Alternative titles; symbols
HGNC Approved Gene Symbol: TBX3
SNOMEDCT: 700211007;
Cytogenetic location: 12q24.21 Genomic coordinates (GRCh38): 12:114,670,255-114,684,175 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q24.21 | Ulnar-mammary syndrome | 181450 | Autosomal dominant | 3 |
The TBX3 gene is a member of a family of transcription factors that share a T-box DNA-binding domain (summary by Meneghini et al., 2006).
In the course of studying the 12q24.1 region where linkage studies indicated that the Holt-Oram syndrome (142900) is located, Li et al. (1997) and Basson et al. (1997) identified the genes TBX3 and TBX5 (601620). The latter gene was found to be the site of mutations responsible for Holt-Oram syndrome.
The cloning of new TBX3 cDNAs allowed Bamshad et al. (1999) to complete the characterization of the TBX3 gene and to identify alternatively transcribed TBX3 transcripts, including 1 that interrupts the T-box. The complete open reading frame of the TBX3 gene encodes a predicted 723-amino acid protein, of which 255 amino acids are encoded by newly identified exons. Comparison of other T-box genes to TBX3 indicated regions of substantial homology outside the DNA-binding domain.
Sowden et al. (2001) examined the role of Drosophila 'optomotor blind' (omb)-related T-box genes in the development of human and mouse retina. Murine Tbx2 (600747), Tbx3, and Tbx5 and human TBX2 cDNAs were isolated from retina cDNA libraries by hybridization to the Drosophila omb gene. Human and mouse TBX2, TBX3, and TBX5 were expressed asymmetrically across the embryonic neural retina, with highest levels of mRNA within dorsal and peripheral retina. The dorsoventral gradient of TBX2 expression disappeared before the ganglion cell layer (GCL) formed. Its expression became restricted to the inner neuroblastic retina and later to the GCL and inner nuclear layer (INL). The dorsal expression domains of TBX5 and TBX3 were maintained during formation of the GCL. As the retina matured, TBX3 expression was restricted to the INL, and TBX5 was expressed within the GCL. The authors concluded that the expression patterns of TBX2, TBX3, and TBX5 within the developing retina support the idea that the encoded transcription factors play a role in providing positional information important for topographic mapping in differentiation of distinct cell types across the laminar axis of the retina.
Hoogaars et al. (2007) found that the sinoatrial node of mouse heart was formed by proliferation of Tbx3-positive precursor cells and not from bordering atrial cells. Tbx3 deficiency resulted in expansion of atrial gene expression into the sinoatrial node domain and partial loss of sinoatrial node-specific gene expression. Ectopic expression of Tbx3 in mice repressed the atrial phenotype and imposed the pacemaker phenotype on the atria, resulting in development of functional ectopic pacemakers.
Niwa et al. (2009) showed that 2 LIF (159540) signaling pathways are each connected to the core circuitry required to maintain pluripotency via different transcription factors. In mouse embryonic stem cells, Klf4 (602253) is mainly activated by the Jak-Stat3 pathway and preferentially activates Sox2 (184429), whereas Tbx3 is preferentially regulated by the phosphatidylinositol-3-OH kinase-Akt and mitogen-activated protein kinase pathways and predominantly stimulates Nanog (607937). In the absence of Lif, artificial expression of Klf4 or Tbx3 was sufficient to maintain pluripotency while maintaining the expression of Oct3/4 (164177). Notably, overexpression of Nanog supported Lif-independent self-renewal of mouse embryonic stem cells in the absence of Klf4 and Tbx3 activity. Therefore, Niwa et al. (2009) concluded that KLF4 and TBX3 are involved in mediating LIF signaling to the core circuitry but are not directly associated with the maintenance of pluripotency, because embryonic stem cells keep pluripotency without their expression in the particular context.
Using genetic lineage analysis, knockout studies, and explant assays, Wiese et al. (2009) found that Tbx18 (604613) was required to establish the large head structure of the mouse sinoatrial node from mesenchymal precursors. Subsequently, Tbx3 induced expression of pacemaker genes for pacemaker function.
