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

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. In a review article, a neuroscientist in the USA has outlined strategies for developing targeted therapeutics for Pitt–Hopkins syndrome. A single gene mutation is responsible for this syndrome, which was first described by two physicians in 1978. Three decades later, researchers found that children with the genetic condition—an autism spectrum disorder characterized by developmental delay and severe intellectual disability—had mutations in the gene TCF4, which encodes a transcription factor involved in many aspects of development. The neuroscientist, David Sweatt at the University of Alabama at Birmingham, discusses the molecular and biochemical mechanisms by which the loss of TCF4 is responsible for the clinical manifestations of Pitt–Hopkins syndrome. He hypothesizes that the TCF4 transcription factor is needed for proper neuronal function in both brain development and ongoing cognitive processing.