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Gene Review

TBX3  -  T-box 3

Homo sapiens

Synonyms: T-box protein 3, T-box transcription factor TBX3, TBX3-ISO, UMS, XHL
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Disease relevance of TBX3

  • Several disease-implicated regulators of p19(ARF) are known to date, among which are the T-box genes TBX2, which resides on an amplicon in primary breast tumors, and TBX3, which is mutated in the human developmental disorder Ulnar-Mammary syndrome [1].
  • This observation may establish a link between the congenital heart defects and the TBX3 mutation in this family [2].
  • The occurrence of UMS in a human cell line derived from a carcinoma of the lung and in a transplantable chicken hepatoma derived from an MC-29 virus-induced liver tumour is described [3].

Psychiatry related information on TBX3


High impact information on TBX3

  • We suggest that during the evolution of TBX3 and TBX5 from a common ancestral gene, each has acquired specific yet complementary roles in patterning the mammalian upper limb [5].
  • We demonstrate that mutations in human TBX3, a member of the T-box gene family, cause ulnar-mammary syndrome in two families [5].
  • Each mutation (a single nucleotide deletion and a splice-site mutation) is predicted to cause haploinsufficiency of TBX3, implying that critical levels of this transcription factor are required for morphogenesis of several organs [5].
  • Functional dissection of the ET protein reveals a novel transcription-repression domain highly conserved among ET, human TBX3, and TBX2 [6].
  • The spectrum of mutations in TBX3: Genotype/Phenotype relationship in ulnar-mammary syndrome [7].

Biological context of TBX3

  • However, the 3' terminus of the open reading frame (ORF) of TBX3 was not identified, and mutations were detected in only two families with UMS [7].
  • The complete ORF of TBX3 is predicted to encode a 723-residue protein, of which 255 amino acids are encoded by newly identified exons [7].
  • TBX3 and its isoform TBX3+2a are functionally distinctive in inhibition of senescence and are overexpressed in a subset of breast cancer cell lines [8].
  • We found that TBX3 and TBX3 + 2a are widely expressed in humans and mice, and alternative splicing could be tissue specific and species specific [8].
  • TBX3, but not TBX3 + 2a, is able to bind to the previously identified T-box binding site in a gel shift assay [8].

Anatomical context of TBX3

  • It recently was found that TBX3 was able to immortalize mouse embryo fibroblast (MEF) cells [8].
  • A subset of human breast cancer cell lines overexpresses TBX3 [8].
  • Mutations of TBX3 cause ulnar-mammary syndrome (MIM 181450) in humans, an autosomal dominant disorder characterized by the absence or underdevelopment of the mammary glands and other congenital anomalies [8].
  • Spontanteous mutations in the T-box gene TBX3, result in the human ulnar-mammary syndrome, a dominant developmental disorder characterized by abnormal forelimb and apocrine gland development [9].
  • The results are consistent with the previous finding that UMS is caused by haploinsufficiency of TBX3, and imply that mild gonadotropin deficiency may be the primary cause for underdeveloped external genitalia in males with UMS [10].

Associations of TBX3 with chemical compounds

  • Furthermore, Tbx3 injection led to inhibition of molecular markers for the ventral retina including Pax-2 and netrin, indicating that Tbx3 plays an important role in retina dorsal/ventral patterning in vertebrates by inhibition of gene expression for ventral retina specification [11].
  • Measurement of R, in this system, involves the first of two conductivity sensors integrated in a urea monitor (UMS, BelIco-Sorin, Mirandola, Italy), and two saline injections [12].
  • Using a spectrofluorometer with the Zeiss Universal Micro-Spectrophotometer 1 (UMSP 1), both nuclear and kinetoplast DNA (N-DNA and K-DNA) in the trypomastigote form of Trypanosoma gambiense (Strain Wellcome) were measured in situ without being extracted [13].

