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Other entities represented in this entry:
HGNC Approved Gene Symbol: TCF3
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:1,609,292-1,652,615 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3 | Agammaglobulinemia 8A, autosomal dominant | 616941 | Autosomal dominant | 3 |
| Agammaglobulinemia 8B, autosomal recessive | 619824 | Autosomal recessive | 3 |
The TCF3 gene, also called E2A, encodes 2 basic helix-loop-helix (bHLH) transcription factors, E12 and E47, through alternative splicing. E12 and E47 are involved in regulation of immunoglobulin gene expression (Bain et al., 1994). TCF3 plays an important role in B-cell development and differentiation (summary by Ben-Ali et al., 2017).
Expression of immunoglobulin genes depends on various sequence motifs in their enhancer and promoter regions. One class of such sequences is the E box, which is found in both heavy and light chain enhancers. The kappa-E2 site has been shown to be important for light chain gene transcription. To isolate cDNAs encoding kappa-E2-binding proteins, Murre et al. (1989) screened a cDNA expression library derived from a human B-cell lymphoma cell line (BJAB) with an oligonucleotide containing a trimerized kappa-E2 site. They identified a partial cDNA encoding a protein that they designated E12. Using the E12 cDNA to rescreen the BJAB cDNA library, Murre et al. (1989) isolated a partial cDNA encoding a protein that they designated E47. Sequence analysis suggested that E12 and E47 are derived from a single gene, called E2A or TCF3, via alternative splicing. E12 contains a leucine zipper; the corresponding region of E47 was not cloned. Both the E12 and E47 proteins contain a region that is homologous to regions in MYOD (159970), members of the MYC family (e.g., 190080), the Drosophila 'daughterless' gene product, and products of the Drosophila 'achaete-scute' and 'twist' gene families. The homologous regions have the potential to form 2 amphipathic helices separated by an intervening loop, and the hydrophobic residues present in the helices are highly conserved.
Henthorn et al. (1990) independently cloned E2A and designated it ITF1.
Murre et al. (1989) showed that both E12 and E47 bound specifically to the kappa-E2 sequence. They demonstrated that E47 bound kappa-E2 as a dimer in vitro. Murre et al. (1989) demonstrated that the helix-loop-helix motif of E12/E47 plays a crucial role in both dimerization and DNA binding.
Saethre-Chotzen syndrome (101400) is an autosomal dominant craniosynostosis syndrome characterized by premature fusion of coronal sutures and limb abnormalities of variable severity. Mutations in TWIST (601622), a class B basic helix-loop-helix (bHLH) transcription factor, have been shown to be responsible for this phenotype. El Ghouzzi et al. (2000) used a yeast 2-hybrid system to study interaction between TWIST and E12, a potential partner in heterodimerization. Missense mutations involving the helical domains of TWIST led to a complete loss of heterodimerization with the E12 protein, and dramatically altered the ability of the TWIST protein to localize in the nucleus of transfected COS cells. The authors hypothesized that the E12-TWIST heterodimer may serve as a negative regulator of transcription in osteoblastic cells.
TAL1 (187040) is necessary for establishment of the hematopoietic system and can either activate or repress transcription depending upon other factors recruited to TAL1-nucleated complexes. Goardon et al. (2006) found that ETO2 (CBFA2T3; 603870) copurified with TAL1 complexes in human and mouse erythroleukemia cells. Protein pull-down assays revealed that ETO2 interacted with E2A and HEB (TCF12; 600480) within the TAL1 complex, but not with TAL1 itself. ETO2 also interacted with E2A in erythroid cells independent of the TAL1 complex. Reporter gene assays revealed that ETO2 repressed the transcriptional activity of the complex. The ETO2 content in TAL1 complexes was high during the proliferative phase in erythroid cells. In contrast, ETO2 was downregulated upon terminal differentiation, concomitant with appearance of histone modifications associated with gene activation and expression of glycophorin A (GPA; 617922) and band 4.2 (EPB42; 177070), which are markers of erythrocyte maturation. Knockdown of ETO2 via small interfering RNA induced growth arrest and differentiation in human and mouse erythroid progenitors. Goardon et al. (2006) concluded that ETO2 is required for expansion of erythroid progenitors, but that it is dispensable for terminal maturation. They proposed that the stoichiometry of ETO2 with the TAL1 complex controls the transition from erythroid progenitor expansion to terminal differentiation.
Using knockdown studies and chromatin immunoprecipitation analysis, Zhou et al. (2018) found that the transcription factor YY1 (600013) bound to the E3-prime enhancer of the immunoglobulin kappa (IgK) locus (see 147200) and suppressed IgK expression in human B lymphoma cells by epigenetically modifying the enhancer. Knockdown of YY1 enhanced IgK expression, which was associated with increased expression of E2A and binding of E2A to the E3-prime enhancer.