Han et al. (2010) showed that the transcription factor Tbx3 significantly improves the quality of induced pluripotent stem (iPS) cells. iPS cells generated with Klf4 and Tbx3 were superior in both germ cell contribution to the gonads and germline transmission frequency. However, global gene expression profiling could not distinguish between the 2 groups of iPS cells. Genomewide chromatin immunoprecipitation sequencing analysis of Tbx3-binding sites in embryonic stem cells suggested that Tbx3 regulates pluripotency-associated and reprogramming factors, in addition to sharing many common downstream regulatory targets with Oct4, Sox2, Nanog, and Smad1 (601595). Han et al. (2010) concluded that their study underscored the intrinsic qualitative differences between iPS cells generated by different methods, and highlighted the need to rigorously characterize iPS cells beyond in vitro studies.
Using lineage tracing in mice, Wang et al. (2015) found that Axin2 (604025) identifies a population of proliferating and self-renewing cells adjacent to the central vein in the liver lobule. These pericentral cells express the early liver progenitor marker Tbx3 and are diploid, and thereby differ from mature hepatocytes, which are mostly polyploid. The descendants of pericentral cells differentiate into Tbx3-negative, polyploid hepatocytes, and can replace all hepatocytes along the liver lobule during homeostatic renewal. Adjacent central vein endothelial cells provide Wnt signals that maintain the pericentral cells, thereby constituting the niche. Wang et al. (2015) concluded that they identified a cell population in the liver that subserves homeostatic hepatocyte renewal, characterizes its anatomic niche, and identifies molecular signals that regulate its activity.
Hepatocellular carcinoma (HCC; 114550) and intrahepatic cholangiocarcinoma (ICC; 615619) differ markedly with regards to their morphology, metastatic potential, and responses to therapy. Seehawer et al. (2018) demonstrated that the hepatic microenvironment epigenetically shapes lineage commitment in mosaic mouse models of liver tumorigenesis. Whereas a necroptosis-associated hepatic cytokine microenvironment determines ICC outgrowth from oncogenically transformed hepatocytes, hepatocytes containing identical oncogenic drivers give rise to HCC if they are surrounded by apoptotic hepatocytes. Epigenome and transcriptome profiling of mouse HCC and ICC singled out Tbx3 and Prdm5 (614161) as major microenvironment-dependent and epigenetically regulated lineage-commitment factors, a function that is conserved in humans. Seehawer et al. (2018) concluded that their results provided insight into lineage commitment in liver tumorigenesis, and explained molecularly why common liver-damaging risk factors can lead to either HCC or ICC.
Yi et al. (2000) determined that the TBX3 gene contains at least 6 exons and spans more than 9.0 kb.
Osterwalder et al. (2018) showed that the pervasive presence of multiple enhancers with similar activities near the same gene confers phenotypic robustness to loss-of-function mutations in individual enhancers. Osterwalder et al. (2018) used genome editing to create 23 mouse deletion lines and intercrosses, including both single and combinatorial enhancer deletions at 7 distinct loci required for limb development including Gli3 (165240), Shox2 (602504), Tbx3, Tbx5 (601620), and Lhx5 (605992). Unexpectedly, none of the 10 deletions of individual enhancers caused noticeable changes in limb morphology. By contrast, the removal of pairs of limb enhancers near the same gene resulted in discernible phenotypes, indicating that enhancers function redundantly in establishing normal morphology. In a genetic background sensitized by reduced baseline expression of the target gene, even single enhancer deletions caused limb abnormalities, suggesting that functional redundancy is conferred by additive effects of enhancers on gene expression levels. A genomewide analysis integrating epigenomic and transcriptomic data from 29 developmental mouse tissues revealed that mammalian genes are very commonly associated with multiple enhancers that have similar spatiotemporal activity. Systematic exploration of 3 representative developmental structures (limb, brain, and heart) uncovered more than 1,000 cases in which 5 or more enhancers with redundant activity patterns were found near the same gene. Osterwalder et al. (2018) concluded that their data indicated that enhancer redundancy is a remarkably widespread feature of mammalian genomes that provides an effective regulatory buffer to prevent deleterious phenotypic consequences upon the loss of individual enhancers.
