Alternative titles; symbols
HGNC Approved Gene Symbol: TBXT
Cytogenetic location: 6q27 Genomic coordinates (GRCh38): 6:166,157,656-166,168,655 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q27 | {Neural tube defects, susceptibility to} | 182940 | Autosomal dominant | 3 |
| Sacral agenesis with vertebral anomalies | 615709 | Autosomal recessive | 3 |
T protein is vital for the formation and differentiation of posterior mesoderm and for axial development in all vertebrates. Edwards et al. (1996) cited as evidence the analysis of T mutant mice and zebrafish. 'Brachyury' mutant mice lack T protein and die in utero with abnormal notochord, absent somites, and reduced allantois. In zebrafish the 'no tail' mutation (ntl) is the homolog of 'Brachyury.' Ntl embryos die after hatching, lack notochords and tails, and possess abnormal trunk somites. The T gene encodes a transcription factor that binds to a specific DNA element via its N-terminal region. A protein motif within the DNA-binding domain, the so-called T box, is highly conserved among T homologs from different species and also defines a broader family of T-box genes; see TBX2 (600747).
Edwards et al. (1996) identified human T genomic clones and derived the mRNA sequence and gene structure. The deduced 435-amino acid human polypeptide shares an overall 91% amino acid identity with mouse T proteins and complete identity across 77 amino acids of the T-box motif within the DNA-binding domain. The authors found that human T expression is very similar to that found for T in other vertebrate species and is confined to cells derived from the notochord.
Using fluorescence in situ hybridization, Edwards et al. (1996) mapped the human T gene to 6q27 at the end of the long arm of chromosome 6. In the mouse, T mapped close to the MHC locus and forms part of the t-complex on mouse chromosome 17. Other human homologs from the mouse t-complex, TCP10 (187020), PLG (173350), IGF2R (147280), TCP1 (186980), THBS2 (188061), and TCTE3 (186977), also map in or close to the tip of 6q. Edwards et al. (1996) referred to genetic analysis using a polymorphism of the human gene to examine the position of the T homolog to some of these markers on 6q27. The authors showed that T lies between TCP1 and TCP10.
Margulies et al. (1982) used recombinant DNA techniques to study the family of genes encoding H-2-like molecules in the mouse. They concluded that there are 10 to 15 H-2-like genes in the murine genome, most of them on chromosome 17, and that at least 3 of these genes map outside the MHC in the Tla region.
Ninomiya et al. (2004) demonstrated that the chordamesoderm of Xenopus possesses an intrinsic antero-posterior (AP) polarity that is necessary for convergent extension, functions in parallel to Wnt (see 164820)/planar cell polarity signaling, as demonstrated by T brachyury and chordin (603475), and determines the direction of tissue elongation. The mechanism that establishes AP polarity involves activin (147290)-like signaling and directly links mesoderm AP patterning to convergent extension.
Hematopoietic and vascular cells are thought to arise from a common progenitor called the hemangioblast. Support for this concept has been provided by embryonic stem (ES) cell differentiation studies that identified the blast colony-forming cell (BL-CFC), a progenitor with both hematopoietic and vascular potential. Using conditions that support the growth of BL-CFCs, Huber et al. (2004) identified comparable progenitors that can form blast cell colonies (displaying hematopoietic and vascular potential) in gastrulating mouse embryos. Cell mixing and limiting dilution analyses provided evidence that these colonies are clonal, indicating that they develop from a progenitor with hemangioblast potential. Embryo-derived hemangioblasts were first detected at the mid-streak stage of gastrulation and peaked in number during the neural plate stage. Analysis of embryos carrying complementary DNA of the green fluorescent protein targeted to the brachyury locus demonstrated that the hemangioblast is a subpopulation of mesoderm that coexpresses T brachyury and Flk1 (also known as Kdr, 191306). Detailed mapping studies revealed that hemangioblasts are found at highest frequency in the posterior region of the primitive streak, indicating that initial stages of hematopoietic and vascular commitment occur before blood island development in the yolk sac.
Susceptibility to Neural Tube Defects
Morrison et al. (1996) reported that an allelic variant of the T locus, referred to as TIVS7-2 (601637.0001), showed a bias in transmission from heterozygous parents to offspring with neural tube defects (NTD; 182940) in Dutch and U.K. families.
Trembath et al. (1999) failed to find excessive transmission of the TIVS7-2 allele to patients with meningomyelocele, but there were only 21 heterozygous parents for testing of transmission bias. Shields et al. (2000) confirmed the involvement of the TIVS7-2 allele among 218 Irish NTD case-parent triads. However, there was no evidence for a pathogenic interaction between the T locus mutation and the thermolabile MTHFR genotype (236250.0002), a known risk factor for folate-sensitive NTDs (601634). It appeared in their study that the proportional contribution of the TIVS7-2 allele to NTDs had decreased in the time shortly before the report.
Speer et al. (2002) investigated the T locus in a series of patients in families with lumbosacral myelomeningocele. They found evidence of considerable polymorphism within this locus, as previously reported by Papapetrou et al. (1999). When the locus was considered as a whole, with all single-nucleotide polymorphisms (SNPs) integrated into a haplotype, there was no evidence for linkage disequilibrium. The authors concluded that the T locus is not a major locus for human NTDs in this sample.
Jensen et al. (2004) observed that individuals carrying 1 or more copies of the TIVS7-2 allele have a 1.6-fold increased risk of spina bifida compared with individuals with 0 copies.
Susceptibility to Chordoma
In 7 affected individuals from 4 unrelated families with chordomas (215400), Yang et al. (2009) identified duplicated regions on chromosome 6q27 ranging from 52 to 489 kb. The results were obtained from a genomewide search for copy number variations (CNVs) using array CGH. Duplications were not detected in 16 individuals from families with melanoma, in 100 controls, or in individuals with chordoma from 3 additional families, suggesting genetic heterogeneity. The duplicated 6q27 regions in all 4 families contained only the T gene, and there were no previously reported CNVs in that gene. Sequence analysis did not identify any pathogenic mutations in the T gene. Quantitative PCR analyses of the T gene confirmed the duplications in all affected subjects and obligate carriers in all 4 families, with 1.42 to 2.22-fold increased changes. In addition, genomic DNA from 7 affected individuals showed clear duplications of the T gene. Bioinformatics analysis revealed that the breakpoints or breakpoint region were located at or near repetitive short and long interspersed repeat (SINE and LINE) elements or involved Alu-mediated nonallelic homologous recombination. Yang et al. (2009) concluded that duplication of the T gene results in increased susceptibility to the development of chordomas.
Pillay et al. (2012) conducted an association study of 40 individuals with chordoma and 358 ancestry-matched controls, with replication in an independent cohort. Whole-exome and Sanger sequencing of T exons showed strong association of the common nonsynonymous SNP rs2305089 with chordoma risk (allelic odds ratio = 6.1, 95% confidence interval = 3.1-12.1; p = 4.4 x 10(-9)), a finding that is substantial in cancers with a nonmendelian mode of inheritance.
Sacral Agenesis With Vertebral Anomalies
In 4 affected children from 3 unrelated consanguineous families with sacral agenesis with vertebral anomalies (SAVA; 615709), Postma et al. (2014) identified a homozygous mutation in the T gene (H171R; 601397.0002). Two sibs died in the neonatal period. The other 2 children were alive, but clinical details were not provided. Imaging of the patients showed abnormal ossification of the vertebral bodies and a persistent nodochordal canal during development.
Using the rat c-myc gene driven by a human metallothionein promoter, Abe et al. (2000) created several transgenic mouse lines. All of the males were sterile except those in line 137, indicating that the transgene is functionless in that line. However, most of the mice in line 137 had a kinked or bent tail. Abe et al. (2000) found that the transgene was integrated within intron 7 of the mouse brachyury (T) gene and referred to the mutation as T-137, a null allele of the T gene. T-137 homozygotes showed an embryonic lethal phenotype. At embryonic day 9.5, fragmentation of the notochord was seen both anteriorly and posteriorly. At embryonic day 10.5, the embryos tended to have an unlooped heart tube and a swollen pericardium cavity, indicating abnormality in heart function. The embryos died after embryonic day 10.5.