By in situ hybridization and Southern analysis of rodent-human somatic cell hybrids, Mellentin et al. (1989) demonstrated that the E2A gene maps to 19p13.3-p13.2, a site associated with nonrandom translocations in acute lymphoblastic leukemias (ALL; 613065). By fluorescence in situ hybridization, Trask et al. (1993) assigned the TCF3 gene to 19p13.3.
Somatic Changes
In a genomewide analysis of leukemic cells from 242 pediatric ALL patients using high resolution, single-nucleotide polymorphism (SNP) arrays and genomic DNA sequencing, Mullighan et al. (2007) identified mutations in genes encoding principal regulators of B-lymphocyte development and differentiation in 40% of B-progenitor ALL cases. Deletions were detected in TCF3, IKZF1 (603023), IKZF3 (606221), EBF1 (164343), and LEF1 (153245). The PAX5 (167414) gene was the most frequent target of somatic mutation, being altered in 31.7% of cases.
Agammaglobulinemia 8A, Autosomal Dominant
In 4 unrelated patients with autosomal dominant agammaglobulinemia-8A (AGM8A; 616941), Boisson et al. (2013) identified a de novo heterozygous missense mutation (E555K; 147141.0001) specific to the E47 isoform of the TCF3 gene. In vitro functional expression studies and studies of patient cells showed that the mutant E47 protein localized properly to the nucleus, but did not perform proper DNA binding and acted in a dominant-negative manner when coexpressed with wildtype. Laboratory studies showed decreased numbers of B cells; the remaining B cells showed intense CD19 expression and absence of the B-cell receptor (Dobbs et al., 2011). The findings suggested that E47 plays a critical role in enforcing the block in the development of B-cell precursors that lack functional antigen receptors.
Agammaglobulinemia 8B, Autosomal Recessive
In 2 sibs, born of consanguineous Tunisian parents, with autosomal recessive agammaglobulinemia-8B (AGM8B; 619824), Ben-Ali et al. (2017) identified a homozygous nonsense mutation in the TCF3 gene (Q270X; 147141.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in public databases. Patient cells showed degradation of mutant transcripts, suggesting nonsense-mediated mRNA decay, and Western blot analysis showed absence of the TCF3 (E2A) protein, consistent with a loss of function.
In a 9-year-old girl, born of consanguineous Pakistani parents, with AGM8B, Qureshi et al. (2019) identified a homozygous out-of-frame intragenic deletion in the TCF3 gene (147141.0003). The deletion was found by targeted next-generation sequencing; segregation within the family was not reported. Functional studies of the variant were not performed, but it was predicted to result in a loss of function.
Evidence presented by Mellentin et al. (1989) suggested that most, and perhaps all, t(1;19)(q23;p13) chromosomal translocations, a frequent cytogenetic change in acute lymphoblastic leukemia, contain rearrangements of the E2A gene.
Hunger (1996) reviewed clinical features and the molecular pathogenesis of acute lymphoblastic leukemia (ALL) caused by chromosomal translocations involving the E2A gene. E2A proteins play an indispensable role in B-cell lymphopoiesis. The pathogenesis of a subset of B-precursor ALLs involves replacement of the bHLH regions of the E2A protein with heterologous DNA-binding domains.
E2A/PBX1 Fusion Gene
Nourse et al. (1990) detected altered E2A transcripts, which lacked sequences encoding the helix-loop-helix DNA-binding motif, in several t(1;19)-carrying cell lines. They cloned fusion cDNAs that crossed the t(1;19) breakpoint. These cDNAs encode an 85-kD protein consisting of the N-terminal two-thirds of E2A fused to a chromosome 1-derived protein. The fusion protein has the features of a chimeric transcription factor in which the DNA-binding domain of E2A is replaced by the putative DNA-binding domain of a homeoprotein from chromosome 1, which Nourse et al. (1990) named PRL (PBX1; 176310) for 'pre-B cell leukemia.' By PCR of 3 t(1;19)-carrying cell lines, the authors detected identical E2A-PRL mRNA junctions, indicating that the fusion transcripts and predicted chimeric protein are a consistent feature of this translocation.
Kamps et al. (1990) found that a cell line with a t(1;19)(q23;p13.3) translocation contains 2 novel chimeric mRNAs, both with the same 5-prime E2A sequences but with different lengths of 3-prime sequence from a gene located on chromosome 1, which they called PRL (PBX1). The chimeric RNAs encode proteins that lack 171 amino acids of E2A, including its DNA-binding and dimerization motifs, but have instead a homeobox-related sequence from PRL. Kamps et al. (1990) suggested that the production of a chimeric E2A-PRL protein may contribute to the acute lymphoblastic phenotype by directly altering the expression of genes normally responsive to the PRL homeoprotein.