Xie et al. (2018) stated that the TBX3 gene consists of 8 exons.
The human TBX3 and TBX5 genes map to chromosome 12q24.1, and the murine homologs, Tbx3 and Tbx5, map to chromosome 5 (Li et al., 1997; Basson et al., 1997).
Tanteles et al. (2017) stated that the TBX3 gene maps to chromosome 12q24.21.
Li et al. (1997) pointed out that TBX3 may be a candidate gene for Noonan syndrome (163950) and ulnar-mammary syndrome (UMS; 181450). The latter possibility indeed proved to be the case; Bamshad et al. (1997) demonstrated mutations in TBX3 in 2 families with ulnar-mammary syndrome (602621.0001-602621.0002). Each mutation was predicted to cause haploinsufficiency of TBX3, implying that critical levels of this transcription factor are required for morphogenesis of several organs. Limb abnormalities of ulnar-mammary syndrome involve posterior elements. Mutations in TBX5 cause anterior limb abnormalities in Holt-Oram syndrome. Because of similarities in structure and function of TBX3 and TBX5 and because of close linkage, Bamshad et al. (1997) proposed that these genes originated from a common ancestral gene, each having acquired specific complementary roles in patterning the mammalian upper limb.
Bamshad et al. (1999) identified novel mutations in the TBX3 gene in all of 8 newly reported families with UMS, including 5 mutations downstream of the region encoding the T-box. This suggested that a domain (or domains) outside the T-box was highly conserved and important for the function of TBX3. Bamshad et al. (1999) found no obvious phenotypic differences between those who had missense mutations and those who had deletions or frameshifts.
To determine how C-terminal mutations may affect transcription, Carlson et al. (2001) created a series of fusion proteins to map regions that conferred transcriptional activity, nuclear localization, and DNA-binding properties of Tbx3. Tbx3 binds the canonic brachyury binding site as a monomer and represses transcription. A key repression domain (RD1) resides in the Tbx3 C terminus that can function as a portable repression domain. Most UMS-associated C-terminal mutants lack the RD1 and exhibit decreased or loss of transcriptional repression activity. A cluster of basic amino acids at residues 292-297 serves as a nuclear localization signal. Two C-terminal truncation mutants exhibited increased rates of protein decay. The RD1 repression domain of Tbx3 was also shown to be capable of immortalizing primary embryo fibroblasts.
In a Japanese mother and her 2 sons with ulnar-mammary syndrome, Sasaki et al. (2002) identified heterozygosity for a nonsense mutation in the TBX3 gene (K273X; 601621.0003).
In affected members of a large 3-generation Turkish family segregating autosomal dominant ulnar-mammary syndrome, Wollnik et al. (2002) identified heterozygosity for a frameshift mutation in TBX3 (601621.0004).
In a boy and his mother with ulnar-mammary syndrome, Linden et al. (2009) identified heterozygosity for a nonsense mutation in the TBX3 gene (601621.0005).
In twin brothers and their father with ulnar-mammary syndrome, Tanteles et al. (2017) identified heterozygosity for a nonsense mutation in the TBX3 gene (601621.0006).
In 3 members of a family with ulnar-mammary syndrome, Meneghini et al. (2006) identified a single-basepair insertion (601621.0007) in exon 6 of the TBX3 gene, resulting in a frameshift and premature stop codon. This mutation was downstream of the T-box DNA-binding domain and thus did not disrupt or alter the T-domain. The authors reviewed the data on previously reported variants and hypothesized a genotype-phenotype correlation, with mutations that disrupt the T-box DNA-binding domain associated with a more severe phenotype.
In a 10-year-old girl with isolated bilateral dorsalization of her fifth fingers and slightly deep fourth web spaces, Al-Qattan et al. (2020) identified a de novo heterozygous 2-basepair duplication in the TBX3 gene (601621.0008), resulting in frameshift and premature termination of the protein. The authors suggested that these clinical findings should be considered a forme fruste phenotype of ulnar-mammary syndrome.
