Pitt-Hopkins Syndrome: intellectual disability due to loss of TCF4-regulated gene transcription

Abstract

TCF4 (transcription factor 4; E2-2, ITF2) is a transcription factor that when haplo-insufficient causes Pitt-Hopkins Syndrome (PTHS), an autism-spectrum disorder that is associated with pervasive developmental delay and severe intellectual disability. The TCF4 gene is also a risk factor with highly significant linkage to schizophrenia, presumably via overexpression of the TCF4 gene product in the central nervous system. This review will present an overview of the clinical manifestations of PTHS and relate those clinical attributes to the underlying molecular genetics of TCF4. In order to provide a molecular biological context for the loss of function of TCF4 in PTHS, the review will also present a brief overview of the basic biochemistry of TCF4-mediated regulation of cellular and neuronal gene expression. In the final section of this review, I will discuss and speculate upon possible roles for the TCF4 transcription factor in neuronal function and comment upon how understanding these roles may give new insights into the molecular neurobiology of human cognition.

Figure 1

Proposed TCF4-related signaling pathways in the nervous system. Major known mechanisms of TCF4 functional regulation include: alternative splicing, dimerization partners and calcium/calmodulin-dependent inhibition. Functional targets are virtually unknown, but possibilities include neurexin 1 (NRXN1) and contactin-associated protein-like 2 (CNTNAP2). Please note that this speculative figure is agnostic on whether the proposed signaling pathways reside in glia, neurons or both.