Wiemels et al. (2002) sequenced the genomic fusion between the E2A and PBX1 genes in 22 pre-B acute lymphoblastic leukemias and 2 cell lines. The prenatal origin of the leukemia was assessed in 15 pediatric patients by screening for the clonotypic E2A-PBX1 translocation in neonatal blood spots, or Guthrie cards, obtained from the children at birth. Two patients were weakly positive for the fusion at birth, in contrast to previously studied childhood leukemia fusions, t(12;21), t(8;21), and t(4;11), which are predominantly prenatal. The presence of extensive N-nucleotides at the point of fusion in the E2A-PBX1 translocation as well as specific characteristics of the IGH (147100)/TCR (see 186880) rearrangements provided additional evidence for a postnatal, pre-B cell origin. Sixteen of 24 breakpoints on the 3.2-kb E2A intron 14 were located within 5 bp, providing evidence for a site-specific recombination mechanism. Breakpoints on the 232-kb PBX1 intron 1 were more dispersed, but were highly clustered proximal to exon 2. Thus, the translocation breakpoints displayed evidence of unique temporal, ontologic, and mechanistic formation in contrast to the previously analyzed pediatric leukemia translocation breakpoints, emphasizing the need to differentiate cytogenetic and molecular subgroups for studies of leukemia causality.
E2A/HLF Fusion Gene
Inaba et al. (1992) showed that a t(17;19) chromosomal translocation in early B-lineage acute leukemia resulted in chimeric transcripts that contained sequences from the E2A basic helix-loop-helix (bHLH) transcription factor gene on chromosome 19, fused to sequences from a gene on chromosome 17 that encodes a hepatic leukemia factor (HLF; 142385). The chimeric protein consisted of the amino-terminal transactivation domain of E2A linked to the carboxyl-terminal basic region-leucine zipper domain of HLF.
Kurosawa et al. (1999) found that E2A/HLF upregulated expression of SRPUL (SRPX2; 300642) and annexin-8 (ANXA8; 602396) in pro-B cells. Transfection of a human myeloid leukemia cell line with E2A/HLF induced expression of ANXA8, but not SRPUL. E2A/HLF protected mouse pro-B cells from apoptosis caused by IL3 (147740) deprivation, but neither ANXA8 or SRPUL could block apoptosis, suggesting that they are not involved in malignant transformation.
Using representational difference analysis, Dang et al. (2001) found that the E2A/HLF fusion protein upregulated expression of several groucho-related genes (GRGs), including Grg2 and Grg6 (TLE6; 612399), following expression in a mouse pro-B cell line. A mutant E2A/HLF protein lacking DNA-binding activity also stimulated expression of GRGs. Among the transcription factors that interact with GRG proteins, only Runx1 (151385) was appreciably downregulated by E2A/HLF.
E2A/TFPT Fusion Gene
Brambillasca et al. (1999) identified 4 cases of acute lymphoblastic leukemia displaying E2A/FB1 (TFPT; 609519) chimeric transcripts that appeared to originate from a cryptic rearrangement of chromosome 19. The 5-prime portion of E2A was interrupted at different positions within exons 13 or 14 and fused to FB1. The fusion was in-frame in 1 case, and the remaining cases showed out-of-frame fusions leading to stop codons in FB1 or to truncation of the predicted chimeric product. Brambillasca et al. (1999) found no evidence of reciprocal chimeric transcripts.
Heterodimers between tissue-specific basic helix-loop-helix (bHLH) proteins and the products of the E2A gene play major roles in determining tissue-specific cell fate. The E2A gene gives rise to 2 proteins, E12 and E47, by differential splicing of E12- and E47-specific bHLH-encoding exons. Although they were initially identified in B cells as immunoglobulin enhancer-binding proteins, they were subsequently found to be present in most cell types. To understand the broad role of E2A in development, Zhuang et al. (1994) generated E2A mutant mice following homologous recombination in embryonic stem cells. Homozygous mutant mice developed to full term without apparent abnormalities, but then displayed a high rate of postnatal death. The surviving mice showed retarded postnatal growth. Detailed examination of hematopoiesis revealed that the homozygous mutant mice contained no B cells, whereas other lineages, including the T cell, granulocyte, macrophage, and erythroid lineages, were intact. The block to B-cell differentiation occurred before the immunoglobulin gene D(H)-J(H) rearrangement. Surprisingly, heterozygous embryos contained, on average, about half as many B cells as did wildtype embryos, suggesting the existence of a counting mechanism that translates levels of E2A into numbers of B cells.