Physical interactions of TBX3


Other interactions of TBX3

  • It has been shown that human TBX5 and TBX3, if mutated, cause developmental disorders, Holt-Oram syndrome (OMIM 142900) and ulnar-mammary syndrome (OMIM 181450), respectively [15].
  • TBX3, the gene mutated in ulnar-mammary syndrome (UMS), is involved in the production of a transcription factor of the T-box family, known to inhibit transcription from the p14ARF (p19ARF in mouse) promoter in fibroblasts and to contribute to cell immortalization [16].
  • We observed increased expression of truncated cSHMT, Tbx3 and utrophin in plasma samples obtained from patients at early stages of disease [17].
  • Our data suggest a new role for Tbx3 in positioning the limb along the main body axis through a genetic interplay between dHand and Gli3 [18].

Analytical, diagnostic and therapeutic context of TBX3

  • Sequence analysis of the TBX3 gene showed a novel heterozygous nonsense mutation (A817T, K273X) in exon 4 of the three patients [10].
  • The deletion and haploinsufficiency of TBX3 was confirmed by fluorescence in situ hybridization using BAC clones representing the deletion on the BAC array [4].
  • Aberrant expression of proteins was validated by immunoblotting of plasma samples with specific antibodies to cSHMT, Tbx3 and utrophin [17].
  • METHODS: Prospectively, 71 CABG patients were randomly allocated to one of the oxygenator groups (UMS: n=25, BPS: n=25 and BAS: n=21) [19].
  • (4) The ratio of nucleic acids (RNA/DNA) measured by microspectrophotometry (Zeiss UMSP-1) in CSF lymphocytes stained with methylgreen and pyronin was 0.58 +/- 0.12 in 17 specimens from the patients and 0.55 +/- 0.07% in 10 specimens from the control; there was no significant difference between them [20].


