How to Cite this Article: Navarrete K, Pedroso I, De Jong S, Stefansson H, Steinberg S, Stefansson K, Ophoff RA, Schalkwyk LC, Collier DA. 2012. TCF4 (e2-2; ITF2): A schizophrenia-associated gene with pleiotropic effects on human disease. Am J Med Genet Part B 162B:1–16.
TCF4 (e2-2; ITF2): A schizophrenia-associated gene with pleiotropic effects on human disease†
Article first published online: 5 NOV 2012
Copyright © 2012 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
Volume 162, Issue 1, pages 1–16, January 2013
How to Cite
Navarrete, K., Pedroso, I., De Jong, S., Stefansson, H., Steinberg, S., Stefansson, K., Ophoff, R. A., Schalkwyk, L. C. and Collier, D. A. (2013), TCF4 (e2-2; ITF2): A schizophrenia-associated gene with pleiotropic effects on human disease. Am. J. Med. Genet., 162: 1–16. doi: 10.1002/ajmg.b.32109
- Issue published online: 18 DEC 2012
- Article first published online: 5 NOV 2012
- Manuscript Accepted: 27 SEP 2012
- Manuscript Received: 6 APR 2012
- Pitt-Hopkins syndrome;
- Fuch's corneal dystrophy;
- genome-wide association;
- protein–protein interaction;
- gene network
Common SNPs in the transcription factor 4 (TCF4; ITF2, E2-2, SEF-2) gene, which encodes a basic Helix-Loop-Helix (bHLH) transcription factor, are associated with schizophrenia, conferring a small increase in risk. Other common SNPs in the gene are associated with the common eye disorder Fuch's corneal dystrophy, while rare, mostly de novo inactivating mutations cause Pitt-Hopkins syndrome. In this review, we present a systematic bioinformatics and literature review of the genomics, biological function and interactome of TCF4 in the context of schizophrenia. The TCF4 gene is present in all vertebrates, and although protein length varies, there is high conservation of primary sequence, including the DNA binding domain. Humans have a unique leucine-rich nuclear export signal. There are two main isoforms (A and B), as well as complex splicing generating many possible N-terminal amino acid sequences. TCF4 is highly expressed in the brain, where plays a role in neurodevelopment, interacting with class II bHLH transcription factors Math1, HASH1, and neuroD2. The Ca2+ sensor protein calmodulin interacts with the DNA binding domain of TCF4, inhibiting transcriptional activation. It is also the target of microRNAs, including mir137, which is implicated in schizophrenia. The schizophrenia-associated SNPs are in linkage disequilibrium with common variants within putative DNA regulatory elements, suggesting that regulation of expression may underlie association with schizophrenia. Combined gene co-expression analyses and curated protein–protein interaction data provide a network involving TCF4 and other putative schizophrenia susceptibility genes. These findings suggest new opportunities for understanding the molecular basis of schizophrenia and other mental disorders. © 2012 Wiley Periodicals, Inc.