TBX5 (gene)
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Location (UCSC) | Chr 12: 114.35 – 114.41 Mb | Chr 5: 119.97 – 120.02 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
T-box transcription factor TBX5, (T-box protein 5) is a protein that in humans is encoded by the TBX5 gene.[5][6][7] Abnormalities in the TBX5 gene can result in altered limb development, Holt-Oram syndrome, Tetra-amelia syndrome, and cardiac and skeletal problems.
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 located on the long arm of chromosome 12.[8] TBX5 produces a protein called T-box protein 5 that acts as a transcription factor.[9] TBX5 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 a transcription factor that codes for the protein called T-box 5. The transcription factors it encodes are necessary for development, especially in the pattern formation of upper limbs and cardiac growth.
This gene 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 skeleton's development.[14] T-box protein 5 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.
The encoded protein plays a major role in
As a protein-coding gene, TBX5 encodes for the protein T-box Transcription Factor 5, which is a part of the T-box family of transcription factors. It also interacts with other genes, such as GATA4 and NKX2-5, and the BAF chromatin-remodeling complex to drive and repress gene expression during development.[18]
Role in non-human animals
Mice that were genetically modified to not have the TBX5 gene did not survive gestation, due to the heart not developing past embryonic day E10.5. Mice that only had one working copy of TBX5 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.[19]
Pigeons with feathered feet have Tbx5 active in the hind feet, which cause them to develop feathered hindlimbs with thicker bones, more similar to their frontlimb wings.[20][21]
Role in human embyronic development
A gene "knockout" model for TBX5 by CRISPR/Cas9 genome editing has been created.[22] This homozygous TBX5 knockout human embryonic stem cell line, called TBX5-KO maintained stem cell-like morphology, pluripotency markers, normal karyotype, and could differentiate into all three germ layers in vivo. This cell line can provide an in vitro platform for studying the pathogenic mechanisms and biological function of TBX5 in the heart development.[22] By understanding what happens in development without this gene, further treatment options for fetuses with a TBX5 mutation might be possible to prevent the severe cardiac defects associated with Holt-Oram Syndrome.
Clinical significance
Mutations in this gene can result in Holt–Oram syndrome, a developmental disorder affecting the heart and upper limbs.[23][10] Holt-Oram syndrome can cause a hole in the septum,[9] bone abnormalities in the fingers, wrists, or arms,[24] and a conduction disease leading to abnormal heart rates and arrhythmias.[8] The most common cardiac issue associated with this condition is the malformation of the septum, which separates the left and right sides of the heart.[25]
Tetra-amelia syndrome is a condition where forelimb malformation occurs because FGF-10 is not triggered due to Tbx5 mutations.[26] This condition can lead to the absence of one or both forelimbs.
Skeletally, there may be abnormally bent fingers, sloping shoulders, and phocomelia. Cardiac defects include ventral and atrial septation and problems with the conduction system.[27] Several transcript variants encoding different isoforms have been described for this gene.[7]
Interactions
TBX5 (gene) has been shown to
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000089225 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000018263 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- S2CID 30763654.
- S2CID 30213.
- ^ a b "Entrez Gene: TBX5 T-box 5".
- ^ PMID 22333898.
- ^ S2CID 43846874.
- ^ PMID 28057264.
- PMID 26212321.
- ^ "TBX5 t-Box Transcription Factor 5 [Homo Sapiens (Human)] - Gene - NCBI". National Center for Biotechnology Information. U.S. National Library of Medicine.
- PMID 26859347.
- PMID 20152185.
- ^ PMID 26249743.
- S2CID 4330287.
- PMID 20152185.
- PMID 28057264.
- S2CID 209238.
- PMID 31247188.
- ^ "Pigeon foot feather genes identified | UNews". unews.utah.edu. Retrieved 28 May 2023.
- ^ S2CID 231753691.
- S2CID 11803484.
- PMID 15923624.
- ^ "Holt-Oram Syndrome". Medlineplus Genetics. U.S. National Library of Medicine. 18 August 2020.
- PMID 20301453
- PMID 12668595.
- ^ S2CID 4304709.
- S2CID 13250085.
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. S2CID 44834807.
- Packham EA, Brook JD (April 2003). "T-box genes in human disorders". Human Molecular Genetics. 12 Spec No 1 (Spec No 1): R37–R44. PMID 12668595.
- Li QY, Newbury-Ecob RA, Terrett JA, Wilson DI, Curtis AR, Yi CH, et al. (January 1997). "Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family". Nature Genetics. 15 (1): 21–29. S2CID 22619598.
- Basson CT, Huang T, Lin RC, Bachinsky DR, Weremowicz S, Vaglio A, et al. (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): 2919–2924. 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): 237–240. 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): 90–95. S2CID 21081225.
- 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): 177–188. PMID 11161571.
- Cross SJ, Ching YH, Li QY, Armstrong-Buisseret L, Spranger S, Lyonnet S, et al. (October 2000). "The mutation spectrum in Holt-Oram syndrome". Journal of Medical Genetics. 37 (10): 785–787. 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): 276–280. S2CID 13250085.
- 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): 44e–44. PMID 11748310.
- He ML, Chen Y, Peng Y, Jin D, Du D, Wu J, et al. (September 2002). "Induction of apoptosis and inhibition of cell growth by developmental regulator hTBX5". Biochemical and Biophysical Research Communications. 297 (2): 185–192. 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): 8780–8785. PMID 12499378.
- Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, et al. (July 2003). "GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5". Nature. 424 (6947): 443–447. S2CID 4304709.
- 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: 115–120. 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): 1191–1195. PMID 14519429.
- Steimle JD, Moskowitz IP (2017). "TBX5: A Key Regulator of Heart Development". Current Topics in Developmental Biology. 122: 195–221. PMID 28057264.
External links
- GeneReviews/NCBI/NIH/UW entry on Holt-Oram Syndrome
- TBX5+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)