TBX5 (gene)

Last updated
TBX5
Protein TBX5 PDB 2X6U.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases TBX5 , HOS, T-box 5, T-box transcription factor 5
External IDs OMIM: 601620 MGI: 102541 HomoloGene: 160 GeneCards: TBX5
Orthologs
SpeciesHumanMouse
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: 119.97 – 120.02 Mb
PubMed search [3] [4]
Wikidata
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.

Contents

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. [12] TBX5 is involved with the development of the four heart chambers, the electrical conducting system, and the septum separating the right and left sides of the heart. [13] 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 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 limb development, specifically during limb bud initiation. [15] For instance, in chickens Tbx5 specifies forelimb status. [16] 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. [15] 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. [15] Together with Tbx4, Tbx5 plays a role in patterning the soft tissues (muscles and tendons) of the musculoskeletal system. [17]

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 interact with:

Related Research Articles

<span class="mw-page-title-main">TBX1</span> Protein-coding gene in the species Homo sapiens

T-box transcription factor TBX1 also known as T-box protein 1 and testis-specific T-box protein is a protein that in humans is encoded by the TBX1 gene. Genes in the T-box family are transcription factors that play important roles in the formation of tissues and organs during embryonic development. To carry out these roles, proteins made by this gene family bind to specific areas of DNA called T-box binding element (TBE) to control the expression of target genes.

<span class="mw-page-title-main">PAX3</span> Paired box gene 3

The PAX3 gene encodes a member of the paired box or PAX family of transcription factors. The PAX family consists of nine human (PAX1-PAX9) and nine mouse (Pax1-Pax9) members arranged into four subfamilies. Human PAX3 and mouse Pax3 are present in a subfamily along with the highly homologous human PAX7 and mouse Pax7 genes. The human PAX3 gene is located in the 2q36.1 chromosomal region, and contains 10 exons within a 100 kb region.

<span class="mw-page-title-main">Holt–Oram syndrome</span> Medical condition

Holt–Oram syndrome is an autosomal dominant disorder that affects bones in the arms and hands and often causes heart problems. The syndrome may include an absent radial bone in the forearm, an atrial septal defect in the heart, or heart block. It affects approximately 1 in 100,000 people.

<span class="mw-page-title-main">Limb development</span>

Limb development in vertebrates is an area of active research in both developmental and evolutionary biology, with much of the latter work focused on the transition from fin to limb.

<span class="mw-page-title-main">T-box</span> Genes that affect limb and heart development

T-box refers to a group of transcription factors involved in embryonic limb and heart development. Every T-box protein has a relatively large DNA-binding domain, generally comprising about a third of the entire protein that is both necessary and sufficient for sequence-specific DNA binding. All members of the T-box gene family bind to the "T-box", a DNA consensus sequence of TCACACCT.

<span class="mw-page-title-main">PITX2</span> Protein-coding gene in the species Homo sapiens

Paired-like homeodomain transcription factor 2 also known as pituitary homeobox 2 is a protein that in humans is encoded by the PITX2 gene.

<span class="mw-page-title-main">Forkhead box C1</span> Protein-coding gene in the species Homo sapiens

Forkhead box C1, also known as FOXC1, is a protein which in humans is encoded by the FOXC1 gene.

<span class="mw-page-title-main">Homeobox protein Nkx-2.5</span> Protein-coding gene in humans

Homeobox protein Nkx-2.5 is a protein that in humans is encoded by the NKX2-5 gene.

<span class="mw-page-title-main">FOXL2</span> Transcription factor gene of the FOX family

Forkhead box protein L2 is a protein that in humans is encoded by the FOXL2 gene.

<span class="mw-page-title-main">PAX9</span> Protein-coding gene in humans

Paired box gene 9, also known as PAX9, is a protein which in humans is encoded by the PAX9 gene. It is also found in other mammals.

<span class="mw-page-title-main">TBX3</span> Protein-coding gene in the species Homo sapiens

T-box transcription factor TBX3 is a protein that in humans is encoded by the TBX3 gene.

