the septum separating the right and left sides of the heart.^[11] A mutation in this gene can cause Holt-Oram syndrome or Amelia syndrome. Holt-Oram syndrome can cause several different defects. One effect of Holt-Oram syndrome is a hole in the septum.^[12] Another symptom of this syndrome is bone abnormalities in the fingers, wrists, or arms.^[13] An additional defect that Holt-Oram syndrome can cause is a conduction disease leading to abnormal heart rates and arrhythmias.^[14] Amelia syndrome is a condition where forelimb malformation occurs because FGF-10 is not triggered due to Tbx5 mutations.^[15] This condition can lead to the absence of one or both forelimbs.

References

1. Basson CT, Bachinsky DR, Lin RC, Levi T, Elkins JA, Soults J, Grayzel D, Kroumpouzou E, Traill TA, Leblanc-Straceski J, Renault B, Kucherlapati R, Seidman JG, Seidman CE (January 1997). "Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome". Nat Genet 15 (1): 30–5. doi:10.1038/ng0197-30. PMID 8988165.
2. Terrett JA, Newbury-Ecob R, Cross GS, Fenton I, Raeburn JA, Young ID, Brook JD (September 1994). "Holt-Oram syndrome is a genetically heterogeneous disease with one locus mapping to human chromosome 12q". Nat Genet 6 (4): 401–4. doi:10.1038/ng0494-401. PMID 8054982.
3. "Entrez Gene: TBX5 T-box 5".
4. Packham EA, Brook JD (2003). "T-box genes in human disorders". Hum. Mol. Genet. 12 (Spec No 1): R37–44. doi:10.1093/hmg/ddg077. PMID 12668595.
5. Takeuchi JK, Ohgi M, Koshiba-Takeuchi K, Shiratori H, Sakaki I, Ogura K, Saijoh Y, Ogura T (2003). "Tbx5 specifies the left/right ventricles and ventricular septum position during cardiogenesis". Development 130 (24): 5953–64. doi:10.1242/dev.00797. PMID 14573514.
6. Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, Rothrock CR, Eapen RS, Hirayama-Yamada K, Joo K, Matsuoka R, Cohen JC, Srivastava D (July 2003). "GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5". Nature 424 (6947): 443–7. doi:10.1038/nature01827. PMID 12845333.
7. Hiroi Y, Kudoh S, Monzen K, Ikeda Y, Yazaki Y, Nagai R, Komuro I (July 2001). "Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation". Nat. Genet. 28 (3): 276–80. doi:10.1038/90123. PMID 11431700.
8. Patel, C., Silcock, L., Mcmullan, D., Brueton, L., & Cox, H (15 February 2012). "TBX5 intragenic duplication: a family with an atypical Holt–Oram syndrome phenotype". European Journal of Human Genetics 20 (8): 863–869. doi:10.1038/ejhg.2012.16.
9. Jhang, W. K., Lee, B. H., Kim, G., Lee, J., & Yoo, H. "Clinical and molecular characterisation of Holt–Oram syndrome focusing on cardiac manifestations". Cardiology in the Young 25 (6): 1093–1098. doi:10.1017/s1047951114001656.
10. Nishimoto, S., Wilde, S., Wood, S., & Logan, M. (2015). "RA Acts in a Coherent Feed-Forward Mechanism with Tbx5 to Control Limb Bud Induction and Initiation". Cell Reports 12 (5): 879–891. doi:10.1016/j.celrep.2015.06.068.
11. Boogerd CJ, Evans SM (8 February 2016). "TBX5 and NuRD Divide the Heart". Developmental Cell 36 (3): 242–244. doi:10.1016/j.devcel.2016.01.015. PMID 26859347.
12. Jhang, W. K., Lee, B. H., Kim, G., Lee, J., & Yoo, H. "Clinical and molecular characterisation of Holt–Oram syndrome focusing on cardiac manifestations". Cardiology in the Young 25 (6): 1093–1098. doi:10.1017/s1047951114001656.
13. Pizard, A., Burgon, P. G., Paul, D. L., Bruneau, B. G., Seidman, C. E., & Seidman, J. G. (2005). "Connexin 40, a Target of Transcription Factor Tbx5, Patterns Wrist, Digits, and Sternum". Molecular and Cellular Biology 25 (12): 5073–5083. doi:10.1128/mcb.25.12.5073-5083.2005.
14. Patel, C., Silcock, L., Mcmullan, D., Brueton, L., & Cox, H (15 February 2012). "TBX5 intragenic duplication: a family with an atypical Holt–Oram syndrome phenotype". European Journal of Human Genetics 20 (8): 863–869. doi:10.1038/ejhg.2012.16.
15. Niemann, Stephan, MD (28 August 2007). "Tetra-Amelia Syndrome". Gene Reviews. PMID 20301453.

