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TCF4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2KWF
Identifiers
Aliases	TCF4, E2-2, ITF-2, ITF2, PTHS, SEF-2, SEF2, SEF2-1, SEF2-1A, SEF2-1B, SEF2-1D, TCF-4, bHLHb19, FECD3, transcription factor 4, CDG2T
External IDs	OMIM: 602272; MGI: 98506; HomoloGene: 2407; GeneCards: TCF4; OMA:TCF4 - orthologs
Gene location (Human) Chr. Chromosome 18 (human) Band 18q21.2 Start 55,222,185 bp End 55,664,787 bp
Gene location (Mouse) Chr. Chromosome 18 (mouse) Band 18|18 E2 Start 69,343,356 bp End 69,689,079 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in endothelial cell skin of hip pericardium entorhinal cortex Parietal Lobe Achilles tendon postcentral gyrus Brodmann area 23 synovial joint ganglionic eminence Top expressed in Rostral migratory stream ganglionic eminence medial ganglionic eminence subiculum ventricular zone barrel cortex lobe of cerebellum dermis internal carotid artery hippocampus proper More reference expression data BioGPS n/a
Gene ontology Molecular function protein dimerization activity protein homodimerization activity DNA-binding transcription factor activity DNA-binding transcription activator activity, RNA polymerase II-specific bHLH transcription factor binding E-box binding protein C-terminus binding protein binding identical protein binding TFIIB-class transcription factor binding protein heterodimerization activity DNA binding RNA polymerase II cis-regulatory region sequence-specific DNA binding DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component transcription regulator complex nucleus beta-catenin-TCF complex beta-catenin-TCF7L2 complex Biological process cell differentiation regulation of transcription, DNA-templated protein-DNA complex assembly transcription, DNA-templated nervous system development positive regulation of transcription, DNA-templated DNA-templated transcription, initiation transcription initiation from RNA polymerase II promoter positive regulation of transcription by RNA polymerase II positive regulation of neuron differentiation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 6925 21413 Ensembl ENSG00000196628 ENSMUSG00000053477 UniProt P15884 Q60722 RefSeq (mRNA) NM_001083962 NM_001243226 NM_001243227 NM_001243228 NM_001243230 NM_001243231 NM_001243232 NM_001243233 NM_001243234 NM_001243235 NM_001243236 NM_001306207 NM_001306208 NM_003199 NM_001330604 NM_001330605 NM_001348211 NM_001348212 NM_001348213 NM_001348214 NM_001348215 NM_001348216 NM_001348217 NM_001348218 NM_001348219 NM_001348220 NM_001369572 NM_001369573 NM_001369574 NM_001369575 NM_001369576 NM_001369577 NM_001369578 NM_001369579 NM_001369580 NM_001369581 NM_001369582 NM_001369583 NM_001369584 NM_001369585 NM_001369586 NM_001369567 NM_001369568 NM_001369569 NM_001369570 NM_001369571 NM_001083967 NM_013685 NM_001361126 NM_001361127 NM_001361128 NM_001361129 RefSeq (protein) NP_001077431 NP_001230155 NP_001230156 NP_001230157 NP_001230159 NP_001230160 NP_001230161 NP_001230162 NP_001230163 NP_001230164 NP_001230165 NP_001293136 NP_001293137 NP_001317533 NP_001317534 NP_003190 NP_001335140 NP_001335141 NP_001335142 NP_001335143 NP_001335144 NP_001335145 NP_001335146 NP_001335147 NP_001335148 NP_001335149 NP_001356501 NP_001356502 NP_001356503 NP_001356504 NP_001356505 NP_001356506 NP_001356507 NP_001356508 NP_001356509 NP_001356510 NP_001356511 NP_001356512 NP_001356513 NP_001356514 NP_001356515 NP_001356496 NP_001356497 NP_001356498 NP_001356499 NP_001356500 NP_001077436 NP_038713 NP_001348055 NP_001348056 NP_001348057 NP_001348058 Location (UCSC) Chr 18: 55.22 – 55.66 Mb Chr 18: 69.34 – 69.69 Mb PubMed search
Wikidata
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Transcription factor 4 (TCF-4) also known as immunoglobulin transcription factor 2 (ITF-2) is a protein that in humans is encoded by the TCF4 gene located on chromosome 18q21.2.

Function

TCF4 proteins act as transcription factors which will bind to the immunoglobulin enhancer mu-E5/kappa-E2 motif. TCF4 activates transcription by binding to the E-box (5’-CANNTG-3’) found usually on SSTR2-INR, or somatostatin receptor 2 initiator element. TCF4 is primarily involved in neurological development of the fetus during pregnancy by initiating neural differentiation by binding to DNA. It is found in the central nervous system, somites, and gonadal ridge during early development. Later in development it will be found in the thyroid, thymus, and kidneys while in adulthood TCF4 it is found in lymphocytes, muscles, mature neurons, and gastrointestinal system.

Clinical significance

Mutations in TCF4 cause Pitt-Hopkins Syndrome (PTHS). These mutations cause TCF4 proteins to not bind to DNA properly and control the differentiation of the nervous system. It has been suggested that TCF4 loss-of-function leads to decreased Wnt signaling and, consequently, a reduced neural progenitor proliferation. In most cases that have been studied, the mutations were de novo, meaning it was a new mutation not found in other family members of the patient. Common symptoms of Pitt-Hopkins Syndrome include a wide mouth, gastrointestinal problems, developmental delay of fine motor skills, speech and breathing problems, epilepsy, and other brain defects.

