title: TCF4 (e2-2; ITF2): a schizophrenia-associated gene with pleiotropic effects on human disease.
abstract: 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 Ca(2+) 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.
authors.affiliation: Social, Genetic and Developmental Psychiatry Centre, King's College London, Institute of Psychiatry, London, UK.
authors.forename: Katherinne
authors.initials: K
authors.lastname: Navarrete
authors.forename: Inti
authors.initials: I
authors.lastname: Pedroso
authors.forename: Simone
authors.initials: S
authors.lastname: De Jong
authors.forename: Hreinn
authors.initials: H
authors.lastname: Stefansson
authors.forename: Stacy
authors.initials: S
authors.lastname: Steinberg
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.forename: Roel A
authors.initials: RA
authors.lastname: Ophoff
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Schalkwyk
authors.forename: David A
authors.initials: DA
authors.lastname: Collier
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D056726:Genetic Association Studies; D058685:Genetic Pleiotropy; D020022:Genetic Predisposition to Disease; D006801:Humans; D060066:Protein Interaction Maps / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors