TBX5 (gene)

T-box transcription factor TBX5 is a protein that in humans is encoded by the TBX5 gene.[5][6][7]

TBX5
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2X6U, 2X6V, 4S0H, 5BQD
Identifiers
Aliases	TBX5, HOS, T-box 5, T-box transcription factor 5
External IDs	OMIM: 601620 MGI: 102541 HomoloGene: 160 GeneCards: TBX5
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12q24.21 Start 114,353,931 bp[1] End 114,408,442 bp[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)[2] Band 5 F|5 60.42 cM Start 119,832,668 bp[2] End 119,885,219 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • sequence-specific DNA binding • RNA polymerase II regulatory region sequence-specific DNA binding • GO:0001077, GO:0001212, GO:0001213, GO:0001211, GO:0001205 DNA-binding transcription activator activity, RNA polymerase II-specific • transcription factor binding • GO:0001948 protein binding • GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity • DNA binding • GO:0000980 RNA polymerase II cis-regulatory region sequence-specific DNA binding • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component • nucleoplasm • cell nucleus • macromolecular complex • protein-DNA complex • cytoplasm Biological process • pattern specification process • forelimb morphogenesis • ventricular cardiac muscle tissue development • regulation of transcription, DNA-templated • bundle of His development • lung development • endocardial cushion development • cardiac muscle cell differentiation • cell-cell signaling • transcription, DNA-templated • morphogenesis of an epithelium • atrial septum morphogenesis • multicellular organism development • negative regulation of cell migration • positive regulation of cardiac muscle cell proliferation • atrioventricular valve morphogenesis • cell migration involved in coronary vasculogenesis • embryonic limb morphogenesis • pericardium development • positive regulation of cardioblast differentiation • positive regulation of secondary heart field cardioblast proliferation • transcription initiation from RNA polymerase II promoter • negative regulation of cardiac muscle cell proliferation • atrial septum development • embryonic forelimb morphogenesis • negative regulation of epithelial to mesenchymal transition • negative regulation of cell proliferation • cardiac left ventricle formation • ventricular septum development • heart development • positive regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase II promoter Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	6910	21388
Ensembl	ENSG00000089225	ENSMUSG00000018263
UniProt	Q99593	P70326
RefSeq (mRNA)	NM_181486 NM_000192 NM_080717 NM_080718	NM_011537
RefSeq (protein)	NP_000183 NP_542448 NP_852259	NP_035667
Location (UCSC)	Chr 12: 114.35 – 114.41 Mb	Chr 5: 119.83 – 119.89 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.

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.[10] This gene impacts the early development of the forelimb by triggering fibroblast growth factor, FGF10.[11]

Function

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.[12] The Tbx5 gene is a transcription factor that codes for the protein called T-box 5. Along with playing roles in the development of the heart, septum, and electrical system of the heart, it also activates genes that are involved in the development of the upper limbs, the arms and hands. This gene is involved in patterning major aspects of the heart; however, it is also involved in the muscle connective tissue for muscle and tendon patterning. A study showed that deletion of Tbx5 in forelimbs causes disruption in the muscle and tendon patterning without affecting the skeletons development.[13] Tbx5 expression is in the cells of the lateral plate mesoderm which form the forelimb bud and the cascade of limb initiation. In its absence no forelimb bud forms. Diseases and defects associated with this gene are Holt-Oram syndrome, both have to do with limb defects and several other abnormalities. The cardiac defects include defects in the septum dividing the left and right sides of the heart, conduction system abnormalities, and other problems. The exact mechanism that Tbx5 activates gene expression is still being discovered and is actively being understood.

Clinical significance

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.[10][14] Skeletally there may be abnormally bent fingers, sloping shoulders, and phocomelia. Cardiac defects include ventral and atrial septation and problems with the conduction system.[15] Several transcript variants encoding different isoforms have been described for this gene.[7]

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 embryonic day 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.[16] Supporting the essential role of TBX5 in the heart development.

The encoded protein plays a major role in limb development, specifically during limb bud initiation.[17] For instance, in chickens Tbx5 specifies forelimb status.[18] The activation of Tbx5 and other T-box proteins by Hox genes activates signaling cascades that involve the Wnt signaling pathway and FGF signals in limb buds.[17] Ultimately, Tbx5 leads to the development of apical ectodermal ridge (AER) and zone of polarizing activity (ZPA) signaling centers in the developing limb bud, which specify the orientation growth of the developing limb.[17] Together with Tbx4, Tbx5 plays a role in patterning the soft tissues (muscles and tendons) of the musculoskeletal system.[19]

A mutation in this gene can cause Holt-Oram syndrome or Amelia syndrome.[10] Holt-Oram syndrome can cause several different defects. One effect of Holt-Oram syndrome is a hole in the septum.[9] Another symptom of this syndrome is bone abnormalities in the fingers, wrists, or arms.[20] An additional defect that Holt-Oram syndrome can cause is a conduction disease leading to abnormal heart rates and arrhythmias.[8] Amelia syndrome is a condition where forelimb malformation occurs because FGF-10 is not triggered due to Tbx5 mutations.[21] This condition can lead to the absence of one or both forelimbs.