  1. The T-box repressors TBX2 and TBX3 specifically regulate the tumor suppressor gene p14ARF via a variant T-site in the initiator. Lingbeek, M.E., Jacobs, J.J., van Lohuizen, M. J. Biol. Chem. (2002) [Pubmed]
  2. Novel TBX3 mutation data in families with Ulnar-Mammary syndrome indicate a genotype-phenotype relationship: mutations that do not disrupt the T-domain are associated with less severe limb defects. Meneghini, V., Odent, S., Platonova, N., Egeo, A., Merlo, G.R. European journal of medical genetics. (2006) [Pubmed]
  3. Undulating membraneous structures associated with the endoplasmic reticulum in tumour cells. Schaff, Z., Lapis, K., Grimley, P.M. Int. J. Cancer (1976) [Pubmed]
  4. Ulnar-mammary syndrome with dysmorphic facies and mental retardation caused by a novel 1.28 Mb deletion encompassing the TBX3 gene. Klopocki, E., Neumann, L.M., T??nnies, H., Ropers, H.H., Mundlos, S., Ullmann, R. Eur. J. Hum. Genet. (2006) [Pubmed]
  5. Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome. Bamshad, M., Lin, R.C., Law, D.J., Watkins, W.C., Krakowiak, P.A., Moore, M.E., Franceschini, P., Lala, R., Holmes, L.B., Gebuhr, T.C., Bruneau, B.G., Schinzel, A., Seidman, J.G., Seidman, C.E., Jorde, L.B. Nat. Genet. (1997) [Pubmed]
  6. Transcription repression by Xenopus ET and its human ortholog TBX3, a gene involved in ulnar-mammary syndrome. He, M., Wen, L., Campbell, C.E., Wu, J.Y., Rao, Y. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  7. The spectrum of mutations in TBX3: Genotype/Phenotype relationship in ulnar-mammary syndrome. Bamshad, M., Le, T., Watkins, W.S., Dixon, M.E., Kramer, B.E., Roeder, A.D., Carey, J.C., Root, S., Schinzel, A., Van Maldergem, L., Gardner, R.J., Lin, R.C., Seidman, C.E., Seidman, J.G., Wallerstein, R., Moran, E., Sutphen, R., Campbell, C.E., Jorde, L.B. Am. J. Hum. Genet. (1999) [Pubmed]
  8. TBX3 and its isoform TBX3+2a are functionally distinctive in inhibition of senescence and are overexpressed in a subset of breast cancer cell lines. Fan, W., Huang, X., Chen, C., Gray, J., Huang, T. Cancer Res. (2004) [Pubmed]
  9. Mammary gland, limb and yolk sac defects in mice lacking Tbx3, the gene mutated in human ulnar mammary syndrome. Davenport, T.G., Jerome-Majewska, L.A., Papaioannou, V.E. Development (2003) [Pubmed]
  10. Novel mutation of TBX3 in a Japanese family with ulnar-mammary syndrome: implication for impaired sex development. Sasaki, G., Ogata, T., Ishii, T., Hasegawa, T., Sato, S., Matsuo, N. Am. J. Med. Genet. (2002) [Pubmed]
  11. Retina dorsal/ventral patterning by Xenopus TBX3. Wong, K., Peng, Y., Kung, H.F., He, M.L. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  12. Direct determination of blood recirculation rate in hemodialysis by a conductivity method. Bosc, J.Y., LeBlanc, M., Garred, L.J., Marc, J.M., Foret, M., Babinet, F., Tetta, C., Canaud, B. ASAIO journal (American Society for Artificial Internal Organs : 1992) (1998) [Pubmed]
  13. In situ microspectrofluorometry of nuclear and kinetoplast DNA in Trypanosoma gambiense. Inoki, S., Osaki, H., Furuya, M. Zentralblatt für Bakteriologie, Parasitenkunde, Infektionskrankheiten und Hygiene. Erste Abteilung Originale. Reihe A: Medizinische Mikrobiologie und Parasitologie. (1979) [Pubmed]
  14. A dominant repression domain in Tbx3 mediates transcriptional repression and cell immortalization: relevance to mutations in Tbx3 that cause ulnar-mammary syndrome. Carlson, H., Ota, S., Campbell, C.E., Hurlin, P.J. Hum. Mol. Genet. (2001) [Pubmed]
  15. Identification, mapping, and phylogenomic analysis of four new human members of the T-box gene family: EOMES, TBX6, TBX18, and TBX19. Yi, C.H., Terrett, J.A., Li, Q.Y., Ellington, K., Packham, E.A., Armstrong-Buisseret, L., McClure, P., Slingsby, T., Brook, J.D. Genomics (1999) [Pubmed]
  16. TBX3, the gene mutated in ulnar-mammary syndrome, promotes growth of mammary epithelial cells via repression of p19ARF, independently of p53. Platonova, N., Scotti, M., Babich, P., Bertoli, G., Mento, E., Meneghini, V., Egeo, A., Zucchi, I., Merlo, G.R. Cell Tissue Res. (2007) [Pubmed]
  17. Increased expression of cSHMT, Tbx3 and utrophin in plasma of ovarian and breast cancer patients. Lomnytska, M., Dubrovska, A., Hellman, U., Volodko, N., Souchelnytskyi, S. Int. J. Cancer (2006) [Pubmed]
  18. Tbx3 can alter limb position along the rostrocaudal axis of the developing embryo. Rallis, C., Del Buono, J., Logan, M.P. Development (2005) [Pubmed]
  19. Reduced complement activation during cardiopulmonary bypass does not affect the postoperative acute phase response. van den Goor, J., Nieuwland, R., van den Brink, A., van Oeveren, W., Rutten, P., Tijssen, J., Eijsman, L. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. (2004) [Pubmed]
  20. Cytological examination of cerebrospinal fluid in eight patients with neuro-Behçet's disease. Nakamura, S., Takase, S., Itahara, K. Tohoku J. Exp. Med. (1980) [Pubmed]
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