Associations Pending Confirmation
Using targeted sequencing, Xie et al. (2018) identified 3 potentially damaging variants in the TBX3 gene (A192T, M65L, and A562V) in 6 of 588 patients with conotruncal heart defects (see 217095), and none in 300 controls without heart defects. The variants occurred at positions highly conserved among vertebrates. Quantitative RT-PCR analysis of A192T and M65L showed that these variants resulted in higher mRNA expression than wildtype (p less than 0.05). On Western blot analysis, protein expression of A192T and A562V was lower than that of wildtype TBX3 (p less than 0.05), indicating that TBX3 variants might lead to protein degradation. Functional analysis of the A192T and A562V proteins showed reduced transcriptional activity over the promoter of MEF2C (600662), a downstream gene of TBX3. The authors hypothesized that variants in TBX3 might contribute to the etiology of conotruncal heart defects.
Meneghini et al. (2006) reviewed data on patients with ulnar-mammary syndrome and proposed that mutations that disrupt the T-box DNA-binding domain were associated with a more severe phenotype. They divided mutations into 2 categories based on whether they were 5-prime or within the T-domain versus 3-prime of the T-domain. Limb defects were present with a penetrance of greater than 85%. The severe limb phenotype, defined as including ulnar and/or humerus involvement, was significantly associated with mutations that abolish or disrupt the T-domain (p = 0.009). Mammary involvement was divided into normal (no appreciable mammary phenotype) or affected; again, the more severe phenotype was associated with disruption of the T-domain, but this finding was not statistically significant (p = 0.092). Tooth abnormalities were more common in patients with a disrupted T-domain (p = 0.052). Data on the apocrine gland/perspiration-axillary hair phenotype were too scant to observe a correlation.
In a Czech mother and 2 daughters who were diagnosed with Holt-Oram syndrome, Borozdin et al. (2006) identified a 2.19 to 2.27-Mb contiguous deletion encompassing the TBX5 and TBX3 genes. Clinical reexamination confirmed the presence of features of ulnar-mammary syndrome that were previously unrecognized. Borozdin et al. (2006) noted that the contiguous deletion also included the RBM19 gene (616444), but commented that it was unlikely to contribute to or modify the phenotype since all the anomalies present in the affected individuals could be explained by either TBX5 or TBX3 haploinsufficiency.
Klopocki et al. (2006) sequenced the TBX3 gene in a 3.5-year-old girl with an ulnar-mammary-like phenotype, dysmorphic facies, and mental retardation, but did not detect any mutation. Microarray CGH revealed heterozygosity for an interstitial 1.28-Mb deletion on chromosome 12q24.21, encompassing the TBX3 gene. The deletion and TBX3 haploinsufficiency were confirmed by FISH. Neither parent carried the deletion. Klopocki et al. (2006) stated that this was the first description of TBX3 haploinsufficiency caused by a genomic deletion in a patient with ulnar-mammary syndrome and suggested that the facial changes and mental retardation observed in this patient might be due to involvement of neighboring genes.
Using the development of the 4-digit chick leg as a model system, Suzuki et al. (2004) studied the role of Tbx2 and Tbx3 in specifying digit identities along the anterior-posterior axis. Misexpression of Tbx2 and Tbx3 induced posterior homeotic transformation of digit III to digit IV and digit II to digit III, respectively. Conversely, misexpression of constitutively active mutants induced anterior transformation. In both cases, alterations in the expression of several markers, including Bmp2 (112261), Shh (600725), and HoxD genes (see 142987), were observed. In addition, Tbx2 and Tbx3 rescued Noggin (602991)-mediated inhibition of interdigital BMP signaling, which was pivotal in establishing digit identities. Suzuki et al. (2004) concluded that, in the developing chick, Tbx3 specifies digit III and the combination of Tbx2 and Tbx3 specifies digit IV, acting together with the interdigital BMP signaling cascade.
