TCF4 Gene: Transcription Factor 4 in Pitt-Hopkins Syndrome and Neurodevelopment
Comprehensive biomedical reference for TCF4 (E2-2, ITF2) – gene function, expression, mutations, and associated disorders
Gene Information Card
| Symbol | TCF4 |
|---|---|
| Full Name | Transcription Factor 4 |
| Gene Type | Protein coding |
| Chromosomal Location | 18q21.2 |
| NCBI Gene ID | 6925 ncbi.nlm.nih.gov/gene/6925 |
| Ensembl ID | ENSG00000196628 |
| UniProt ID | P15884 |
| OMIM ID | 602272 |
| HGNC ID | 11634 |
| Aliases | E2-2, ITF2, SEF2, TCF-4, bHLHb19, PTHS |
Description
TCF4 encodes a basic helix-loop-helix (bHLH) transcription factor that binds to E-box sequences and regulates gene expression critical for neurodevelopment, cell proliferation, and differentiation. Mutations in TCF4 cause Pitt-Hopkins syndrome (PTHS), and common variants are associated with schizophrenia. The protein forms homodimers or heterodimers with other bHLH factors and is widely expressed in the brain and other tissues.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Pitt-Hopkins syndrome (PTHS) | Haploinsufficiency due to heterozygous loss-of-function mutations or deletions leads to impaired transcriptional regulation of target genes during neurodevelopment. | OMIM #610954; ClinVar pathogenic variants; multiple case reports. |
| Schizophrenia | Common intronic variants (e.g., rs9960767) are associated with increased risk; altered TCF4 expression may disrupt neuronal connectivity. | GWAS (Schizophrenia Working Group, Nature 2014); replicated in multiple cohorts. |
| Intellectual disability | De novo missense and truncating mutations cause non-syndromic intellectual disability with or without PTHS features. | ClinVar; literature reports (e.g., de Pontual et al., 2009). |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain (cerebral cortex) | 12.5 | Medium |
| Brain (cerebellum) | 10.2 | Medium |
| Lung | 8.1 | Low |
| Testis | 6.7 | Low |
| Spleen | 5.3 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | 15.3 | Neuronal model; high expression |
| HEK293 (embryonic kidney) | 9.8 | Moderate expression |
| HepG2 (hepatocellular carcinoma) | 7.2 | Low expression |
| K562 (leukemia) | 4.1 | Very low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1723C>T (p.Arg575*) | Nonsense | <0.01% | Loss of function; truncation; pathogenic in PTHS |
| c.992G>A (p.Arg331Gln) | Missense | <0.01% | Dominant negative effect; reduced DNA binding; pathogenic |
| c.1145_1146del (p.Thr382Argfs*19) | Frameshift | <0.01% | Loss of function; premature stop; pathogenic |
| rs9960767 (intronic) | SNP | ~10% (allele frequency) | Risk allele for schizophrenia; regulatory effect |
Mutation functional classification
Loss of Function (LOF)
Nonsense, frameshift, and splice-site mutations leading to haploinsufficiency are the primary cause of Pitt-Hopkins syndrome.
Gain of Function (GOF)
Not well documented; most pathogenic variants are loss-of-function or dominant negative.
Dominant Negative (DN)
Missense mutations in the bHLH domain (e.g., p.Arg331Gln) can interfere with dimerization and DNA binding, exerting a dominant negative effect.
View complete mutation data：
Gene Ontology (GO)
Pathways
• REACT: R-HSA-212436 – Generic Transcription Pathway
• REACT: R-HSA-1989781 – Neurotrophin signaling pathway
• REACT: R-HSA-9006934 – Signaling by Receptor Tyrosine Kinases
Protein Summary
TCF4 (E2-2) is a 667-amino-acid bHLH transcription factor that binds E-box sequences (CANNTG) as a dimer. It contains a basic DNA-binding domain and a helix-loop-helix dimerization domain. The protein is widely expressed, with highest levels in the brain, and regulates genes involved in neurogenesis, synaptic function, and cell cycle. Alternative splicing generates multiple isoforms. Nuclear localization is essential for its transcriptional activity.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| TCF4 Knockout HEK293 Cell Line | EDJ-KQ2215 | Human | 6925 | Details Get a Quote |
| TCF4 Knockout A-549 Cell Line | EDJ-KQ22477 | Human | 6925 | Details Get a Quote |
| TCF4 Knockout HeLa Cell Line | EDJ-KQ54623 | Human | 6925 | Details Get a Quote |
| TCF4 Knockout HCT 116 Cell Line | EDJ-KQ71578 | Human | 6925 | Details Get a Quote |
