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, and gastrointestinal system.
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. 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.
^de Pontual L, Mathieu Y, Golzio C, Rio M, Malan V, Boddaert N, et al. (Apr 2009). "Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome". Human Mutation. 30 (4): 669–76. doi:10.1002/humu.20935. PMID19235238.
^Pscherer A, Dörflinger U, Kirfel J, Gawlas K, Rüschoff J, Buettner R, Schüle R (Dec 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): 6680–90. PMID8978694.
^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): 988–93. doi:10.1086/515582. PMID17436254.
Herbst A, Helferich S, Behrens A, Göke B, Kolligs FT (Oct 2009). "The transcription factor ITF-2A induces cell cycle arrest via p21(Cip1)". Biochemical and Biophysical Research Communications. 387 (4): 736–40. doi:10.1016/j.bbrc.2009.07.102. PMID19635457.
Purcell SM, Wray NR, Stone JL, Visscher PM, O'Donovan MC, Sullivan PF, Sklar P (Aug 2009). "Common polygenic variation contributes to risk of schizophrenia and bipolar disorder". Nature. 460 (7256): 748–52. doi:10.1038/nature08185. PMID19571811.
Kalscheuer VM, Feenstra I, Van Ravenswaaij-Arts CM, Smeets DF, Menzel C, Ullmann R, Musante L, Ropers HH (Aug 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): 2053–9. doi:10.1002/ajmg.a.32419. PMID18627065.
Herbst A, Bommer GT, Kriegl L, Jung A, Behrens A, Csanadi E, et al. (Aug 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. PMID19394332.
Nagasawa M, Schmidlin H, Hazekamp MG, Schotte R, Blom B (Sep 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): 2389–400. doi:10.1002/eji.200838470. PMID18792017.
Rosenfeld JA, Leppig K, Ballif BC, Thiese H, Erdie-Lalena C, Bawle E, Sastry S, Spence JE, Bandholz A, Surti U, Zonana J, Keller K, Meschino W, Bejjani BA, Torchia BS, Shaffer LG (Nov 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. PMID19938247.