T-box transcription factor TBX5 is a protein that in humans is encoded by the TBX5gene.[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[clarification needed] 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.[4] Tbx5 produces a protein called T-box 5 that acts as a transcription factor.[5] The Tbx5 gene is involved with forelimb and heart development.[6] This gene impacts the early development of the forelimb by triggering fibroblast growth factor, FGF10.[7]
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.[8]
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.[6][9] Skeletally there may be abnormally bent fingers, sloping shoulders, and phocomelia. Cardiac defects include ventral and atrial septation and problems with the conduction system.[10] Several transcript variants encoding different isoforms have been described for this gene.[3]
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.[11] 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.[12] For instance, in chickens Tbx5 specifies forelimb status.[13] 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.[12] 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.[12] Together with Tbx4, Tbx5 plays a role in patterning the soft tissues (muscles and tendons) of the musculoskeletal system.[14]
A mutation in this gene can cause Holt-Oram syndrome or Amelia syndrome.[6] Holt-Oram syndrome can cause several different defects. One effect of Holt-Oram syndrome is a hole in the septum.[15] Another symptom of this syndrome is bone abnormalities in the fingers, wrists, or arms.[16] An additional defect that Holt-Oram syndrome can cause is a conduction disease leading to abnormal heart rates and arrhythmias.[17] Amelia syndrome is a condition where forelimb malformation occurs because FGF-10 is not triggered due to Tbx5 mutations.[18] This condition can lead to the absence of one or both forelimbs.
↑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. PMID8988165.
↑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. PMID8054982.
↑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. PMID25216260.
↑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. PMID27048037.
↑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. PMID12668595.
↑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. PMID14573514.
↑ 12.012.112.2Tickle 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. PMID26249743.
↑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. PMID25216260.
↑"Tetra-Amelia Syndrome". Gene Reviews. 28 August 2007. PMID20301453.
↑ 19.019.1Garg 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. PMID12845333.
↑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. PMID11431700.
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. PMID10199965.
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. PMID12668595.
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. PMID8988164.
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. PMID12237100.
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. PMID12845333.
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. PMID12858531.
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. PMID14519429.