Further reading

• Simon H (1999). "T-box genes and the formation of vertebrate forelimb- and hindlimb specific pattern". Cell Tissue Res. 296 (1): 57–66. doi:10.1007/s004410051266. PMID 10199965.
• Packham EA, Brook JD (2003). "T-box genes in human disorders". Hum. Mol. Genet. 12 (Spec No 1): R37–44. doi:10.1093/hmg/ddg077. PMID 12668595.
• Li QY, Newbury-Ecob RA, Terrett JA, et al. (1997). "Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family". Nat. Genet. 15 (1): 21–9. doi:10.1038/ng0197-21. PMID 8988164.
• Basson CT, Huang T, Lin RC, et al. (1999). "Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations". Proc. Natl. Acad. Sci. U.S.A. 96 (6): 2919–24. doi:10.1073/pnas.96.6.2919. PMC: 15870. PMID 10077612.
• Yang J, Hu D, Xia J, et al. (2000). "Three novel TBX5 mutations in Chinese patients with Holt-Oram syndrome". Am. J. Med. Genet. 92 (4): 237–40. doi:10.1002/(SICI)1096-8628(20000605)92:4<237::AID-AJMG2>3.0.CO;2-G. PMID 10842287.
• Hatcher CJ, Goldstein MM, Mah CS, et al. (2000). "Identification and localization of TBX5 transcription factor during human cardiac morphogenesis". Dev. Dyn. 219 (1): 90–5. doi:10.1002/1097-0177(200009)219:1<90::AID-DVDY1033>3.0.CO;2-L. PMID 10974675.
• Hatcher CJ, Kim MS, Mah CS, et al. (2001). "TBX5 transcription factor regulates cell proliferation during cardiogenesis". Dev. Biol. 230 (2): 177–88. doi:10.1006/dbio.2000.0134. PMID 11161571.
• Cross SJ, Ching YH, Li QY, et al. (2001). "The mutation spectrum in Holt-Oram syndrome". J. Med. Genet. 37 (10): 785–7. doi:10.1136/jmg.37.10.785. PMC: 1757164. PMID 11183182.
• Hiroi Y, Kudoh S, Monzen K, et al. (2001). "Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation". Nat. Genet. 28 (3): 276–80. doi:10.1038/90123. PMID 11431700.
• Akrami SM, Winter RM, Brook JD, Armour JA (2002). "Detection of a large TBX5 deletion in a family with Holt-Oram syndrome". J. Med. Genet. 38 (12): E44. doi:10.1136/jmg.38.12.e44. PMC: 1734777. PMID 11748310.
• He ML, Chen Y, Peng Y, et al. (2002). "Induction of apoptosis and inhibition of cell growth by developmental regulator hTBX5". Biochem. Biophys. Res. Commun. 297 (2): 185–92. doi:10.1016/S0006-291X(02)02142-3. PMID 12237100.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC: 139241. PMID 12477932.
• Fan C, Liu M, Wang Q (2003). "Functional analysis of TBX5 missense mutations associated with Holt-Oram syndrome". J. Biol. Chem. 278 (10): 8780–5. doi:10.1074/jbc.M208120200. PMC: 1579789. PMID 12499378.
• Garg V, Kathiriya IS, Barnes R, et al. (2003). "GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5". Nature 424 (6947): 443–7. doi:10.1038/nature01827. PMID 12845333.
• Huang T, Lock JE, Marshall AC, et al. (2003). "Causes of clinical diversity in human TBX5 mutations". Cold Spring Harb. Symp. Quant. Biol. 67: 115–20. doi:10.1101/sqb.2002.67.115. PMID 12858531.
• Collavoli A, Hatcher CJ, He J, et al. (2004). "TBX5 nuclear localization is mediated by dual cooperative intramolecular signals". J. Mol. Cell. Cardiol. 35 (10): 1191–5. doi:10.1016/S0022-2828(03)00231-1. PMID 14519429.

External links

• GeneReviews/NCBI/NIH/UW entry on Holt-Oram Syndrome
• TBX5 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)