TCF4, schizophrenia, and Pitt-Hopkins Syndrome

Abstract

Genome-wide association studies allied with the identification of rare copy number variants have provided important insights into the genetic risk factors for schizophrenia. Recently, a meta-analysis of several genome-wide association studies found, in addition to several other markers, a single nucleotide polymorphism in intron 4 of the TCF4 gene that was associated with schizophrenia. TCF4 encodes a basic helix-loop-helix transcription factor that interacts with other transcription factors to activate or repress gene expression. TCF4 mutations also cause Pitt-Hopkins Syndrome, an autosomal-dominant neurodevelopmental disorder associated with severe mental retardation. Variants in the TCF4 gene may therefore be associated with a range of neuropsychiatric phenotypes, including schizophrenia. Recessive forms of Pitt-Hopkins syndrome are caused by mutations in NRXN1 and CNTNAP2. Interestingly, NRXN1 deletions have been reported in schizophrenia, whereas CNTNAP2 variants are associated with several neuropsychiatric phenotypes. These data suggest that TCF4, NRXN1, and CNTNAP2 may participate in a biological pathway that is altered in patients with schizophrenia and other neuropsychiatric disorders.

Fig. 1.

The TCF4 Interactome. Although capable of homodimerization, TCF4 appears to activate or repress gene expression by forming heterodimers with other transcription factors, most notably members of the basic helix-loop-helix (bHLH) superfamily. From a functional perspective, it is necessary to consider the protein-protein interactions that constitute the TCF4 interactome alongside TCF4 itself. The BioGRID database (http://www.thebiogrid.org) was search for genes interacting with human and murine TCF4. Importantly, the list of interactors was manually curated to remove genes that interact with TCF7L2. Functional clusters with group A and group D bHLH proteins are indicated. T-cell/B-cell bHLH transcription factors have been identified with an asterisk. Gene names: AR, androgen receptor; ASCL1, achaete-scute complex homolog 1, also known as HASH1 or MASH1; ATOH1, atonal homolog 1, also known as MATH1; CDC73, cell division cycle 73; ID1–4, inhibitor of DNA binding 1–4; JUN, jun oncogene; LYL1, lymphoblastic leukemia derived sequence 1; MSC, musculin; MYOD1, myogenic differentiation 1; NEUROD1, neurogenic differentiation 1; PARP, poly (ADP-ribose) polymerase 1; RUNX1T1, runt-related transcription factor 1; TAL1, T-cell acute lymphocytic leukemia 1; TAL2, T-cell acute lymphocytic leukemia 2; XRCC5, X-ray repair complementing defective repair in Chinese hamster cells 5; XRCC6, X-ray repair complementing defective repair in Chinese hamster cells 6.