Sun (1994) generated transgenic mice in which the Id1 gene (600349) was constitutively overexpressed in the B-cell lineage. The product of this gene is an inhibitor of the DNA-binding activity of bHLH proteins such as the E2A gene product. The phenotype of these transgenic mice depicted severe defects in early B-cell development, suggesting that the bHLH proteins play pivotal roles in B-cell development and that the downregulation of Id1 gene expression is necessary for B cells to differentiate.
Bain et al. (1994) likewise generated E2A-null mice by gene targeting and found that they failed to generate mature B cells. The arrest of B-cell development occurred at an early stage since no immunoglobulin DJ rearrangements could be detected. The finding suggested a crucial role for E2A products in the regulation of early B-cell differentiation.
To investigate the biologic role of the E2A-HLF fusion gene, Honda et al. (1999) generated transgenic mice expressing E2A-HLF in the lymphoid lineage. The transgenic mice exhibited abnormal development in the thymus and spleen and were susceptible to infection. The thymus contained small numbers of thymocytes and showed a high population of thymocytes undergoing apoptosis. The spleen exhibited a marked reduction in lymphocytes, and studies showed that B-cell maturation was blocked at a very early developmental stage. Several transgenic mice developed acute leukemia, classified as T-ALL. Smith et al. (1999) likewise studied the function of the fusion gene in transgenic mice. Approximately 60% of E2A-HLF mice developed lymphoid malignancies with a mean latency of 10 months. Tumors were monoclonal, consistent with the requirement for secondary genetic events. Smith et al. (1999) concluded that the fusion gene disrupts the differentiation of T-lymphoid precursors in vivo, leading to profound postnatal thymic depletion and rendering B- and T-cell progenitors susceptible to malignant transformation.
The TCF3 gene, also known as E2A, should not be confused with the the TCF7L1 gene (604652), which was initially designated TCF3. TCF3 encodes the bHLH transcription factors E12 and E47, whereas TCF7L1 encodes a TCF/LEF transcription factor involved in Wnt (see 164820) signaling.
The article by Kim et al. (2009) on DNA demethylation in hormone-induced transcriptional derepression was retracted.
The article by Kim et al. (2007) regarding the regulation of the transcription of CYP27B1 (609506) by the vitamin D receptor-interacting repressor (VDIR) was retracted.
In 4 unrelated patients with autosomal dominant agammaglobulinemia-8A (AGM8A; 616941), Boisson et al. (2013) identified a de novo heterozygous c.1663G-A transition in exon 18b, which is specific to the E47 isoform of the TCF3 gene, resulting in a glu555-to-lys (E555K) substitution at a highly conserved residue in the DNA-binding domain. The mutation, which was found in the first patient by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 132), Exome Variant Server, or 1000 Genomes Project databases, or in 450 individuals from an in-house database or 1,052 controls from the CEPH panel. In vitro functional expression studies and studies of patient cells showed that the mutant E47 protein localized properly to the nucleus, but did not perform proper DNA binding and acted in a dominant-negative manner when coexpressed with wildtype. The patients presented with early-onset recurrent infections. Laboratory studies showed decreased numbers of B cells; the remaining B cells showed intense CD19 expression and absence of the B-cell receptor. The findings suggested that E47 plays a critical role in enforcing the block in the development of B-cell precursors that lack functional antigen receptors. The patients had previously been reported by Dobbs et al. (2011).
In 2 sibs, born of consanguineous Tunisian parents, with autosomal recessive agammaglobulinemia-8B (AGM8B; 619824), Ben-Ali et al. (2017) identified a homozygous c.808C-T transition in exon 9 of the TCF3 gene, resulting in a gln270-to-ter (Q270X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in public databases. Patient cells showed degradation of mutant transcripts, suggesting nonsense-mediated mRNA decay, and Western blot analysis showed absence of the TCF3 (E2A) protein, consistent with a loss of function. If a truncated protein was produced, it would lack the bHLH domain and thus disrupt the interaction with target genes, leading to aberrant maturation of lymphoid lineages and expansion of undifferentiated progenitor cell populations. In addition to agammaglobulinemia, the proband (P1) developed B-cell acute lymphocytic leukemia (B-ALL), resulting in death at age 10 years. Detailed immunologic workup of the sib (P2) showed a decrease in peripheral blood B cells (3%), decreased immunoglobulins, and an increase in effector memory CD8+ T cells with nearly absent terminally differentiated effector T cells (TEMRA). P2 also had an impaired antibody response to tetanus vaccination.
In a 9-year-old girl, born of consanguineous Pakistani parents, with autosomal recessive agammaglobulinemia-8B (AGM8B; 619824), Qureshi et al. (2019) identified a homozygous deletion spanning exons 5 through 11 of the TCF3 gene. The deletion was found by targeted next-generation sequencing; segregation within the family was not reported. The deletion was predicted to be out of frame and result in a loss of function. Functional studies of the variant were not performed.
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