In a mother and son with ulnar-mammary syndrome (UMS; 181450), Bamshad et al. (1997) found that the TBX3 gene had deletion of nucleotide 227, a thymidine, resulting in shift of the reading frame and a premature termination codon after 11 novel amino acids. A hand x-ray in the mother showed complete absence of the fourth digit (metacarpal and phalanges) and fusion of the capitate and hamate bones on the right. The mutated protein in this family was predicted to encode a markedly truncated protein containing only 86 amino acids and lacking the entire T-box domain. This mutant protein should be incapable of binding DNA. Affected members of this family demonstrated limb and apocrine anomalies.
In a mother and daughter with ulnar-mammary syndrome (UMS; 181450), Bamshad et al. (1997) demonstrated heterozygosity for a G-to-C transversion in the first nucleotide of intron 2. This substitution altered the consensus splice donor site and was predicted to alter gene splicing. This family exhibited limb, apocrine, and genital anomalies.
In a Japanese mother and her 2 sons with ulnar-mammary syndrome (UMS; 181450), Sasaki et al. (2002) found a heterozygous 817A-T mutation in exon 4 of the TBX3 gene, leading to a lys273-to-ter substitution. The mutation is expected to impair the DNA-binding capacity of the TBX3 protein.
Wollnik et al. (2002) reported a large Turkish family in which 10 members spanning 3 generations had autosomal dominant ulnar-mammary syndrome (UMS; 181450). The phenotypic expression of the disease was highly variable among the affected family members showing posterior (ulnar or postaxial) limb deficiencies and/or duplications, mammary gland hypoplasia, apocrine dysfunction, and dental and genital abnormalities. Mutation analysis identified a 1-bp insertion (88insA) in the TBX3 gene. The truncated protein lacked almost all functionally important parts of TBX3 and probably had complete loss of function.
In a boy and his mother with ulnar-mammary syndrome (UMS; 181450), Linden et al. (2009) identified heterozygosity for a 991C-T transition in exon 5 of the TBX3 gene, resulting in a gln331-to-ter (Q331X) substitution. The boy had phenotypic features not theretofore described in UMS, including hypoplastic anterior pituitary and ectopic posterior pituitary gland, ventricular septal defect, and cardiac conduction defects consistent with Wolff-Parkinson-White syndrome (see 194200). The boy's mother did not show the classic features of UMS, supporting the variable expressivity of UMS within the same family.
By targeted Sanger sequencing of the TBX3 gene in a Cypriot family in which twin brothers and their father had ulnar-mammary syndrome (UMS; 181450), Tanteles et al. (2017) identified heterozygosity for a c.1423C-T transition in exon 6 of the TBX3 gene, resulting in a glu475-to-ter (Q475X) substitution. The mutation segregated with the disorder in the family. The twins showed classic features of the disorder, whereas their father was mildly affected.
In 3 members of a family with ulnar-mammary syndrome (UMS; 181450), Meneghini et al. (2006) identified a single-basepair insertion (c.1586_1587insC) in exon 6 of the TBX3 gene, resulting in a frameshift at codon 399 and premature stop codon at codon 406. The mutation was identified by targeted sequencing and segregated with the disorder in the family. Hand malformations were reported in 3 other members of the paternal family, but these individuals were not available for analysis. This mutation was downstream of the T-box DNA-binding domain and thus did not disrupt or alter the T-domain. Functional studies were not performed.
In a 10-year-old girl with isolated bilateral dorsalization of her fifth fingers and slightly deep fourth web spaces (UMS; 181450), Al-Qattan et al. (2020) identified a de novo heterozygous 2-basepair duplication (c.1920_1921dup, NM_005996.3) in the TBX3 gene, resulting in a frameshift variant and premature stop codon (Pro641ArgfsTer229, P641RfsX229). The mutation was identified by trio whole-exome sequencing and confirmed by Sanger sequencing. Functional studies or studies of patient cells were not performed. The authors suggested that these findings should be considered a forme fruste phenotype of ulnar-mammary syndrome.
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