<span class="mw-page-title-main">HEY2</span> Protein-coding gene in the species Homo sapiens

Hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2) also known as cardiovascular helix-loop-helix factor 1 (CHF1) is a protein that in humans is encoded by the HEY2 gene.

<span class="mw-page-title-main">SALL4</span> Protein-coding gene in the species Homo sapiens

Sal-like protein 4(SALL4) is a transcription factor encoded by a member of the Spalt-like (SALL) gene family, SALL4. The SALL genes were identified based on their sequence homology to Spalt, which is a homeotic gene originally cloned in Drosophila melanogaster that is important for terminal trunk structure formation in embryogenesis and imaginal disc development in the larval stages. There are four human SALL proteins with structural homology and playing diverse roles in embryonic development, kidney function, and cancer. The SALL4 gene encodes at least three isoforms, termed A, B, and C, through alternative splicing, with the A and B forms being the most studied. SALL4 can alter gene expression changes through its interaction with many co-factors and epigenetic complexes. It is also known as a key embryonic stem cell (ESC) factor.

<span class="mw-page-title-main">TBX2</span> Protein-coding gene in the species Homo sapiens

T-box transcription factor 2 Tbx2 is a transcription factor that is encoded by the Tbx2 gene on chromosome 17q21-22 in humans. This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. Tbx2 and Tbx3 are the only T-box transcription factors that act as transcriptional repressors rather than transcriptional activators, and are closely related in terms of development and tumorigenesis. This gene plays a significant role in embryonic and fetal development through control of gene expression, and also has implications in various cancers. Tbx2 is associated with numerous signaling pathways, BMP, TGFβ, Wnt, and FGF, which allow for patterning and proliferation during organogenesis in fetal development.

<span class="mw-page-title-main">HAND1</span> Protein-coding gene in the species Homo sapiens

Heart- and neural crest derivatives-expressed protein 1 is a protein that in humans is encoded by the HAND1 gene.

<span class="mw-page-title-main">OSR1</span> Protein-coding gene in the species Homo sapiens

Protein odd-skipped-related 1 is a transcription factor that in humans is encoded by the OSR1 gene. The OSR1 and OSR2 transcription factors participate in the normal development of body parts such as the kidney.

<span class="mw-page-title-main">TBX22</span> Protein-coding gene in the species Homo sapiens

T-box transcription factor TBX22 is a protein that in humans is encoded by the TBX22 gene.

<span class="mw-page-title-main">SOX14</span> Protein-coding gene in the species Homo sapiens

Transcription factor SOX-14 is a protein that in humans is encoded by the SOX14 gene.

T-box transcription factor Tbx4 is a transcription factor that belongs to T-box gene family that is involved in the regulation of embryonic developmental processes. The transcription factor is encoded by the TBX4 gene located on human chromosome 17. Tbx4 is known mostly for its role in the development of the hindlimb, but it also plays a critical role in the formation of the umbilicus. Tbx4 has been shown to be expressed in the allantois, hindlimb, lung and proctodeum.