Morrison et al. (1996) identified a T-to-C transition polymorphism in the T gene located 79 bp downstream from the 5-prime end of intron 7. They referred to this variant as 'TIVS7-2.' They observed a bias in transmission of the C allele from heterozygous parents to offspring with neural tube defects (NTD; 182940) in Dutch and U.K. families.
Shields et al. (2000) also found an association between the TIVS7-2 allele and neural tube defects. However, Trembath et al. (1999) and Speer et al. (2002) found no association.
Jensen et al. (2004) developed a genotyping assay for the TIVS7 T/C polymorphism and used it to genotype spina bifida case-parent trios. Analyses of the data demonstrated that heterozygous parents transmitted the C allele to their offspring with spina bifida significantly more frequently than expected under the assumption of mendelian inheritance. Moreover, the analyses suggested that the C allele acts in a dominant fashion, such that individuals carrying 1 or more copies of this allele have a 1.6-fold increased risk of spina bifida compared with individuals with 0 copies.
In 4 affected individuals from 3 unrelated consanguineous families with sacral agenesis with vertebral anomalies (SAVA; 615709), Postma et al. (2014) identified a homozygous c.796A-G transition in the T gene, resulting in a his171-to-arg (H171R) substitution at a highly conserved residue in a region of the T-box domain that forms the dimerization interface. The mutation, which was found by homozygosity mapping followed by candidate gene sequencing, segregated with the disorder in the families. It was not found in 600 control chromosomes, or in the dbSNP, 1000 Genomes Project or the Exome Variant Server databases. In vitro functional expression studies in a cell line with chondrogenic potential showed that the mutant protein had about 50% loss of DNA-binding activity compared to wildtype. In a reporter construct, the mutant protein showed a complete loss of function on a T-box half site, while it only showed a significant decrease on a full consensus T-site. These findings suggested that the binding of the mutant to the T-half site is thermodynamically unfavorable, whereas a homodimer may be more stable. Overexpression of the mutant protein in embryonic cells resulted in an increase in alkaline phosphatase, suggesting a misdirection towards the endoderm lineage in vitro. The mutation also caused an increase in cell growth and interfered with the normal expression of genes involved in ossification, notochord maintenance, and axial mesoderm development.
Abe, K., Yamamura, K., Suzuki, M. Molecular and embryological characterization of a new transgene-induced null allele of mouse Brachyury locus. Mammalian Genome 11: 238-240, 2000. [PubMed: 10723731] [Full Text: https://doi.org/10.1007/s003350010044]
Edwards, Y. H., Putt, W., Lekoape, K. M., Stott, D., Fox, M., Hopkinson, D. A., Sowden, J. The human homolog T of the mouse T (Brachyury) gene: gene structure, cDNA sequence, and assignment to chromosome 6q27. Genome Res. 6: 226-233, 1996. [PubMed: 8963900] [Full Text: https://doi.org/10.1101/gr.6.3.226]
Huber, T. L., Kouskoff, V., Fehling, H. J., Palis, J., Keller, G. Haemangioblast commitment is initiated in the primitive streak of the mouse embryo. Nature 432: 625-630, 2004. [PubMed: 15577911] [Full Text: https://doi.org/10.1038/nature03122]
Jensen, L. E., Barbaux, S., Hoess, K., Fraterman, S., Whitehead, A. S., Mitchell, L. E. The human T locus and spina bifida risk. Hum. Genet. 115: 475-482, 2004. [PubMed: 15449172] [Full Text: https://doi.org/10.1007/s00439-004-1185-8]