Interactions

TBX5 (gene) has been shown to interact with:

• GATA4[22] and
• NKX2-5.[22][23]

References

1. GRCh38: Ensembl release 89: ENSG00000089225 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000018263 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. 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". Nature Genetics. 15 (1): 30–5. doi:10.1038/ng0197-30. PMID 8988165.
6. Terrett JA, Newbury-Ecob R, Cross GS, Fenton I, Raeburn JA, Young ID, Brook JD (April 1994). "Holt-Oram syndrome is a genetically heterogeneous disease with one locus mapping to human chromosome 12q". Nature Genetics. 6 (4): 401–4. doi:10.1038/ng0494-401. PMID 8054982.
7. "Entrez Gene: TBX5 T-box 5".
8. Patel C, Silcock L, McMullan D, Brueton L, Cox H (August 2012). "TBX5 intragenic duplication: a family with an atypical Holt-Oram syndrome phenotype". European Journal of Human Genetics. 20 (8): 863–9. doi:10.1038/ejhg.2012.16. PMC 3400730. PMID 22333898.
9. Jhang WK, Lee BH, Kim GH, Lee JO, Yoo HW (August 2015). "Clinical and molecular characterisation of Holt-Oram syndrome focusing on cardiac manifestations". Cardiology in the Young. 25 (6): 1093–8. doi:10.1017/s1047951114001656. PMID 25216260.
10. Steimle JD, Moskowitz IP (2017). "TBX5: A Key Regulator of Heart Development". Current Topics in Developmental Biology. 122: 195–221. doi:10.1016/bs.ctdb.2016.08.008. PMC 5371404. PMID 28057264.
11. Nishimoto S, Wilde SM, Wood S, Logan MP (August 2015). "RA Acts in a Coherent Feed-Forward Mechanism with Tbx5 to Control Limb Bud Induction and Initiation". Cell Reports. 12 (5): 879–91. doi:10.1016/j.celrep.2015.06.068. PMC 4553633. PMID 26212321.
12. Boogerd CJ, Evans SM (February 2016). "TBX5 and NuRD Divide the Heart". Developmental Cell. 36 (3): 242–4. doi:10.1016/j.devcel.2016.01.015. PMC 5542051. PMID 26859347.
13. Hasson, Peleg; DeLaurier, April; Bennett, Michael; Grigorieva, Elena; Naiche, L. A.; Papaioannou, Virginia E.; Mohun, Timothy J.; Logan, Malcolm P. O. (19 January 2010). "Tbx4 and Tbx5 Acting in Connective Tissue Are Required for Limb Muscle and Tendon Patterning". Developmental Cell. 18 (1): 148–156. doi:10.1016/j.devcel.2009.11.013. ISSN 1534-5807. PMC 3034643. PMID 20152185.
14. Virdis G, Dessole M, Dessole S, Ambrosini G, Cosmi E, Cherchil PL, Capobianco G (2016). "Holt Oram syndrome: a case report and review of the literature". Clinical and Experimental Obstetrics & Gynecology. 43 (1): 137–9. PMID 27048037.
15. Packham EA, Brook JD (April 2003). "T-box genes in human disorders". Human Molecular Genetics. 12 Spec No 1 (Spec No 1): R37-44. doi:10.1093/hmg/ddg077. PMID 12668595.
16. Takeuchi JK, Ohgi M, Koshiba-Takeuchi K, Shiratori H, Sakaki I, Ogura K, Saijoh Y, Ogura T (December 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.
17. Tickle C (October 2015). "How the embryo makes a limb: determination, polarity and identity". Journal of Anatomy. 227 (4): 418–30. doi:10.1111/joa.12361. PMC 4580101. PMID 26249743.
18. Rodriguez-Esteban C, Tsukui T, Yonei S, Magallon J, Tamura K, Izpisua Belmonte JC (April 1999). "The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity". Nature. 398 (6730): 814–8. Bibcode:1999Natur.398..814R. doi:10.1038/19769. PMID 10235264.
19. Hasson P, DeLaurier A, Bennett M, Grigorieva E, Naiche LA, Papaioannou VE, Mohun TJ, Logan MP (January 2010). "Tbx4 and tbx5 acting in connective tissue are required for limb muscle and tendon patterning". Developmental Cell. 18 (1): 148–56. doi:10.1016/j.devcel.2009.11.013. PMC 3034643. PMID 20152185.
20. Pizard A, Burgon PG, Paul DL, Bruneau BG, Seidman CE, Seidman JG (June 2005). "Connexin 40, a target of transcription factor Tbx5, patterns wrist, digits, and sternum". Molecular and Cellular Biology. 25 (12): 5073–83. doi:10.1128/mcb.25.12.5073-5083.2005. PMC 1140596. PMID 15923624.
21. Niemann, Stephan (1993), Tetra-Amelia Syndrome, GeneReviews, University of Washington, Seattle, PMID 20301453
22. 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.
23. 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". Nature Genetics. 28 (3): 276–80. doi:10.1038/90123. PMID 11431700.

