3.1 What TCF4 does
3.1 What TCF4 does
TCF4, like other similar transcription factors, is used in many different processes and places in the body.9 We know that TCF4 is involved the development of B- and T-cells (two important cell-types which help defend your body against sicknesses),10,11 in epithelial mesenchymal transition (the process through which cells from skinlike parts of your body can get loose and travel through your body to make new parts grow before you are born, or to make wounds heal) 12 and in neurodevelopment (the development of your nerves and brain).13 It has a specific part (called the bHLH domain) which can stick to DNA and which can form combinations with another identical TCF4 protein (homodimer) and with other proteins (heterodimer).9,10,11 ASCL1 is another transcription factor involved in the development of a specific part of the nerves (noradrenergic neuronal development). Changes in TCF4 that cause Pitt Hopkins syndrome have been shown to make interaction with ASCL1 hard or impossible. The interaction problems between TCF4 and ASCL1 may explain at least some of the Pitt Hopkins symptoms, such as breathing too fast (hyperbreathing)14,15 (Figure 2A).
FIGURE 2 Functions of TCF4.
(A)
Within the basic region of its bHLH domain, TCF4 binds to E-box motifs in promoter regions of transcriptional target genes. It forms homodimer and heterodimer, for example, with other bHLH domain proteins such as ASCL1 which is involved in regulation of the noradrenergic system via the ASCL1-PHOX2B-RET pathway. Mutations in this pathway are associated with breathing phenotypes and Hirschsprung disease.
(B)
The long arm of chromosome 18 (UCSC genome browser) with location of TCF4 in 18q21.2. Deletions within the region represented by the dark blue bar are associated with a typical PTHS phenotype. Larger deletions including TCF4 and expanding into the regions represented by the middle blue bars are associated with a less typical phenotype but with severe ID and other clinical aspects of PTHS.
(C)
Schematic drawing of TCF4 with non-coding (light gray), coding (dark gray), and bHLH domain encoding (black) exons. Above the scheme, different aberrations associated with a PTHS or PTHS-like phenotype are depicted, below the scheme are aberrations associated with mild intellectual disability. Sequence variants or deletions affecting exons represented by the dark blue bar cause typical PTHS, those in exons represented by the middle blue bar are associated with a more variable PTHS-like phenotype with severe intellectual disability, and variants located in regions represented by the light blue bar are associated with mild and/or non-specific intellectual disability. *, truncating variants; orange circles, missense variants; #, frameshifting variants with protein elongation; magenta circle: in-frame inclusion of an amino acid; black circles with lines: translocations; red lines, deletions; blue line, duplication