Margulies, D. H., Evans, G. A., Flaherty, L., Seidman, J. G. H-2-like genes in the Tla region of mouse chromosome 17. Nature 295: 168-170, 1982. [PubMed: 6276757] [Full Text: https://doi.org/10.1038/295168a0]
Morrison, K., Papapetrou, C., Attwood, J., Hol, F., Lynch, S. A., Sampath, A., Hamel, B., Burn, J., Sowden, J., Stott, D., Mariman, E., Edwards, Y. H. Genetic mapping of the human homologue (T) of mouse T(Brachyury) and a search for allele association between human T and spina bifida. Hum. Molec. Genet. 5: 669-674, 1996. [PubMed: 8733136] [Full Text: https://doi.org/10.1093/hmg/5.5.669]
Ninomiya, H., Elinson, R. P., Winklbauer, R. Antero-posterior tissue polarity links mesoderm convergent extension to axial patterning. Nature 430: 364-367, 2004. [PubMed: 15254540] [Full Text: https://doi.org/10.1038/nature02620]
Papapetrou, C., Drummond, F., Reardon, W., Winter, R., Spitz, L., Edwards, Y. H. A genetic study of the human T gene and its exclusion as a major candidate gene for sacral agenesis with anorectal atresia. J. Med. Genet. 36: 208-213, 1999. [PubMed: 10204846]
Pillay, N., Plagnol, V., Tarpey, P. S., Lobo, S. B., Presneau, N., Szuhai, K., Halai, D., Berisha, F., Cannon, S. R., Mead, S., Kasperaviciute, D., Palmen, J., Talmud, P. J., Kindblom, L.-G., Amary, M. F., Tirabosco, R., Flanagan, A. M. A common single-nucleotide variant in T is strongly associated with chordoma. Nature Genet. 44: 1185-1187, 2012. [PubMed: 23064415] [Full Text: https://doi.org/10.1038/ng.2419]
Postma, A. V., Alders, M., Sylva, M., Bilardo, C. M., Pajkrt, E., van Rijn, R. R., Schulte-Merker, S., Bulk, S., Stefanovic, S., Ilgun, A., Barnett, P., Mannens, M. M. A. M., Moorman, A. F. M., Oostra, R. J., van Maarle, M. C. Mutations in the T (brachyury) gene cause a novel syndrome consisting of sacral agenesis, abnormal ossification of the vertebral bodies and a persistent notochordal canal. J. Med. Genet. 51: 90-97, 2014. [PubMed: 24253444] [Full Text: https://doi.org/10.1136/jmedgenet-2013-102001]
Shields, D. C., Ramsbottom, D., Donoghue, C., Pinjon, E., Kirke, P. N., Molloy, A. M., Edwards, Y. H., Mills, J. L., Mynett-Johnson, L., Weir, D. G., Scott, J. M., Whitehead, A. S. Association between historically high frequencies of neural tube defects and the human T homologue of mouse T (Brachyury). Am. J. Med. Genet. 92: 206-211, 2000. [PubMed: 10817656]
Speer, M. C., Melvin, E. C., Viles, K. D., Bauer, K. A., Rampersaud, E., Drake, C., George, T. M., Enterline, D. S., Mackey, J. F., Worley, G., Gilbert, J. R., Nye, J. S., NTD Collaborative Group. T locus shows no evidence for linkage disequilibrium or mutation in American Caucasian neural tube defect families. Am. J. Med. Genet. 110: 215-218, 2002. [PubMed: 12116228] [Full Text: https://doi.org/10.1002/ajmg.10436]
Trembath, D., Sherbondy, A. L., Vandyke, D. C., Shaw, G. M., Todoroff, K., Lammer, E. J., Finnell, R. H., Marker, S., Lerner, G., Murray, J. C. Analysis of select folate pathway genes, PAX3, and human T in a midwestern neural tube defect population. Teratology 59: 331-341, 1999. [PubMed: 10332959] [Full Text: https://doi.org/10.1002/(SICI)1096-9926(199905)59:5<331::AID-TERA4>3.0.CO;2-L]
Yang, X. R., Ng, D., Alcorta, D. A., Liebsch, N. J., Sheridan, E., Li, S., Goldstein, A. M., Parry, D. M. Kelley, M. J.: T (brachyury) gene duplication confers major susceptibility to familial chordoma. Nature Genet. 41: 1176-1178, 2009. [PubMed: 19801981] [Full Text: https://doi.org/10.1038/ng.454]