<span class="mw-page-title-main">TBX15</span> Human protein and coding gene

T-box transcription factor TBX15 is protein that is encoded in humans by the Tbx15 gene, mapped to Chromosome 3 in mice and Chromosome 1 in humans. Tbx15 is a transcription factor that plays a key role in embryonic development. Like other members of the T-box subfamily, Tbx15 is expressed in the notochord and primitive streak, where it assists with the formation and differentiation of the mesoderm. It is steadily downregulated after segmentation of the paraxial mesoderm.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000089225 - Ensembl, May 2017
  2. 1 2 3 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, et al. (January 1997). "Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome". Nature Genetics. 15 (1): 30–35. doi:10.1038/ng0197-30. PMID   8988165. S2CID   30763654.
  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): 401–404. doi:10.1038/ng0494-401. PMID   8054982. S2CID   30213.
  7. 1 2 "Entrez Gene: TBX5 T-box 5".
  8. 1 2 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): 863–869. doi:10.1038/ejhg.2012.16. PMC   3400730 . PMID   22333898.
  9. 1 2 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): 1093–1098. doi:10.1017/s1047951114001656. PMID   25216260. S2CID   43846874.
  10. 1 2 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): 879–891. doi:10.1016/j.celrep.2015.06.068. PMC   4553633 . PMID   26212321.
  12. ↑ "TBX5 t-Box Transcription Factor 5 [Homo Sapiens (Human)] - Gene - NCBI". National Center for Biotechnology Information. U.S. National Library of Medicine.
  13. ↑ Boogerd CJ, Evans SM (February 2016). "TBX5 and NuRD Divide the Heart". Developmental Cell. 36 (3): 242–244. doi:10.1016/j.devcel.2016.01.015. PMC   5542051 . PMID   26859347.
  14. ↑ Hasson P, DeLaurier A, Bennett M, Grigorieva E, Naiche LA, Papaioannou VE, et al. (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 . PMC   3034643 . PMID   20152185.
  15. 1 2 3 Tickle C (October 2015). "How the embryo makes a limb: determination, polarity and identity". Journal of Anatomy. 227 (4): 418–430. doi:10.1111/joa.12361. PMC   4580101 . PMID   26249743.
  16. ↑ 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): 814–818. Bibcode:1999Natur.398..814R. doi:10.1038/19769. PMID   10235264. S2CID   4330287.
  17. ↑ Hasson P, DeLaurier A, Bennett M, Grigorieva E, Naiche LA, Papaioannou VE, et al. (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. PMC   3034643 . PMID   20152185.
  18. ↑ 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.
  19. ↑ Takeuchi JK, Ohgi M, Koshiba-Takeuchi K, Shiratori H, Sakaki I, Ogura K, et al. (December 2003). "Tbx5 specifies the left/right ventricles and ventricular septum position during cardiogenesis". Development. 130 (24): 5953–5964. doi:10.1242/dev.00797. PMID   14573514. S2CID   209238.
  20. ↑ Boer EF, Van Hollebeke HF, Park S, Infante CR, Menke DB, Shapiro MD (October 2019). "Pigeon foot feathering reveals conserved limb identity networks". Developmental Biology. 454 (2): 128–144. doi:10.1016/j.ydbio.2019.06.015. PMC   6726567 . PMID   31247188.
  21. ↑ "Pigeon foot feather genes identified | UNews". unews.utah.edu. Retrieved 28 May 2023.
  22. 1 2 Zhao T, Bai R, Wu F, Lu WJ, Zhang J (March 2021). "Generation of a TBX5 homozygous knockout embryonic stem cell line (WAe009-A-45) by CRISPR/Cas9 genome editing". Stem Cell Research. 51: 102156. doi: 10.1016/j.scr.2021.102156 . PMID   33497883. S2CID   231753691.
  23. ↑ 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): 137–139. doi: 10.12891/ceog3060.2016 . PMID   27048037. S2CID   11803484.
  24. ↑ 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): 5073–5083. doi:10.1128/mcb.25.12.5073-5083.2005. PMC   1140596 . PMID   15923624.
  25. ↑ "Holt-Oram Syndrome". Medlineplus Genetics. U.S. National Library of Medicine. 18 August 2020.
  26. ↑ Niemann S (1993), "Tetra-Amelia Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY", Tetra-Amelia Syndrome, GeneReviews, University of Washington, Seattle, PMID   20301453
  27. ↑ Packham EA, Brook JD (April 2003). "T-box genes in human disorders". Human Molecular Genetics. 12 Spec No 1 (Spec No 1): R37–R44. doi: 10.1093/hmg/ddg077 . PMID   12668595.
  28. 1 2 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. Bibcode:2003Natur.424..443G. doi:10.1038/nature01827. PMID   12845333. S2CID   4304709.
  29. ↑ 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. doi:10.1038/90123. PMID   11431700. S2CID   13250085.

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