[1]

Further reading

• Simon H (April 1999). "T-box genes and the formation of vertebrate forelimb- and hindlimb specific pattern". Cell and Tissue Research. 296 (1): 57–66. doi:10.1007/s004410051266. PMID 10199965.
• Packham EA, Brook JD (April 2003). "T-box genes in human disorders". Human Molecular Genetics. 12 Spec No 1 (Spec No 1): R37-44. doi:10.1093/hmg/ddg077. PMID 12668595.
• Li QY, Newbury-Ecob RA, Terrett JA, Wilson DI, Curtis AR, Yi CH, Gebuhr T, Bullen PJ, Robson SC, Strachan T, Bonnet D, Lyonnet S, Young ID, Raeburn JA, Buckler AJ, Law DJ, Brook JD (January 1997). "Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family". Nature Genetics. 15 (1): 21–9. doi:10.1038/ng0197-21. PMID 8988164.
• Basson CT, Huang T, Lin RC, Bachinsky DR, Weremowicz S, Vaglio A, Bruzzone R, Quadrelli R, Lerone M, Romeo G, Silengo M, Pereira A, Krieger J, Mesquita SF, Kamisago M, Morton CC, Pierpont ME, Müller CW, Seidman JG, Seidman CE (March 1999). "Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations". Proceedings of the National Academy of Sciences of the United States of America. 96 (6): 2919–24. doi:10.1073/pnas.96.6.2919. PMC 15870. PMID 10077612.
• Yang J, Hu D, Xia J, Yang Y, Ying B, Hu J, Zhou X (June 2000). "Three novel TBX5 mutations in Chinese patients with Holt-Oram syndrome". American Journal of Medical Genetics. 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, Delia CS, Basson CT (September 2000). "Identification and localization of TBX5 transcription factor during human cardiac morphogenesis". Developmental Dynamics. 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, Goldstein MM, Wong B, Mikawa T, Basson CT (February 2001). "TBX5 transcription factor regulates cell proliferation during cardiogenesis". Developmental Biology. 230 (2): 177–88. doi:10.1006/dbio.2000.0134. PMID 11161571.
• Cross SJ, Ching YH, Li QY, Armstrong-Buisseret L, Spranger S, Lyonnet S, Bonnet D, Penttinen M, Jonveaux P, Leheup B, Mortier G, Van Ravenswaaij C, Gardiner CA (October 2000). "The mutation spectrum in Holt-Oram syndrome". Journal of Medical Genetics. 37 (10): 785–7. doi:10.1136/jmg.37.10.785. PMC 1757164. PMID 11183182.
• 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". Nature Genetics. 28 (3): 276–80. doi:10.1038/90123. PMID 11431700.
• Akrami SM, Winter RM, Brook JD, Armour JA (December 2001). "Detection of a large TBX5 deletion in a family with Holt-Oram syndrome". Journal of Medical Genetics. 38 (12): E44. doi:10.1136/jmg.38.12.e44. PMC 1734777. PMID 11748310.
• He ML, Chen Y, Peng Y, Jin D, Du D, Wu J, Lu P, Lin MC, Kung HF (September 2002). "Induction of apoptosis and inhibition of cell growth by developmental regulator hTBX5". Biochemical and Biophysical Research Communications. 297 (2): 185–92. doi:10.1016/S0006-291X(02)02142-3. PMID 12237100.
• Fan C, Liu M, Wang Q (March 2003). "Functional analysis of TBX5 missense mutations associated with Holt-Oram syndrome". The Journal of Biological Chemistry. 278 (10): 8780–5. doi:10.1074/jbc.M208120200. PMC 1579789. PMID 12499378.
• 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.
• Huang T, Lock JE, Marshall AC, Basson C, Seidman JG, Seidman CE (2003). "Causes of clinical diversity in human TBX5 mutations". Cold Spring Harbor Symposia on Quantitative Biology. 67: 115–20. doi:10.1101/sqb.2002.67.115. PMID 12858531.
• Collavoli A, Hatcher CJ, He J, Okin D, Deo R, Basson CT (October 2003). "TBX5 nuclear localization is mediated by dual cooperative intramolecular signals". Journal of Molecular and Cellular Cardiology. 35 (10): 1191–5. doi:10.1016/S0022-2828(03)00231-1. PMID 14519429.
• Steimle JD, Moskowitz IP (2017). "TBX5: A Key Regulator of Heart Development". Curr Top Dev Biol. 122: 195–221. doi:10.1016/bs.ctdb.2016.08.008. PMC 5371404. PMID 28057264.

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)

1. Reference, Genetics Home (2010). "TBX5 gene". Genetics Home Reference. 18: 148–56. doi:10.1016/j.devcel.2009.11.013. PMC 3034643. PMID 20152185. Retrieved 13 April 2020.