References

1. ^ GRCh38: Ensembl release 89: ENSG00000196628 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000053477 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Henthorn P, McCarrick-Walmsley R, Kadesch T (February 1990). "Sequence of the cDNA encoding ITF-2, a positive-acting transcription factor". Nucleic Acids Research. 18 (3): 678. doi:10.1093/nar/18.3.678. PMC 333500. PMID 2308860.
6. de Pontual L, Mathieu Y, Golzio C, Rio M, Malan V, Boddaert N, et al. (April 2009). "Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome". Human Mutation. 30 (4): 669–676. doi:10.1002/humu.20935. PMID 19235238. S2CID 25375730.
7. Pscherer A, Dörflinger U, Kirfel J, Gawlas K, Rüschoff J, Buettner R, Schüle R (December 1996). "The helix-loop-helix transcription factor SEF-2 regulates the activity of a novel initiator element in the promoter of the human somatostatin receptor II gene". The EMBO Journal. 15 (23): 6680–6690. doi:10.1002/j.1460-2075.1996.tb01058.x. PMC 452492. PMID 8978694.
8. D'Rozario M, Zhang T, Waddell EA, Zhang Y, Sahin C, Sharoni M, et al. (April 2016). "Type I bHLH Proteins Daughterless and Tcf4 Restrict Neurite Branching and Synapse Formation by Repressing Neurexin in Postmitotic Neurons". Cell Reports. 15 (2): 386–397. doi:10.1016/j.celrep.2016.03.034. PMC 4946342. PMID 27050508.
9. Papes F, Camargo AP, de Souza JS, Carvalho VM, Szeto RA, LaMontagne E, et al. (May 2022). "Transcription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content". Nature Communications. 13 (1): 2387. Bibcode:2022NatCo..13.2387P. doi:10.1038/s41467-022-29942-w. PMC 9061776. PMID 35501322.
10. Amiel J, Rio M, de Pontual L, Redon R, Malan V, Boddaert N, et al. (May 2007). "Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction". American Journal of Human Genetics. 80 (5): 988–993. doi:10.1086/515582. PMC 1852736. PMID 17436254.
11. Zweier C, Peippo MM, Hoyer J, Sousa S, Bottani A, Clayton-Smith J, et al. (May 2007). "Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome)". American Journal of Human Genetics. 80 (5): 994–1001. doi:10.1086/515583. PMC 1852727. PMID 17436255.

Further reading

• Herbst A, Helferich S, Behrens A, Göke B, Kolligs FT (October 2009). "The transcription factor ITF-2A induces cell cycle arrest via p21(Cip1)". Biochemical and Biophysical Research Communications. 387 (4): 736–740. doi:10.1016/j.bbrc.2009.07.102. PMID 19635457.
• Cisse B, Caton ML, Lehner M, Maeda T, Scheu S, Locksley R, et al. (October 2008). "Transcription factor E2-2 is an essential and specific regulator of plasmacytoid dendritic cell development". Cell. 135 (1): 37–48. doi:10.1016/j.cell.2008.09.016. PMC 2631034. PMID 18854153.
• Bain G, Murre C (April 1998). "The role of E-proteins in B- and T-lymphocyte development". Seminars in Immunology. 10 (2): 143–153. doi:10.1006/smim.1998.0116. PMID 9618760.
• Yerges LM, Klei L, Cauley JA, Roeder K, Kammerer CM, Moffett SP, et al. (December 2009). "High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men". Journal of Bone and Mineral Research. 24 (12): 2039–2049. doi:10.1359/jbmr.090524. PMC 2791518. PMID 19453261.
• Purcell SM, Wray NR, Stone JL, Visscher PM, O'Donovan MC, Sullivan PF, Sklar P (August 2009). "Common polygenic variation contributes to risk of schizophrenia and bipolar disorder". Nature. 460 (7256): 748–752. Bibcode:2009Natur.460..748P. doi:10.1038/nature08185. PMC 3912837. PMID 19571811.
• Kalscheuer VM, Feenstra I, Van Ravenswaaij-Arts CM, Smeets DF, Menzel C, Ullmann R, et al. (August 2008). "Disruption of the TCF4 gene in a girl with mental retardation but without the classical Pitt-Hopkins syndrome". American Journal of Medical Genetics. Part A. 146A (16): 2053–2059. doi:10.1002/ajmg.a.32419. PMID 18627065. S2CID 205309738.
• Herbst A, Bommer GT, Kriegl L, Jung A, Behrens A, Csanadi E, et al. (August 2009). "ITF-2 is disrupted via allelic loss of chromosome 18q21, and ITF-2B expression is lost at the adenoma-carcinoma transition". Gastroenterology. 137 (2): 639–48, 648.e1-9. doi:10.1053/j.gastro.2009.04.049. PMID 19394332.
• Nagasawa M, Schmidlin H, Hazekamp MG, Schotte R, Blom B (September 2008). "Development of human plasmacytoid dendritic cells depends on the combined action of the basic helix-loop-helix factor E2-2 and the Ets factor Spi-B". European Journal of Immunology. 38 (9): 2389–2400. doi:10.1002/eji.200838470. PMID 18792017. S2CID 205784742.
• Rosenfeld JA, Leppig K, Ballif BC, Thiese H, Erdie-Lalena C, Bawle E, et al. (November 2009). "Genotype-phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations". Genetics in Medicine. 11 (11): 797–805. doi:10.1097/GIM.0b013e3181bd38a9. PMID 19938247.
• Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D, et al. (August 2009). "Common variants conferring risk of schizophrenia". Nature. 460 (7256): 744–747. Bibcode:2009Natur.460..744S. doi:10.1038/nature08186. PMC 3077530. PMID 19571808.

External links

• TCF4+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• FactorBook TCF4

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