Alt. symbols: E2A | ITF1 | MGC129647 | MGC129648 | bHLHb21 | VDIR | E47 | p75

Approved name: transcription factor 3
Alt. names: transcription factor E2-alpha, immunoglobulin transcription factor 1, kappa-E2-binding factor, E2A immunoglobulin enhancer-binding factor E12/E47, VDR interacting repressor

Location: 19p13.3: 1609291 - 1652615 (-)
Gene type: protein_coding, 21 transcripts.

Scores: LoFtool: 0.497000 | pLI: 0.18564714 | LOEUF: 0.498

HGNC: 11633

NCBI: 6929, RefSeq: NG_029953.2

Ensembl: ENSG00000071564.19

LRG_1325 | Status: public

OMIM: 147141

Expression | ProteinAtlas

TCF3 encodes 2 broadly expressed transcription factors: E12 and E47, which are identical except for their bHLH domain. Both E12 and E47 bind the consensus DNA sequence 5’-CANNTG-3’ as a homodimer or heterodimer with other basic helix-loop-helix (bHLH) proteins. TCF3 acts a transcriptional regulator, involved in the initiation of neuronal differentiation and in B cell development. Heterodimers between TCF3 and bHLH proteins play major roles in determining tissue-specific cell fate during embryogenesis, like muscle or early B-cell differentiation. TCF3 binds to the kappa-E2 site in the kappa immunoglobulin gene enhancer, and to IEB1 and IEB2, which are short DNA sequences in the insulin gene transcription control region.

Mutations in TCF3 have been associated with a condition called Agammaglobulinemia 8 (AGM8) [MIM:616941], with both autosomal dominant and autosomal recessive patterns of inheritance described. In 4 unrelated patients with AGM8, has been identified a de novo heterozygous missense mutation (E555K; 147141.0001) specific to the E47 isoform of the TCF3 gene (PMID: 24216514). In vitro functional expression studies and studies of patient cells showed that the mutant E47 protein localized properly to th e 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 (PMID: 21693761). 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. However, biallelic loss of function mutations in TCF3 have been subsequently reported in a 9-year-old from Pakistan with autosomal recessive agammaglobulinemia (deletion of exons 5 to 11) (Qureshi, Sheikh and Qamar, 2019), and in 2 siblings of a Tunisian family (p.Q270X) with autosomal recessive agammaglobulinemia (Ben-Ali et al., 2017). [Load More]