Alternative titles; symbols
HGNC Approved Gene Symbol: TBX6
Cytogenetic location: 16p11.2 Genomic coordinates (GRCh38) : 16:30,085,793-30,091,924 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p11.2 | Spondylocostal dysostosis 5 | 122600 | Autosomal dominant; Autosomal recessive | 3 |
Somites, the segmented mesodermal units of the vertebrate embryo, are the precursors of adult skeletal muscle, bone, and cartilage. During embryogenesis, somite progenitor cells ingress through the primitive streak, move laterally to a paraxial position (alongside the body axis), and segment into epithelial somites. Chapman et al. (1996) described a mouse T-box gene, Tbx6, which codes for a putative DNA-binding protein. The embryonic pattern of expression of Tbx6 in somite precursor cells suggested that this gene may be involved in the specification of paraxial mesoderm.
By fluorescence in situ hybridization, Papapetrou et al. (1999) mapped the human TBX6 gene to 16p11.2. This region of chromosome 16 shows homology of synteny with mouse chromosome 7, cM position 61, the localization reported for the mouse Tbx6 gene (Chapman et al., 1996).
Yasuhiko et al. (2006) found that Tbx6 was essential for Mesp2 (605195) expression during somitogenesis in mouse. Tbx6 directly bound to the Mesp2 gene upstream region and mediated Notch (see 190198) signaling and subsequent Mesp2 transcription in the anterior presomitic mesoderm.
Takemoto et al. (2011) demonstrated that TBX6-dependent regulation of SOX2 (184429) determines the fate of axial stem cells. In wildtype mouse embryos, enhancer N1 of the neural primordial gene Sox2 is activated in the caudal lateral epiblast, and the cells staying in the superficial layer sustain N1 activity and activate Sox2 expression in the neural plate. In contrast, the cells destined to become mesoderm activate Tbx6 and turn off enhancer N1 before migrating into the paraxial mesoderm compartment. In Tbx6 mutant embryos, however, enhancer N1 activity persists in the paraxial mesoderm compartment, eliciting ectopic Sox2 activation and transforming the paraxial mesoderm into neural tubes. An enhancer-N1-specific deletion mutation introduced into Tbx6 mutant embryos prevented this Sox2 activation into the mesodermal compartment and subsequent development of ectopic neural tubes, indicating that Tbx6 regulates Sox2 via enhancer N1. Tbx6-dependent repression of Wnt3a (606359) in the paraxial mesodermal compartment is implicated in this regulatory process. Paraxial mesoderm-specific misexpression of a Sox2 transgene in wildtype embryos resulted in ectopic neural tube development. Thus, Takemoto et al. (2011) concluded that Tbx6 represses Sox2 by inactivating enhancer N1 to inhibit neural development, and this is an essential step for the specification of paraxial mesoderm from the axial stem cells.
In 3 affected members of a 3-generation Macedonian family with autosomal dominant spondylocostal dysostosis (SCDO5; 122600), Sparrow et al. (2013) identified heterozygosity for a mutation in the TBX6 gene (602427.0001) that segregated with the disease in the family. The mutation disrupts the natural stop codon, resulting in a mutant protein with approximately half the transcriptional activation activity of wildtype TBX6.
Wu et al. (2015) identified a total of 17 heterozygous TBX6-null mutations in 161 individuals with sporadic congenital scoliosis (11%), and did not observe any null mutations in TBX6 in 166 controls (p less than 3.8 x 10(-6)). These null alleles included copy number variants (12 instances of a 16p11.2 deletion affecting TBX6) and single-nucleotide variants comprising 1 nonsense (602427.0002) and 4 frameshift mutations (see, e.g., 602427.0004-602427.0005). However, dominant inheritance was not supported by the low penetrance of congenital scoliosis in persons carrying the 16p11.2 deletion affecting TBX6. Wu et al. (2015) subsequently identified a common TBX6 haplotype (T-C-A; 602427.0003) as the second risk allele in all 17 affected carriers of TBX6 null mutations (p less than 1.1 x 10(-6)). Replication studies involving additional persons with congenital scoliosis who carried a deletion affecting TBX6 confirmed this compound inheritance model. In vitro functional assays suggested that the haplotype functions as a hypomorphic allele. Wu et al. (2015) also studied an additional 76 individuals with congenital scoliosis, 6 of whom (8%) had TBX6 compound inheritance (p less than 8.4 x 10(-4)). Finally, in a series of 42 patients with a 16p11.2 deletion, 5 of 6 persons with congenital scoliosis (83%) had the phenotype explained by TBX6 compound inheritance (p = 0.004). All patients were of Han Chinese extraction.
