Transcription factor 4 and its association with psychiatric disorders

Abstract

The human transcription factor 4 gene (TCF4) encodes a helix-loop-helix transcription factor widely expressed throughout the body and during neural development. Mutations in TCF4 cause a devastating autism spectrum disorder known as Pitt-Hopkins syndrome, characterized by a range of aberrant phenotypes including severe intellectual disability, absence of speech, delayed cognitive and motor development, and dysmorphic features. Moreover, polymorphisms in TCF4 have been associated with schizophrenia and other psychiatric and neurological conditions. Details about how TCF4 genetic variants are linked to these diseases and the role of TCF4 during neural development are only now beginning to emerge. Here, we provide a comprehensive review of the functions of TCF4 and its protein products at both the cellular and organismic levels, as well as a description of pathophysiological mechanisms associated with this gene.

Fig. 1. Schematic representation of the TCF4 genomic locus.

The genomic locus is located on chromosome 18 (top line; exon sizes and distances between exons shown to scale), coding exons (middle lines; exon sizes, but not distances, shown to scale), and TCF4 protein domain structure (bottom line; domain sizes not to scale). The last exon on the right, displayed in gray, is non-coding. Only transcript variants coding for isoforms TCF4-B and TCF4-A are shown, which are transcribed from alternative promoters starting at exons 3 and 10, respectively. AD activation domain, NLS nuclear localization signal, NES nuclear export signal, bHLH basic helix–loop–helix DNA-binding domain, CE conserved element, Rep repression domain. In the bottom line, the protein motifs inside the bHLH domain are shown in detail in the enlarged inset. Based on refs. ^,.