Among 102 Japanese patients with congenital scoliosis, Otomo et al. (2019) identified five 16p11.2 deletions (complete loss of TBX6), 1 splice site variant, and 3 missense variants in TBX6; all patients carried the risk haplotype (602427.0003) in trans. One of 4 patients with spondylocostal dysostosis had biallelic missense variants in TBX6 (c.356G-A, R119H; c.449G-A, R150H); this patient did not have the risk haplotype on either allele. Otomo et al. (2019) suggested that biallelic loss-of-function variants of TBX6 cause a spectrum of phenotypes, including CS and SCOD, depending on the severity of the loss of TBX6 function. In vitro functional assays for the missense variants showed that most caused abnormal localization of TBX6 proteins.
By retrospective analysis, Ren et al. (2020) found that humans who carried the duplicated chromosome 6p11.2 BP4-BP5 region containing TBX6 had increased risk of congenital vertebral malformations (CVMs). Similarly, they found that increased Tbx6 expression in a mouse model was associated with increased incidence of CVMs in cervical vertebrae.
Chapman and Papaioannou (1998) created a mutation in mouse Tbx6 that profoundly affected the differentiation of paraxial mesoderm. Irregular somites formed in the neck region of mutant embryos, whereas more posterior paraxial tissue did not form somites but instead differentiated along a neural pathway, forming neural-tube-like structures that flanked the axial neural tube. These paraxial tubes showed dorsal/ventral patterning that is characteristic of the neural tube and had differentiated motor neurons. These results indicated that Tbx6 is needed for cells to choose between a mesodermal and a neuronal differentiation pathway during gastrulation; Tbx6 is essential for the specification of posterior paraxial mesoderm, and in its absence cells destined to form posterior somites differentiate along a neuronal pathway.
Sparrow et al. (2013) generated Tbx6 +/- mice and studied the vertebral phenotype at embryonic day 14.5. Almost half of the mutant embryos showed a mild cervical or sacral vertebral defect, whereas no defects were seen in wildtype embryos. The cervical defects were restricted to the axis and atlas, and included vertebrae in which the distal part of the spinous process was not attached to the rest of the spinous process, as well as vertebrae in which foramina were present in the most distal portion of the spinous processes. In addition, there were occasional threads of cartilage leading from the spinous process of the axis to the atlas. Similar defects were noted in the sacral vertebrae.
In 3 affected members of a 3-generation Macedonian family segregating autosomal dominant spondylocostal dysostosis (SCDO5; 122600), originally reported by Gucev et al. (2010), Sparrow et al. (2013) identified heterozygosity for a c.1311A-T transversion in the TBX6 gene, which disrupts the natural stop codon and is predicted to result in the addition of 81 amino acids to the C terminus (Ter437CysextTer81). The mutation was not found in unaffected family members. Transfection studies demonstrated significant impairment of transcriptional activation activity with the TBX6 mutant, to approximately 50% of wildtype activity.
In a 16-year-old Han Chinese female with thoracic and lumbar butterfly vertebrae and right and left thoracic hemivertebrae (SCDO5; 122600), Wu et al. (2015) identified a c.844C-T transition in the TBX6 gene, resulting in an arg282-to-ter (R282X) substitution. On the other allele, the patient carried a hypomorphic haplotype defined by 3 common TBX6 SNPs (see 602427.0003). This mutation was not observed in any of 166 Han Chinese controls.
Wu et al. (2015) identified a common haplotype among the Han Chinese characterized by rs2289292C-T, rs3809624T-C, and rs3809627C-A. In vitro luciferase assays in human and mouse cells demonstrated that these SNPs serve as a hypomorphic allele. All 23 persons identified by Wu et al. (2015) with TBX6-related congenital scoliosis (SCDO5; 122600) carried a null allele of TBX6 (frameshift, nonsense, or 16p11.2 deletion) and the T-C-A haplotype on the other allele of TBX6. Wu et al. (2015) noted that this haplotype has a prevalence of 44% among Asians.
In a 7-year-old female with a left lumbar hemivertebra, atrial septal defect, and missing bilateral twelfth ribs (SCDO5; 122600), Wu et al. (2015) identified compound heterozygosity for a frameshift insertion of a T nucleotide in the TBX6 gene (c.1250_1251insT) and the T-C-A haplotype (602427.0003). This mutation was not observed in any of 166 Han Chinese controls.
In a 5-year-old male with left hemivertebra between T12 and L1 and a missing right twelfth rib (SCDO5; 122600), Wu et al. (2015) identified compound heterozygosity for a frameshift insertion of a C nucleotide in the TBX6 gene (c.266_267insC) and the T-C-A haplotype (602427.0003). This mutation was not observed in any of 166 Han Chinese controls.
In 3 unrelated individuals of Han Chinese extraction with various vertebral malformations resulting in a diagnosis of congenital scoliosis (SCDO5; 122600), Wu et al. (2015) identified compound heterozygosity for a c.434C-T transition in the TBX6 gene, resulting in a pro145-to-leu (P145L) substitution, and the T-C-A haplotype (602427.0003). In one patient the P145L mutation was shown to be a de novo event. Vertebral malformations included extensive defects of formation and segmentation involving cervical and thoracic vertebrae, hemivertebrae, and butterfly vertebrae. Other congenital malformations included atrial septal bulge, bilateral 13 ribs, missing ribs, and fused ribs. This missense mutation was not identified in the 1000 Genomes Project database, and was suggested to be damaging by at least 3 bioinformatic tools. This mutation was not observed in any of 166 Han Chinese controls.
Chapman, D. L., Agulnik, I., Hancock, S., Silver, L. M., Papaioannou, V. E. Tbx6, a mouse T-box gene implicated in paraxial mesoderm formation at gastrulation. Dev. Biol. 180: 534-542, 1996. [PubMed: 8954725] [Full Text: https://doi.org/10.1006/dbio.1996.0326]
Chapman, D. L., Papaioannou, V. E. Three neural tubes in mouse embryos with mutations in the T-box gene Tbx6. Nature 391: 695-697, 1998. [PubMed: 9490412] [Full Text: https://doi.org/10.1038/35624]
Gucev, Z. S., Tasic, V., Pop-Jordanova, N., Sparrow, D. B., Dunwoodie, S. L., Ellard, S., Young, E., Turnpenny, P. D. Autosomal dominant spondylocostal dysostosis in three generations of a Macedonian family: negative mutation analysis of DLL3, MESP2, HES7, and LFNG. Am. J. Med. Genet. 152A: 1378-1382, 2010. [PubMed: 20503311] [Full Text: https://doi.org/10.1002/ajmg.a.33471]
Otomo, N., Takeda, K., Kawai, S., Kou, I., Guo, L., Osawa, M., Alev, C., Kawakami, N., Miyake, N., Matsumoto, N., Yasuhiko, Y., Kotani, T., and 17 others. Bi-allelic loss of function variants of TBX6 causes (sic) a spectrum of malformation of spine and rib including congenital scoliosis and spondylocostal dysostosis. J. Med. Genet. 56: 622-628, 2019. [PubMed: 31015262] [Full Text: https://doi.org/10.1136/jmedgenet-2018-105920]
Papapetrou, C., Putt, W., Fox, M., Edwards, Y. H. The human TBX6 gene: cloning and assignment to chromosome 16p11.2. Genomics 55: 238-241, 1999. [PubMed: 9933572] [Full Text: https://doi.org/10.1006/geno.1998.5646]
Ren, X., Yang, N., Wu, N., Xu, X., Chen, W., Zhang, L., Li, Y., Du, R.-Q., Dong, S., Zhao, S., Chen, S., Jiang, L.-P., Wang, L., Zhang, J., Wu, Z., Jin, L., Qiu, G., Lupski, J. R., Shi, J., Zhang, F., Liu, P. Increased TBX6 gene dosages induce congenital cervical malformations in humans and mice. J. Med. Genet. 57: 371-379, 2020. [PubMed: 31888956] [Full Text: https://doi.org/10.1136/jmedgenet-2019-106333]
Sparrow, D. B., McInerney-Leo, A., Gucev, Z. S., Gardiner, B., Marshall, M., Leo, P. J., Chapman, D. L., Tasic, V., Shishko, A., Brown, M. A., Duncan, E. L., Dunwoodie, S. L. Autosomal dominant spondylocostal dysostosis is caused by mutation in TBX6. Hum. Molec. Genet. 22: 1625-1631, 2013. [PubMed: 23335591] [Full Text: https://doi.org/10.1093/hmg/ddt012]
Takemoto, T., Uchikawa, M., Yoshida, M., Bell, D. M., Lovell-Badge, R., Papaioannou, V. E., Kondoh, H. Tbx6-dependent Sox2 regulation determines neural or mesodermal fate in axial stem cells. Nature 470: 394-398, 2011. [PubMed: 21331042] [Full Text: https://doi.org/10.1038/nature09729]
Wu, N., Ming, X., Xiao, J., Wu, Z., Chen, X., Shinawi, M., Shen, Y., Yu, G., Liu, J., Xie, H., Gucev, Z. S., Liu, S., and 46 others. TBX6 null variants and a common hypomorphic allele in congenital scoliosis. New Eng. J. Med. 372: 341-350, 2015. [PubMed: 25564734] [Full Text: https://doi.org/10.1056/NEJMoa1406829]
Yasuhiko, Y., Haraguchi, S., Kitajima, S., Takahashi, Y., Kanno, J., Saga, Y. Tbx6-mediated Notch signaling controls somite-specific Mesp2 expression. Proc. Nat. Acad. Sci. 103: 3651-3656, 2006. [PubMed: 16505380] [Full Text: https://doi.org/10.1073/pnas.0508238103]